0	31777202	Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood.	('CYP46A1', 'Gene', (80, 87))	('hallmark of many cancers', 'Disease', (151, 175))	('loss', 'Var', (72, 76))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('glioblastoma', 'Disease', (187, 199))	('Dysregulated cholesterol metabolism', 'Phenotype', 'HP:0003107', (110, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('GBM', 'Phenotype', 'HP:0012174', (201, 204))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('CYP46A1', 'Gene', '10858', (80, 87))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (151, 175))	('glioblastoma', 'Disease', (97, 109))	('cholesterol', 'Chemical', 'MESH:D002784', (36, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('cholesterol', 'Chemical', 'MESH:D002784', (123, 134))	('Dysregulated cholesterol metabolism', 'MPA', (110, 145))	('glioblastoma', 'Disease', 'MESH:D005909', (187, 199))	('human', 'Species', '9606', (91, 96))
4	31777202	RNA-seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling.	('24OHC', 'Chemical', 'MESH:C496310', (50, 55))	('tumour', 'Disease', (67, 73))	('suppressed', 'NegReg', (56, 66))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('regulation', 'MPA', (89, 99))	('24OHC', 'Var', (50, 55))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (67, 73))
5	31777202	Efavirenz, an activator of CYP46A1 that is known to penetrate the blood-brain barrier, inhibited GBM growth in vivo.	('rat', 'Species', '10116', (57, 60))	('inhibited', 'NegReg', (87, 96))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))	('Efavirenz', 'Chemical', 'MESH:C098320', (0, 9))	('CYP46A1', 'Var', (27, 34))	('GBM growth', 'CPA', (97, 107))
7	31777202	Loss of CYP46A1 partially caused excessive cholesterol accumulation in glioblastoma cells contributing to the maintenance of tumour cell viability and a malignant state.	('CYP46A1', 'Gene', (8, 15))	('glioblastoma', 'Disease', (71, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('cholesterol accumulation', 'MPA', (43, 67))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('cholesterol', 'Chemical', 'MESH:D002784', (43, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('excessive cholesterol', 'Phenotype', 'HP:0003124', (33, 54))	('tumour cell viability', 'Disease', (125, 146))	('Loss', 'Var', (0, 4))	('tumour cell viability', 'Disease', 'MESH:D018295', (125, 146))
18	31777202	Recently, it has been shown that 27OHC can inhibit prostate cancer growth through depletion of intracellular cholesterol levels (Alfaqih et al, 2017).	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('depletion of intracellular cholesterol levels', 'MPA', (82, 127))	('cholesterol', 'Chemical', 'MESH:D002784', (109, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('inhibit', 'NegReg', (43, 50))	('27OHC', 'Chemical', 'MESH:C496310', (33, 38))	('prostate cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('27OHC', 'Var', (33, 38))
19	31777202	Yet, others have shown, in breast cancer cells, that 27OHC induces an epithelial-to-mesenchymal transition (EMT) leading to increased tumour growth (Torres et al, 2011; Wu et al, 2013).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('epithelial-to-mesenchymal transition', 'CPA', (70, 106))	('increased', 'PosReg', (124, 133))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('induces', 'Reg', (59, 66))	('breast cancer', 'Disease', (27, 40))	('tumour', 'Disease', (134, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('27OHC', 'Chemical', 'MESH:C496310', (53, 58))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))	('27OHC', 'Var', (53, 58))
22	31777202	First, de novo cholesterol synthesis is suppressed in GBM cells compared with normal human astrocytes leading to exogenous cholesterol uptake through up-regulation of the low-density lipoprotein receptor (LDLR) (Villa et al, 2016).	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('GBM', 'Var', (54, 57))	('cholesterol', 'Chemical', 'MESH:D002784', (15, 26))	('suppressed', 'NegReg', (40, 50))	('cholesterol', 'Chemical', 'MESH:D002784', (123, 134))	('exogenous cholesterol uptake', 'MPA', (113, 141))	('low-density lipoprotein receptor', 'Gene', (171, 203))	('up-regulation', 'PosReg', (150, 163))	('LDLR', 'Gene', (205, 209))	('human', 'Species', '9606', (85, 90))	('low-density lipoprotein receptor', 'Gene', '3949', (171, 203))	('LDLR', 'Gene', '3949', (205, 209))	('de novo cholesterol synthesis', 'MPA', (7, 36))
35	31777202	Our results show that changes in CYP46A1 are critical for the dysregulation of cholesterol homeostasis in GBM and that targeting CYP46A1/24OHC may provide a new opportunity for GBM therapy.	('dysregulation of cholesterol homeostasis', 'Phenotype', 'HP:0003107', (62, 102))	('24OHC', 'Chemical', 'MESH:C496310', (137, 142))	('changes', 'Var', (22, 29))	('CYP46A1', 'Gene', (33, 40))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('GBM', 'Disease', (177, 180))	('cholesterol', 'Chemical', 'MESH:D002784', (79, 90))	('GBM', 'Phenotype', 'HP:0012174', (177, 180))	('dysregulation of cholesterol homeostasis', 'MPA', (62, 102))	('CYP46A1/24OHC', 'Var', (129, 142))
46	31777202	Differential analysis based on the Chinese Glioma Genome Atlas (CGGA) dataset also revealed CYP46A1 as one of the most dysregulated transcripts (log2 fold change = 1.966, adjusted P = 4.63E-09) between GBM (n = 128) and normal brain (n = 5; Fig EV1A-C).	('Glioma', 'Disease', (43, 49))	('GBM', 'Var', (202, 205))	('GBM', 'Phenotype', 'HP:0012174', (202, 205))	('CYP46A1', 'Gene', (92, 99))	('Glioma', 'Disease', 'MESH:D005910', (43, 49))	('Glioma', 'Phenotype', 'HP:0009733', (43, 49))
48	31777202	After ranking by P-value, CYP46A1 emerged among the top 3 genes (APOBR, CELA3A and CYP46A1) associated with GBM prognosis (Fig EV1D).	('APOBR', 'Gene', (65, 70))	('APOBR', 'Gene', '55911', (65, 70))	('GBM', 'Disease', (108, 111))	('CYP46A1', 'Var', (26, 33))	('CELA3A', 'Gene', (72, 78))	('CELA3A', 'Gene', '10136', (72, 78))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('associated', 'Reg', (92, 102))	('CYP46A1', 'Gene', (83, 90))
49	31777202	By analysing the Cancer Genome Atlas (TCGA) pan-cancer data including 31 different cancer types, the expression of CYP46A1 was found to be significantly increased in normal brain compared with GBM and LGG (Appendix Fig S2A).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CYP46A1', 'Var', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('increased', 'PosReg', (153, 162))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('expression', 'MPA', (101, 111))	('GBM', 'Phenotype', 'HP:0012174', (193, 196))	('cancer', 'Disease', (83, 89))
52	31777202	CYP46A1 was highly expressed at the leading edge (which is mainly comprised of normal brain cells) compared with other tumour regions (Appendix Fig S2C).	('CYP46A1', 'Var', (0, 7))	('tumour regions', 'Disease', 'MESH:D009369', (119, 133))	('tumour regions', 'Disease', (119, 133))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))
53	31777202	Single-cell RNA-seq data (Darmanis et al, 2017) further demonstrated that CYP46A1 is mainly expressed in neurons, astrocytes and oligodendrocyte precursor cells (OPCs) and to a lesser extent in tumour cells (Appendix Fig S2D).	('tumour', 'Disease', (194, 200))	('CYP46A1', 'Var', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('rat', 'Species', '10116', (63, 66))	('tumour', 'Disease', 'MESH:D009369', (194, 200))
60	31777202	Here, H3K27ac peaks (marker of active promoters) within the promoter region of CYP46A1 were lower in GBMs compared with normal brain tissue (Appendix Fig S3A).	('CYP46A1', 'Gene', (79, 86))	('GBMs', 'Var', (101, 105))	('S3A', 'Gene', (154, 157))	('S3A', 'Gene', '6189', (154, 157))	('H3K27ac', 'Protein', (6, 13))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('lower', 'NegReg', (92, 97))
61	31777202	We also examined the active enhancer landscape of CYP46A1 across three matched pairs of GSCs and differentiated glioma cells (DGCs).	('glioma', 'Disease', (112, 118))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('CYP46A1', 'Var', (50, 57))
63	31777202	GBM patients with high CYP46A1 mRNA levels (based on the median value) exhibited significantly better overall survival (OS) as well as progression-free survival (PFS) (Fig 1H and I).	('high CYP46A1 mRNA', 'Var', (18, 35))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('patients', 'Species', '9606', (4, 12))	('progression-free survival', 'CPA', (135, 160))	('overall survival', 'CPA', (102, 118))	('better', 'PosReg', (95, 101))
64	31777202	CYP46A1 was also a prognostic indicator in LGG patients (Fig 1H and I).	('CYP46A1', 'Var', (0, 7))	('LGG', 'Disease', (43, 46))	('patients', 'Species', '9606', (47, 55))
65	31777202	CYP46A1 was also validated as an independent prognostic indicator using univariate and multivariate Cox regression analysis of OS (HR = 0.390, 95% CI = 0.262 to 0.581, P < 0.001; Appendix Table S1) in CGGA patients and showed a prognostic trend in multivariate analysis of TCGA patients.	('patients', 'Species', '9606', (278, 286))	('CYP46A1', 'Var', (0, 7))	('CGGA', 'Disease', (201, 205))	('patients', 'Species', '9606', (206, 214))
66	31777202	Lentivirus was used to over-express CYP46A1 in LN229, LN18 and GBM#P3, as validated by qRT-PCR (P < 0.001; Fig 2A) or Western blot (Fig 2B and Appendix Fig S5A).	('CYP46A1', 'Var', (36, 43))	('S5A', 'Gene', (156, 159))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('S5A', 'Gene', '5710', (156, 159))	('LN229', 'CellLine', 'CVCL:0393', (47, 52))	('over-express', 'PosReg', (23, 35))
67	31777202	Furthermore, increased expression of CYP46A1 in GSCs (GBM#P3) inhibited tumorsphere formation, a critical glioma stem-like property (P < 0.05; Appendix Fig S5B and C).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('tumor', 'Disease', (72, 77))	('inhibited', 'NegReg', (62, 71))	('S5B', 'Gene', '5711', (156, 159))	('glioma', 'Disease', (106, 112))	('CYP46A1', 'Var', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('S5B', 'Gene', (156, 159))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
69	31777202	For both cell types, CYP46A1 overexpression inhibited tumour growth, as observed in haematoxylin and eosin (HE) staining (Fig 2E), and prolonged overall survival in mice (P < 0.05; Fig 2F).	('overexpression', 'PosReg', (29, 43))	('mice', 'Species', '10090', (165, 169))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('overall survival', 'CPA', (145, 161))	('inhibited', 'NegReg', (44, 53))	('eosin', 'Chemical', 'MESH:D004801', (101, 106))	('prolonged', 'PosReg', (135, 144))	('CYP46A1', 'Var', (21, 28))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('haematoxylin', 'Chemical', 'MESH:C018328', (84, 96))
70	31777202	Overexpression of CYP46A1 also led to reduced levels of the proliferation marker PCNA but increased expression of the apoptotic marker cleaved caspase-3 (Fig 2G, Appendix Fig S5D and E).	('CYP46A1', 'Var', (18, 25))	('rat', 'Species', '10116', (67, 70))	('caspase-3', 'Gene', '836', (143, 152))	('reduced', 'NegReg', (38, 45))	('increased', 'PosReg', (90, 99))	('levels of the proliferation marker PCNA', 'MPA', (46, 85))	('expression', 'MPA', (100, 110))	('caspase-3', 'Gene', (143, 152))
71	31777202	These data confirm a tumour-suppressive role for CYP46A1 in human GBM.	('GBM', 'Disease', (66, 69))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('tumour', 'Disease', (21, 27))	('CYP46A1', 'Var', (49, 56))	('human', 'Species', '9606', (60, 65))
75	31777202	Ectopic expression of CYP46A1 in GBM cells in vitro, however, led to a dramatic increase in 24OHC concentration in culture media (Fig 3B) as well as in GBM cell pellets (P < 0.01; Appendix Fig S6B).	('GBM', 'Phenotype', 'HP:0012174', (33, 36))	('rat', 'Species', '10116', (105, 108))	('increase', 'PosReg', (80, 88))	('CYP46A1', 'Var', (22, 29))	('GBM', 'Phenotype', 'HP:0012174', (152, 155))	('24OHC concentration', 'MPA', (92, 111))	('24OHC', 'Chemical', 'MESH:C496310', (92, 97))
76	31777202	Exogenous 24OHC inhibited LN229 growth in a dose- and time-dependent manner (Appendix Fig S6C and D).	('24OHC', 'Var', (10, 15))	('inhibited', 'NegReg', (16, 25))	('24OHC', 'Chemical', 'MESH:C496310', (10, 15))	('LN229 growth', 'CPA', (26, 38))	('LN229', 'CellLine', 'CVCL:0393', (26, 31))
80	31777202	24OHC also elevated caspase-3/7 activity in LN229 (Appendix Fig S6E and F) and dramatically inhibited colony formation in LN229 and LN18 compared with controls (P < 0.001, Fig 3F).	('caspase-3', 'Gene', '836', (20, 29))	('24OHC', 'Chemical', 'MESH:C496310', (0, 5))	('inhibited', 'NegReg', (92, 101))	('colony formation', 'CPA', (102, 118))	('activity', 'MPA', (32, 40))	('LN229', 'CellLine', 'CVCL:0393', (122, 127))	('LN229', 'CellLine', 'CVCL:0393', (44, 49))	('caspase-3', 'Gene', (20, 29))	('elevated', 'PosReg', (11, 19))	('24OHC', 'Var', (0, 5))
83	31777202	Finally, treatment of GSCs, GBM#P3, GBM#BG7 and GBM#BG5, with 24OHC, led to a reduced tumorsphere formation (Fig 3H and I).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('24OHC', 'Chemical', 'MESH:C496310', (62, 67))	('BG7', 'CellLine', 'CVCL:6570', (40, 43))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('GBM', 'Var', (48, 51))	('reduced', 'NegReg', (78, 85))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
85	31777202	In summary, these data show that 24OHC specifically inhibits GBM growth.	('GBM growth', 'CPA', (61, 71))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('24OHC', 'Var', (33, 38))	('inhibits', 'NegReg', (52, 60))	('24OHC', 'Chemical', 'MESH:C496310', (33, 38))
89	31777202	These results therefore show that 24OHC inhibits GBM cell growth by depleting intracellular cholesterol.	('24OHC', 'Chemical', 'MESH:C496310', (34, 39))	('cholesterol', 'Chemical', 'MESH:D002784', (92, 103))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('inhibits', 'NegReg', (40, 48))	('depleting', 'NegReg', (68, 77))	('GBM cell growth', 'CPA', (49, 64))	('24OHC', 'Var', (34, 39))
92	31777202	Cholesterol also attenuated apoptosis caused by 24OHC in both LN229 and GBM#P3 (Fig 4D) and decreased cleaved PARP (Fig 4E).	('attenuated', 'NegReg', (17, 27))	('LN229', 'CellLine', 'CVCL:0393', (62, 67))	('PARP', 'Gene', '1302', (110, 114))	('24OHC', 'Chemical', 'MESH:C496310', (48, 53))	('LN229', 'Gene', (62, 67))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('apoptosis', 'CPA', (28, 37))	('PARP', 'Gene', (110, 114))	('GBM', 'Gene', (72, 75))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('decreased', 'NegReg', (92, 101))	('24OHC', 'Var', (48, 53))
93	31777202	Cholesterol also compensated for the reduction in GSC sphere formation caused by 24OHC in both GBM#P3 and GBM#BG7 cells (P < 0.05; Fig 4F).	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('BG7', 'CellLine', 'CVCL:6570', (110, 113))	('reduction', 'NegReg', (37, 46))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('Cholesterol', 'Chemical', 'MESH:D002784', (0, 11))	('GSC sphere formation', 'CPA', (50, 70))	('24OHC', 'Var', (81, 86))	('24OHC', 'Chemical', 'MESH:C496310', (81, 86))
95	31777202	In conclusion, these results demonstrated that 24OHC suppresses GBM growth by depleting cellular cholesterol.	('suppresses', 'NegReg', (53, 63))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('rat', 'Species', '10116', (36, 39))	('GBM growth', 'CPA', (64, 74))	('depleting', 'NegReg', (78, 87))	('cellular cholesterol', 'MPA', (88, 108))	('24OHC', 'Var', (47, 52))	('cholesterol', 'Chemical', 'MESH:D002784', (97, 108))	('24OHC', 'Chemical', 'MESH:C496310', (47, 52))
98	31777202	In addition, inflammatory signalling pathways including IL-10 and NF-kappaB pathways were regulated by 24OHC (Fig 5B).	('inflammatory signalling pathways', 'Pathway', (13, 45))	('regulated', 'Reg', (90, 99))	('24OHC', 'Var', (103, 108))	('24OHC', 'Chemical', 'MESH:C496310', (103, 108))	('IL-10', 'Gene', '3586', (56, 61))	('NF-kappaB pathways', 'Pathway', (66, 84))	('IL-10', 'Gene', (56, 61))
100	31777202	Moreover, GSEA showed that 24OHC was associated with positive regulation of cholesterol efflux, but negatively associated with gene signatures linked to cholesterol homeostasis, SREBP targets and stem cell proliferation (Fig 5D).	('24OHC', 'Var', (27, 32))	('positive', 'PosReg', (53, 61))	('negatively', 'NegReg', (100, 110))	('stem cell proliferation', 'CPA', (196, 219))	('24OHC', 'Chemical', 'MESH:C496310', (27, 32))	('rat', 'Species', '10116', (213, 216))	('cholesterol', 'Chemical', 'MESH:D002784', (76, 87))	('cholesterol efflux', 'MPA', (76, 94))	('cholesterol', 'Chemical', 'MESH:D002784', (153, 164))
106	31777202	These results indicate that 24OHC might kill GBM cells not only through activation of LXR, but also through other mechanisms.	('activation', 'PosReg', (72, 82))	('LXR', 'Enzyme', (86, 89))	('24OHC', 'Chemical', 'MESH:C496310', (28, 33))	('GBM cells', 'CPA', (45, 54))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('24OHC', 'Var', (28, 33))
107	31777202	Based on the RNA-seq data, 24OHC was also found to suppress SREBP signalling (Fig 5D and E).	('SREBP signalling', 'MPA', (60, 76))	('24OHC', 'Var', (27, 32))	('24OHC', 'Chemical', 'MESH:C496310', (27, 32))	('suppress', 'NegReg', (51, 59))
111	31777202	On Western blots, proteins levels were correspondingly altered; 24OHC caused a decrease in protein levels of nuclear SREBP1 (N-SREBP1), precursor SREBP1 (P-SREBP1) and LDLR as well as an induction of ABCA1 (Fig 5H and Appendix Fig S7C).	('SREBP1', 'Gene', '6720', (146, 152))	('SREBP1', 'Gene', (127, 133))	('24OHC', 'Chemical', 'MESH:C496310', (64, 69))	('SREBP1', 'Gene', '6720', (156, 162))	('SREBP1', 'Gene', '6720', (117, 123))	('SREBP1', 'Gene', (117, 123))	('LDLR', 'Gene', (168, 172))	('decrease', 'NegReg', (79, 87))	('protein levels', 'MPA', (91, 105))	('LDLR', 'Gene', '3949', (168, 172))	('ABCA1', 'Gene', '19', (200, 205))	('SREBP1', 'Gene', (146, 152))	('SREBP1', 'Gene', '6720', (127, 133))	('SREBP1', 'Gene', (156, 162))	('ABCA1', 'Gene', (200, 205))	('24OHC', 'Var', (64, 69))
116	31777202	Based on the findings that CYP46A1 inhibits GBM growth by converting cholesterol to 24OHC, we investigated the effect of efavirenz (EFV) (Fig 6A), which is an anti-HIV medication known to activate CYP46A1 activity through binding to the enzyme's allosteric site (Mast et al, 2014, 2017a; Anderson et al, 2016).	('24OHC', 'Chemical', 'MESH:C496310', (84, 89))	('activate', 'PosReg', (188, 196))	('GBM growth', 'CPA', (44, 54))	('binding', 'Interaction', (222, 229))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('inhibits', 'NegReg', (35, 43))	('activity', 'MPA', (205, 213))	('HIV', 'Disease', (164, 167))	('efavirenz', 'Chemical', 'MESH:C098320', (121, 130))	('converting cholesterol to 24OHC', 'MPA', (58, 89))	('HIV', 'Disease', 'MESH:D015658', (164, 167))	('cholesterol', 'Chemical', 'MESH:D002784', (69, 80))	('CYP46A1', 'Var', (27, 34))
122	31777202	Flow cytometry analysis demonstrated that EFV induced apoptosis in GBM cells (P < 0.001, Fig 6G), while sparing normal brain organoids and NHAs (Appendix Fig S9A-C).	('apoptosis', 'CPA', (54, 63))	('EFV', 'Var', (42, 45))	('organoid', 'Chemical', 'None', (125, 133))	('sparing', 'NegReg', (104, 111))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))	('rat', 'Species', '10116', (31, 34))
124	31777202	At the molecular level, EFV led to increased levels of the LXR target ABCA1 and the apoptosis marker cleaved PARP, but to decreased levels of SREBP1 and LDLR, as well as PCNA and SOX2 (Fig 6I).	('levels', 'MPA', (45, 51))	('increased', 'PosReg', (35, 44))	('EFV', 'Var', (24, 27))	('levels', 'MPA', (132, 138))	('SREBP1', 'Gene', '6720', (142, 148))	('ABCA1', 'Gene', '19', (70, 75))	('SREBP1', 'Gene', (142, 148))	('LDLR', 'Gene', (153, 157))	('ABCA1', 'Gene', (70, 75))	('PARP', 'Gene', '1302', (109, 113))	('SOX2', 'Gene', '6657', (179, 183))	('PARP', 'Gene', (109, 113))	('LDLR', 'Gene', '3949', (153, 157))	('decreased', 'NegReg', (122, 131))	('SOX2', 'Gene', (179, 183))
125	31777202	Finally, exogenous cholesterol treatment (Appendix Fig S9D) or CYP46A1 knockdown (Appendix Fig S9E and F) partially restored EFV-induced growth inhibition of GBM cells.	('restored', 'PosReg', (116, 124))	('cholesterol', 'Chemical', 'MESH:D002784', (19, 30))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('growth inhibition', 'CPA', (137, 154))	('knockdown', 'Var', (71, 80))	('CYP46A1', 'Gene', (63, 70))
132	31777202	Overall survival of mice was prolonged (median survival: 29 versus 35 days for GBM#P3; 27 versus 44 days for LN229; Fig 6K).	('mice', 'Species', '10090', (20, 24))	('GBM', 'Phenotype', 'HP:0012174', (79, 82))	('Overall survival', 'CPA', (0, 16))	('LN229', 'CellLine', 'CVCL:0393', (109, 114))	('prolonged', 'PosReg', (29, 38))	('GBM#P3', 'Var', (79, 85))
133	31777202	For GBM#P3, bioluminescence imaging revealed a significant inhibition of tumour growth at day 21 (P < 0.01, Fig 6L and M).	('inhibition', 'NegReg', (59, 69))	('tumour', 'Disease', (73, 79))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('GBM#P3', 'Var', (4, 10))
134	31777202	IHC staining of brain sections from tumour-bearing mice also demonstrated that EFV suppressed the expression of PCNA and induced protein levels of cleaved caspase-3 (Appendix Fig S10A-D).	('S10A', 'Var', (179, 183))	('caspase-3', 'Gene', (155, 164))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('PCNA', 'Gene', (112, 116))	('mice', 'Species', '10090', (51, 55))	('tumour', 'Disease', (36, 42))	('caspase-3', 'Gene', '836', (155, 164))	('induced', 'PosReg', (121, 128))	('rat', 'Species', '10116', (68, 71))	('protein levels', 'MPA', (129, 143))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('S10A', 'SUBSTITUTION', 'None', (179, 183))	('suppressed', 'NegReg', (83, 93))	('expression', 'MPA', (98, 108))
140	31777202	The expression of CYP46A1 was negatively correlated with WHO grade and malignant clinicopathological features of gliomas.	('CYP46A1', 'Var', (18, 25))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('expression', 'MPA', (4, 14))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('negatively', 'NegReg', (30, 40))
143	31777202	CYP46A1 is specifically expressed in the brain and is responsible for the conversion of cholesterol into 24 (S)-hydroxycholesterol (24OHC), which crosses the BBB into the systemic circulation for metabolism (Lutjohann et al, 1996; Bjorkhem et al, 1997, 1998).	('cholesterol', 'Chemical', 'MESH:D002784', (88, 99))	('cholesterol', 'Chemical', 'MESH:D002784', (119, 130))	('responsible', 'Reg', (54, 65))	('(S)-hydroxycholesterol', 'Chemical', 'MESH:D006888', (108, 130))	('CYP46A1', 'Var', (0, 7))	('24OHC', 'Chemical', 'MESH:C496310', (132, 137))
145	31777202	Dysregulation of CYP46A1 expression has been shown to occur in several neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington diseases (Bjorkhem et al, 2013; Leoni et al, 2013; Soncini et al, 2016; Swan et al, 2016).	("Alzheimer's", 'Disease', 'MESH:D000544', (122, 133))	('Alzheimer', 'Disease', (122, 131))	("Parkinson's", 'Disease', 'MESH:D010300', (109, 120))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (71, 97))	('Parkinson', 'Disease', (109, 118))	('Dysregulation', 'Var', (0, 13))	('neurodegenerative diseases', 'Disease', (71, 97))	('Huntington diseases', 'Disease', (138, 157))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (71, 96))	('CYP46A1', 'Gene', (17, 24))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (71, 97))	('Huntington diseases', 'Disease', 'MESH:D006816', (138, 157))	('occur', 'Reg', (54, 59))
148	31777202	In the present study, we found lower levels of histone modification of H3K4me3 and H3K27ac sites at the promoter region of CYP46A1, which may partially account for the decreased expression of CYP46A1 in GBM relative to normal brain.	('histone modification', 'MPA', (47, 67))	('decreased', 'NegReg', (168, 177))	('expression', 'MPA', (178, 188))	('H3K4me3', 'Chemical', 'MESH:C024755', (71, 78))	('H3K27ac', 'Var', (83, 90))	('lower', 'NegReg', (31, 36))	('GBM', 'Phenotype', 'HP:0012174', (203, 206))	('CYP46A1', 'Gene', (123, 130))	('H3K4me3', 'Protein', (71, 78))
150	31777202	In functional assays, we observed that overexpression of CYP46A1 repressed GBM proliferation both in vitro and in vivo.	('overexpression', 'PosReg', (39, 53))	('CYP46A1', 'Var', (57, 64))	('GBM proliferation', 'CPA', (75, 92))	('rat', 'Species', '10116', (86, 89))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))
151	31777202	CYP46A1 accelerates the conversion of cholesterol into 24OHC through its enzyme activity.	('enzyme activity', 'MPA', (73, 88))	('cholesterol', 'Chemical', 'MESH:D002784', (38, 49))	('24OHC', 'Chemical', 'MESH:C496310', (55, 60))	('conversion of cholesterol into 24OHC', 'MPA', (24, 60))	('CYP46A1', 'Var', (0, 7))	('accelerates', 'PosReg', (8, 19))	('rat', 'Species', '10116', (14, 17))
154	31777202	Previous studies have identified 24OHC as an activator of LXR and inducer of several genes involved in cellular cholesterol efflux (Lehmann et al, 1997; Janowski et al, 1999), such as the ATP-binding cassette transporter A1 (ABCA1) in both neurons and glia (Fukumoto et al, 2002) and apoE in astrocytes (Liang et al, 2004).	('apoE', 'Gene', (284, 288))	('apoE', 'Gene', '348', (284, 288))	('ATP-binding cassette transporter A1', 'Gene', (188, 223))	('ATP-binding cassette transporter A1', 'Gene', '19', (188, 223))	('cholesterol', 'Chemical', 'MESH:D002784', (112, 123))	('24OHC', 'Var', (33, 38))	('cellular', 'MPA', (103, 111))	('ABCA1', 'Gene', '19', (225, 230))	('24OHC', 'Chemical', 'MESH:C496310', (33, 38))	('ABCA1', 'Gene', (225, 230))
155	31777202	RNA-seq revealed that 24OHC caused an up-regulation of LXR targets, such as ABCA1, ABCG1 and IDOL (the E3 ligase of LDLR), and down-regulation of several SREBP target genes.	('ABCA1', 'Gene', (76, 81))	('up-regulation', 'PosReg', (38, 51))	('LDLR', 'Gene', (116, 120))	('ABCG1', 'Gene', (83, 88))	('LDLR', 'Gene', '3949', (116, 120))	('IDOL', 'Gene', '29116', (93, 97))	('24OHC', 'Var', (22, 27))	('ABCA1', 'Gene', '19', (76, 81))	('ABCG1', 'Gene', '9619', (83, 88))	('down-regulation', 'NegReg', (127, 142))	('IDOL', 'Gene', (93, 97))	('24OHC', 'Chemical', 'MESH:C496310', (22, 27))
156	31777202	In summary, these data show that 24OHC acts, at least partially, by regulating the activity of two essential transcription factors, LXR and SREBP, involved in cholesterol homeostasis.	('activity', 'MPA', (83, 91))	('regulating', 'Reg', (68, 78))	('24OHC', 'Var', (33, 38))	('24OHC', 'Chemical', 'MESH:C496310', (33, 38))	('cholesterol', 'Chemical', 'MESH:D002784', (159, 170))
157	31777202	Although 24OHC likely modulates cell death also through other pathways (Noguchi et al, 2015), our results show that inhibition of CYP46A1/24OHC is a critical underlying regulator of cholesterol homeostasis in GBM.	('inhibition', 'Var', (116, 126))	('24OHC', 'Chemical', 'MESH:C496310', (138, 143))	('CYP46A1/24OHC', 'Gene', (130, 143))	('GBM', 'Phenotype', 'HP:0012174', (209, 212))	('cholesterol', 'Chemical', 'MESH:D002784', (182, 193))	('24OHC', 'Chemical', 'MESH:C496310', (9, 14))	('modulates', 'Reg', (22, 31))
162	31777202	More recently, EFV has been shown to reduce phosphorylated Tau (pTau) accumulation in a human iPSC-derived AD model (van der Kant et al, 2019).	('reduce', 'NegReg', (37, 43))	('phosphorylated Tau', 'MPA', (44, 62))	('pTau', 'Disease', (64, 68))	('EFV', 'Var', (15, 18))	('human', 'Species', '9606', (88, 93))	('pTau', 'Disease', 'None', (64, 68))
164	31777202	In the current study, we observed that EFV (20 uM) significantly suppressed GBM growth and induced tumour cell death.	('induced', 'Reg', (91, 98))	('tumour cell death', 'Disease', (99, 116))	('suppressed', 'NegReg', (65, 75))	('EFV', 'Var', (39, 42))	('GBM growth', 'CPA', (76, 86))	('tumour cell death', 'Disease', 'MESH:D003643', (99, 116))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
166	31777202	Notably, exogenous cholesterol treatment or CYP46A1 knockdown partially restored growth inhibition of GBM cells induced by EFV, suggesting that the anti-cancer effect of EFV is mediated at least partially, by regulating cholesterol levels.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cholesterol levels', 'MPA', (220, 238))	('cancer', 'Disease', (153, 159))	('cholesterol', 'Chemical', 'MESH:D002784', (19, 30))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('CYP46A1', 'Var', (44, 51))	('growth inhibition', 'CPA', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cholesterol', 'Chemical', 'MESH:D002784', (220, 231))
171	31777202	We show that accumulation of cholesterol and dysregulated cholesterol homeostasis in GBM is mediated by loss of CYP46A1 and that CYP46A1 represents a viable therapeutic target in GBMs.	('accumulation', 'PosReg', (13, 25))	('cholesterol', 'Chemical', 'MESH:D002784', (29, 40))	('loss', 'Var', (104, 108))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('dysregulated cholesterol homeostasis', 'Disease', (45, 81))	('dysregulated cholesterol homeostasis', 'Phenotype', 'HP:0003107', (45, 81))	('cholesterol', 'Chemical', 'MESH:D002784', (58, 69))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('CYP46A1', 'Gene', (112, 119))	('dysregulated cholesterol homeostasis', 'Disease', 'MESH:D021081', (45, 81))	('cholesterol', 'MPA', (29, 40))
195	31777202	Corresponding reagents such as 24OHC (HY-N2370, MedChemExpress) and efavirenz (EFV; HY-10572, MedChemExpress) were added to cells in DMEM containing 1% FBS and 1% penicillin/streptomycin for established cell lines or neurobasal medium for patient-derived GSCs.	('patient', 'Species', '9606', (239, 246))	('efavirenz', 'Chemical', 'MESH:C098320', (68, 77))	('HY-N2370', 'Var', (38, 46))	('FBS', 'Disease', (152, 155))	('24OHC', 'Chemical', 'MESH:C496310', (31, 36))	('streptomycin', 'Chemical', 'MESH:D013307', (174, 186))	('penicillin', 'Chemical', 'MESH:D010406', (163, 173))	('FBS', 'Disease', 'MESH:D005198', (152, 155))
196	31777202	Cell viability assays were performed using the trypan blue assay (15250061, Gibco/Thermo Fisher Scientific) or the Cell Counting Kit-8 (CK04, Dojindo; Rockville, MD) according to the manufacturer's protocol.	('trypan blue assay', 'MPA', (47, 64))	('15250061', 'Var', (66, 74))	('trypan blue', 'Chemical', 'MESH:D014343', (47, 58))
224	31777202	The following antibodies were used: anti-H3K27ac (ab4729, 1:100, Abcam), anti-H3K4me3 (ab8580, 1:100, Abcam) and normal rabbit IgG (#2729, 1:100, Cell Signaling Technology).	('anti-H3K27ac', 'Var', (36, 48))	('rabbit', 'Species', '9986', (120, 126))	('H3K4me3', 'Chemical', 'MESH:C024755', (78, 85))	('anti-H3K4me3', 'Var', (73, 85))
257	31777202	Using this approach, we identified the gene CYP46A1 as one of the most dramatically down-regulated genes involved in GBM cholesterol homeostasis.	('cholesterol', 'Chemical', 'MESH:D002784', (121, 132))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('CYP46A1', 'Var', (44, 51))	('down-regulated', 'NegReg', (84, 98))
259	31777202	Mechanistically, ectopic expression of CYP46A1 suppressed glioma stem cell proliferation and in vivo tumour growth by increasing 24OHC, which led to a decrease in GBM cholesterol levels.	('suppressed', 'NegReg', (47, 57))	('increasing', 'PosReg', (118, 128))	('tumour', 'Disease', (101, 107))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('CYP46A1', 'Var', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('decrease', 'NegReg', (151, 159))	('cholesterol', 'Chemical', 'MESH:D002784', (167, 178))	('24OHC', 'MPA', (129, 134))	('rat', 'Species', '10116', (82, 85))	('24OHC', 'Chemical', 'MESH:C496310', (129, 134))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('GBM cholesterol levels', 'MPA', (163, 185))	('glioma', 'Disease', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
261	31777202	EFV increased 24OHC levels in GBM cells and suppressed GBM cell growth.	('suppressed', 'NegReg', (44, 54))	('EFV', 'Var', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (30, 33))	('24OHC', 'Chemical', 'MESH:C496310', (14, 19))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('24OHC levels', 'MPA', (14, 26))	('GBM cell growth', 'CPA', (55, 70))	('increased', 'PosReg', (4, 13))
336	30401716	Although co-expression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood.	('EGFR', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('growth', 'MPA', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('influence', 'Reg', (94, 103))	('EGFRvIII', 'Gene', (35, 43))	('co-expression', 'Var', (9, 22))
338	30401716	EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors co-expressing EGFR and EGFRvIII led to decreased infiltration of macrophages.	('decreased', 'NegReg', (154, 163))	('EGFRvIII', 'Gene', (138, 146))	('glioblastoma', 'Disease', (39, 51))	('knockout', 'Var', (88, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CCL2', 'Gene', (100, 104))	('CCL2', 'Gene', '6347', (78, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('infiltration of macrophages', 'CPA', (164, 191))	('tumors', 'Disease', (108, 114))	('patient', 'Species', '9606', (52, 59))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('EGFR', 'Gene', (129, 133))	('CCL2', 'Gene', (78, 82))	('CCL2', 'Gene', '6347', (100, 104))
342	30401716	Amplification of the Epidermal Growth Factor Receptor (EGFR) is identified in more than half of tumors.	('Epidermal Growth Factor Receptor', 'Gene', '1956', (21, 53))	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Epidermal Growth Factor Receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))
344	30401716	Amplification of EGFRvIII always occurs in tumors that also amplify EGFR, suggesting that co-amplification of those molecules confers a growth advantage.	('growth', 'MPA', (136, 142))	('amplify', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('EGFR', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
349	30401716	EGFRvIII potentiates the expression of IL-6, IL-8 and LIF, indicating that EGFRvIII signals to the glioma microenvironment through upregulating specific cytokines.	('potentiates', 'PosReg', (9, 20))	('IL-8', 'Gene', '3576', (45, 49))	('expression', 'MPA', (25, 35))	('IL-6', 'Gene', (39, 43))	('IL-6', 'Gene', '3569', (39, 43))	('glioma', 'Disease', (99, 105))	('EGFRvIII', 'Var', (75, 83))	('specific cytokines', 'MPA', (144, 162))	('IL-8', 'Gene', (45, 49))	('LIF', 'Gene', (54, 57))	('upregulating', 'PosReg', (131, 143))	('LIF', 'Gene', '3976', (54, 57))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
378	30401716	The CD38 (ab216343), CD68 (ab955) and TMEM119 (ab209064) antibodies were purchased from Abcam and were used at a concentration of 1:100.	('ab216343', 'Var', (10, 18))	('CD68', 'Gene', '968', (21, 25))	('CD38', 'Gene', (4, 8))	('TMEM119', 'Gene', '338773', (38, 45))	('CD38', 'Gene', '952', (4, 8))	('TMEM119', 'Gene', (38, 45))	('CD68', 'Gene', (21, 25))
382	30401716	Three washing steps in TBST were followed by incubation with secondary antibodies at room temperature for 1 hr diluted in Dako REAL Antibody Diluent (anti-mouse AF488, anti-rabbit AF594, anti-rat AF647, Thermo Fisher, 1:1000).	('anti-mouse AF488', 'Var', (150, 166))	('anti-rabbit AF594', 'Var', (168, 185))	('anti-rat AF647', 'Var', (187, 201))	('mouse', 'Species', '10090', (155, 160))
399	30401716	To test whether inhibition of EGFR and EGFRvIII decreased macrophage attraction, we analyzed short-term cultures from two primary patient-derived xenograft (PDX) lines (GBM6 and GBM39--both EGFR and EGFRvIII co-amplified), treated with DMSO or the EGFR inhibitor lapatinib.	('patient', 'Species', '9606', (130, 137))	('DMSO', 'Chemical', 'MESH:D004121', (236, 240))	('macrophage attraction', 'CPA', (58, 79))	('decreased', 'NegReg', (48, 57))	('lapatinib', 'Chemical', 'MESH:C490728', (263, 272))	('inhibition', 'Var', (16, 26))
402	30401716	Intracranial xenografted tumors co-expressing EGFR and EGFRvIII also showed significantly more CD45+ cells, compared to tumors expressing either EGFR or EGFRvIII alone (Figure 1E and1F).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('EGFR', 'Var', (46, 50))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CD45+ cells', 'MPA', (95, 106))	('more', 'PosReg', (90, 94))	('EGFRvIII', 'Gene', (55, 63))
403	30401716	Together, these results show that co-expression of EGFR and EGFRvIII increases infiltration of immune cells in glioblastoma tumors.	('increases', 'PosReg', (69, 78))	('infiltration of immune cells', 'CPA', (79, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('EGFR', 'Gene', (51, 55))	('co-expression', 'Var', (34, 47))	('EGFRvIII', 'Gene', (60, 68))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (111, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('glioblastoma tumors', 'Disease', (111, 130))
406	30401716	Tumors co-expressing EGFR and EGFRvIII showed significantly more CD38+ cells and CD206+ cells, compared to tumors expressing either EGFR or EGFRvIII singly (Figure 2A - C).	('more', 'PosReg', (60, 64))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CD38', 'Gene', (65, 69))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CD38', 'Gene', '952', (65, 69))	('CD206', 'Gene', '4360', (81, 86))	('EGFRvIII', 'Var', (30, 38))	('CD206', 'Gene', (81, 86))	('EGFR', 'Var', (21, 25))
407	30401716	Thus, in these xenografted tumors, co-expression of EGFR and EGFRvIII increases infiltration of both M1 and M2 macrophages.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EGFR', 'Gene', (52, 56))	('increases', 'PosReg', (70, 79))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('EGFRvIII', 'Gene', (61, 69))	('co-expression', 'Var', (35, 48))	('infiltration of', 'CPA', (80, 95))
409	30401716	Established tumors co-expressing EGFR and EGFRvIII showed significantly more infiltration of CD68+ monocyte lineage cells, compared to tumors expressing either EGFR or EGFRvIII alone (Figure 2D).	('EGFRvIII', 'Var', (42, 50))	('more', 'PosReg', (72, 76))	('CD68', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EGFR', 'Var', (33, 37))	('CD68', 'Gene', '968', (93, 97))	('infiltration', 'CPA', (77, 89))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
411	30401716	Tumors co-expressing EGFR and EGFRvIII also showed significantly more TMEM119+ cells, compared to tumors expressing either EGFR or EGFRvIII alone (Figure 2E).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('TMEM119', 'Gene', '338773', (70, 77))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('TMEM119', 'Gene', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('more', 'PosReg', (65, 69))	('EGFRvIII', 'Var', (30, 38))	('EGFR', 'Var', (21, 25))
418	30401716	We demonstrated that cells expressing EGFR or EGFRvIII alone, at cell surface receptor density comparable to that of cells co-expressing EGFR and EGFRvIII failed to induce significant amounts of CCL2.	('CCL2', 'Gene', '6347', (195, 199))	('EGFRvIII', 'Var', (46, 54))	('CCL2', 'Gene', (195, 199))
424	30401716	Consistent with the RNA-seq data, co-expression of EGFR and EGFRvIII also upregulated IL1B, CCL2 and other cytokine at the protein level (Figure 3E, 3F, 3G and S2).	('upregulated', 'PosReg', (74, 85))	('EGFR', 'Gene', (51, 55))	('IL1B', 'Gene', (86, 90))	('co-expression', 'Var', (34, 47))	('IL1B', 'Gene', '3553', (86, 90))	('CCL2', 'Gene', '6347', (92, 96))	('EGFRvIII', 'Gene', (60, 68))	('CCL2', 'Gene', (92, 96))
429	30401716	Conditioned media from cells co-expressing EGFR and EGFRvIII, after CRISPR/Cas9 mediated deletion of CCL2, also led to decreased macrophage infiltration (Figure 4B and S3A).	('decreased', 'NegReg', (119, 128))	('CCL2', 'Gene', '6347', (101, 105))	('deletion', 'Var', (89, 97))	('CCL2', 'Gene', (101, 105))	('decreased macrophage infiltration', 'Phenotype', 'HP:0012648', (119, 152))	('macrophage infiltration', 'CPA', (129, 152))
430	30401716	Knockout of CCL2 in intracranial xenografted tumors co-expressing EGFR and EGFRvIII led to significant decreases in the abundance of infiltrating CD45+ cells (Figure 1E and 1F) and modestly enhanced survival (Figure 4C).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('EGFR', 'Gene', (66, 70))	('decreases', 'NegReg', (103, 112))	('survival', 'CPA', (199, 207))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('CCL2', 'Gene', '6347', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('EGFRvIII', 'Gene', (75, 83))	('Knockout', 'Var', (0, 8))	('CCL2', 'Gene', (12, 16))	('enhanced', 'PosReg', (190, 198))
436	30401716	Consistently, conditioned media from cells co-expressing EGFR and EGFRvIII, and knocked out for KRAS, attracted fewer macrophages than conditioned media from the same cells with intact KRAS (Figure 5D).	('KRAS', 'Gene', '3845', (96, 100))	('EGFRvIII', 'Gene', (66, 74))	('knocked out', 'Var', (80, 91))	('KRAS', 'Gene', '3845', (185, 189))	('fewer', 'NegReg', (112, 117))	('KRAS', 'Gene', (96, 100))	('macrophages', 'MPA', (118, 129))	('EGFR', 'Gene', (57, 61))	('KRAS', 'Gene', (185, 189))
445	30401716	Our RNA-seq results show that co-expression of EGFR and EGFRvIII upregulated CCL2, as well as stem cell markers such as CD90/THY1 and SOX1 (Figure S5A).	('THY1', 'Gene', (125, 129))	('SOX1', 'Gene', (134, 138))	('EGFRvIII', 'Gene', (56, 64))	('co-expression', 'Var', (30, 43))	('CCL2', 'Gene', '6347', (77, 81))	('THY1', 'Gene', '7070', (125, 129))	('CD90', 'Gene', '7070', (120, 124))	('upregulated', 'PosReg', (65, 76))	('CCL2', 'Gene', (77, 81))	('SOX1', 'Gene', '6656', (134, 138))	('CD90', 'Gene', (120, 124))	('EGFR', 'Gene', (47, 51))
450	30401716	Amplification of EGFR and EGFRvIII represents hallmark genetic changes in glioblastoma.	('glioblastoma', 'Disease', (74, 86))	('Amplification', 'Var', (0, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('EGFRvIII', 'Gene', (26, 34))	('EGFR', 'Gene', (17, 21))
451	30401716	Amplification of EGFRvIII occurs only in tumors that amplify EGFR, suggesting that those two molecules could cooperate to promote tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('amplify', 'Var', (53, 60))	('tumor', 'Disease', (41, 46))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('promote', 'PosReg', (122, 129))	('cooperate', 'Interaction', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (130, 135))	('EGFR', 'Gene', (61, 65))
459	30401716	Although CCL2 is a major chemokine recruiting macrophages, knockout of CCL2 in cells co-expressing EGFR and EGFRvIII did not completely block EGFR and EGFRvIII-induced macrophage attraction in vitro, indicating that other chemokines also contribute to macrophage recruitment.	('EGFR', 'Gene', (99, 103))	('CCL2', 'Gene', '6347', (9, 13))	('CCL2', 'Gene', '6347', (71, 75))	('knockout', 'Var', (59, 67))	('CCL2', 'Gene', (9, 13))	('CCL2', 'Gene', (71, 75))	('EGFRvIII', 'Gene', (108, 116))
467	30401716	Our results showed that co-expression of EGFR and EGFRvIII promoted infiltration of both tumor promoting (M2) and tumor suppressive macrophages (M1).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('EGFR', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('EGFRvIII', 'Gene', (50, 58))	('co-expression', 'Var', (24, 37))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (114, 119))	('infiltration', 'CPA', (68, 80))	('promoted', 'PosReg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
468	30401716	This may be one reason why knockout of CCL2 in cells co-expressing EGFR and EGFRvIII only modestly impacted survival.	('EGFRvIII', 'Gene', (76, 84))	('impacted', 'Reg', (99, 107))	('knockout', 'Var', (27, 35))	('CCL2', 'Gene', '6347', (39, 43))	('EGFR', 'Gene', (67, 71))	('CCL2', 'Gene', (39, 43))
500	29993362	Sequence data are particularly useful when an oncogenic driver is both a drug target and a biomarker of drug response, such as BRAFV600E in melanoma or BCR-ABL in chronic myelogenous leukemia .	('BCR-ABL', 'Gene', (152, 159))	('BRAFV600E', 'Var', (127, 136))	('BCR-ABL', 'Gene', '25', (152, 159))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (171, 191))	('BRAFV600E', 'Mutation', 'rs113488022', (127, 136))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (163, 191))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('myelogenous leukemia', 'Disease', (171, 191))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (171, 191))
525	29993362	In all other cycles antibodies are directly conjugated to fluorophores, typically Alexa 488, 555 or 647 (for a description of different modes of CyCIF see).	('Alexa 488', 'Chemical', '-', (82, 91))	('555', 'Var', (93, 96))	('647', 'Var', (100, 103))
548	29993362	In preliminary studies, we have tested a range of other fluorophores for their compatibility with t-CyCIF including FITC, TRITC, phycoerythrin, Allophycocyanin, eFluor 570 and eFluor 660 (eBioscience).	('tested', 'Reg', (32, 38))	('t-CyCIF', 'Chemical', '-', (98, 105))	('TRITC', 'Chemical', 'MESH:C009434', (122, 127))	('FITC', 'Chemical', 'MESH:D016650', (116, 120))	('eFluor', 'Var', (161, 167))	('eFluor', 'Var', (176, 182))
568	29993362	The repeatability of staining (as measured in cycles 3, 7, 12 and 16) was performed using anti-PCNA-Alexa 488, anti-Vimentin-Alexa 555 and anti-Tubulin- Alexa 647 which bind abundant proteins with distrinct cellular distributions (Figure 5B).	('Vimentin', 'Gene', '7431', (116, 124))	('Alexa 555', 'Chemical', '-', (125, 134))	('Alexa 488', 'Chemical', '-', (100, 109))	('PCNA', 'Gene', (95, 99))	('anti-Tubulin-', 'Var', (139, 152))	('Alexa 647', 'Chemical', 'MESH:C569686', (153, 162))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('PCNA', 'Gene', '5111', (95, 99))	('Vimentin', 'Gene', (116, 124))
590	29993362	Many other physiologically relevant correlations are also observed, for example between the levels of pERKT202/Y204 (the phosphorylated, active form of the kinase) and activating phosphorylation of the downstream kinase pS6S235/S236 (r = 0.81).	('pERK', 'Gene', (102, 106))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('pERK', 'Gene', '9451', (102, 106))	('pS6S235/S236', 'Var', (220, 232))	('activating phosphorylation', 'MPA', (168, 194))
596	29993362	Approximately 90% of sporadic PDACs also harbor driver mutations in KRAS, activating the MAPK pathway and promoting tumourigenesis.	('activating', 'PosReg', (74, 84))	('PDAC', 'Chemical', '-', (30, 34))	('MAPK', 'Gene', '5594', (89, 93))	('mutations', 'Var', (55, 64))	('MAPK', 'Gene', (89, 93))	('tumourigenesis', 'CPA', (116, 130))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('promoting', 'PosReg', (106, 115))	('PDACs', 'Disease', (30, 35))
601	29993362	When we gated for cells that were both Ki67high and PCNAhigh, and thus likely to be malignant, the co-occurrence of different relationship between pERK and beta-catenin levels on a cellular level was again evident.	('pERK', 'Gene', '9451', (147, 151))	('pERK', 'Gene', (147, 151))	('Ki67high', 'Var', (39, 47))	('beta-catenin', 'Gene', (156, 168))	('PCNA', 'Gene', (52, 56))	('beta-catenin', 'Gene', '1499', (156, 168))	('PCNA', 'Gene', '5111', (52, 56))
871	29342360	An example of this can be seen in Manome et al., where poly(D,L-lactide-co-glycolide) (PLGA) sheets exhibited a sudden burst release of DXR around 30 days in vitro.	('DXR', 'MPA', (136, 139))	('burst release', 'MPA', (119, 132))	('poly', 'Var', (55, 59))	('poly(D,L-lactide-co-glycolide)', 'Chemical', 'MESH:D000077182', (55, 85))
899	29342360	Rabbit polyclonal antibody against glial fibrillary acidic protein (GFAP, #Z0334) and protein block (#X0909) were both purchased from DAKO/Agilent Technologies (Santa Clara, CA).	('glial fibrillary acidic protein', 'Gene', '14580', (35, 66))	('GFAP', 'Gene', '14580', (68, 72))	('GFAP', 'Gene', (68, 72))	('glial fibrillary acidic protein', 'Gene', (35, 66))	('protein block', 'Disease', 'MESH:D006327', (86, 99))	('protein block', 'Disease', (86, 99))	('#X0909', 'Var', (101, 107))	('Rabbit', 'Species', '9986', (0, 6))
900	29342360	Human glioma cell lines U87-MG, LN-18, and LN-229 were purchased from American Type Culture Collection (ATCC; Manassas, VA; #HTB-14, #CRL-2610, and #CRL-2611, respectively).	('Human', 'Species', '9606', (0, 5))	('U87-MG', 'CellLine', 'CVCL:0022', (24, 30))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('#CRL-2611', 'Var', (148, 157))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('glioma', 'Disease', (6, 12))	('LN-229', 'CellLine', 'CVCL:0393', (43, 49))
907	29342360	This procedure was repeated for BCNU at concentrations of 0.01, 0.05, 0.1, 0.25, 0.5, 0.75, and 1 mM.	('0.1', 'Var', (70, 73))	('0.05', 'Var', (64, 68))	('rat', 'Species', '10116', (47, 50))	('0.25', 'Var', (75, 79))	('0.01', 'Var', (58, 62))	('BCNU', 'Chemical', 'MESH:D002330', (32, 36))
953	29342360	This resulted in 27 mice being included in the study with the following breakdown for groups: no treatment control (n=5), Ace-DEX/blank (n=5), PLA/blank (n=6), Ace-DEX/10DXR (n=7), PLA/10DXR (n=4).	('PLA/10DXR', 'Var', (181, 190))	('Ace', 'Gene', (122, 125))	('PLA', 'Chemical', 'MESH:C033616', (143, 146))	('PLA', 'Chemical', 'MESH:C033616', (181, 184))	('Ace', 'Gene', '11421', (160, 163))	('mice', 'Species', '10090', (20, 24))	('Ace', 'Gene', (160, 163))	('Ace', 'Gene', '11421', (122, 125))
967	29342360	Antigen retrieval for CD45 and GFAP was performed for 20 min at 100oC in Bond  Epitope Retrieval Solution 1 (pH 6.0) and in Bond  Enzyme 1 for 5 minutes followed by a 10 minute protein block.	('CD45', 'Gene', (22, 26))	('100oC', 'Var', (64, 69))	('GFAP', 'Gene', '14580', (31, 35))	('CD45', 'Gene', '19264', (22, 26))	('protein block', 'Disease', (177, 190))	('protein block', 'Disease', 'MESH:D006327', (177, 190))	('GFAP', 'Gene', (31, 35))
968	29342360	After pre-treatment, slides were incubated for 30 minutes with CD45 (1:100) and GFAP (1:2500), and for 1 hour with F4/80 (1:100).	('GFAP', 'Gene', (80, 84))	('F4/80', 'Gene', (115, 120))	('F4/80', 'Gene', '13733', (115, 120))	('GFAP', 'Gene', '14580', (80, 84))	('1:2500', 'Var', (86, 92))	('CD45', 'Gene', '19264', (63, 67))	('CD45', 'Gene', (63, 67))
984	29342360	Evaluating DXR release in vitro over time, PLA/10DXR scaffolds had a higher burst release compared to Ace-DEX/10DXR, with 46 +- 7.1% and 28 +- 1.6% of DXR released in the first 24 hours respectively.	('PLA/10DXR', 'Var', (43, 52))	('Ace', 'Gene', '11421', (102, 105))	('DXR', 'MPA', (11, 14))	('burst release', 'MPA', (76, 89))	('Ace', 'Gene', (102, 105))	('PLA', 'Chemical', 'MESH:C033616', (43, 46))
1013	29342360	By comparison, treatment with PLA/10DXR led to an initial decrease in tumor size and control of tumor regrowth for the first 2 weeks, but ultimately the tumor growth rate reached exponential rates similar to untreated control mice.	('PLA/10DXR', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mice', 'Species', '10090', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('rat', 'Species', '10116', (191, 194))	('rat', 'Species', '10116', (166, 169))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('decrease', 'NegReg', (58, 66))	('control', 'CPA', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PLA', 'Chemical', 'MESH:C033616', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
1056	29342360	Despite the slow steady state release of DXR from PLA/10DXR scaffolds, treatment with PLA/10DXR extended median survival from 29 to 63 days over PLA/blank.	('PLA', 'Chemical', 'MESH:C033616', (86, 89))	('PLA', 'Chemical', 'MESH:C033616', (145, 148))	('median survival', 'CPA', (105, 120))	('PLA/10DXR', 'Var', (86, 95))	('extended', 'PosReg', (96, 104))	('PLA', 'Chemical', 'MESH:C033616', (50, 53))
1074	29342360	In this case, PLA/10DXR resulted in an initial decrease in tumor burden, possibly due to the burst release of DXR from the scaffold; however, tumor regrowth ultimately outpaced the slow steady state DXR release from the PLA scaffold (Figure 5f).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('outpaced', 'NegReg', (168, 176))	('tumor', 'Disease', (59, 64))	('PLA', 'Chemical', 'MESH:C033616', (220, 223))	('tumor', 'Disease', (142, 147))	('PLA/10DXR', 'Var', (14, 23))	('decrease', 'NegReg', (47, 55))	('PLA', 'Chemical', 'MESH:C033616', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
1092	29552579	We demonstrate here that T cells expressing CD28.zeta and 41BB.zeta CARs with short spacers had similar effector function, resulting in potent antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('41BB.zeta CARs', 'Var', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CD28.zeta', 'Var', (44, 53))
1104	29552579	In addition, T cells expressing CARs with 41BB.zeta or CD28.41BB.zeta endodomains might have superior antitumor activity than CD28.zeta CAR T cells.	('superior', 'PosReg', (93, 101))	('CD28.41BB.zeta', 'Var', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('41BB.zeta', 'Var', (42, 51))	('tumor', 'Disease', (106, 111))
1105	29552579	We therefore generated and compared a panel of EphA2-specific CARs that contain an IgG1-derived short spacer region, which is devoid of Fc receptor binding sites, and different signaling domains (CD28.zeta, 41BB.zeta, or CD28.41BB.zeta).	('EphA2', 'Gene', '1969', (47, 52))	('CD28.zeta', 'Var', (196, 205))	('41BB.zeta', 'Var', (207, 216))	('G1', 'Chemical', 'MESH:C104227', (85, 87))	('EphA2', 'Gene', (47, 52))	('CD28.41BB.zeta', 'Var', (221, 235))
1113	29552579	T cells stably expressed tCD19 on their cell surface, with a mean transduction efficiency rate of 65.32% (SD +-12.43%) for CD28.zeta, 59.21% (SD +-10.7%) for 41BB.zeta, and 66.24% (SD +-5.76%) for CD28.41BB.zeta, and no significant differences in transduction efficiency among the constructs (Figures 1B and 1C).	('transduction', 'MPA', (66, 78))	('CD19', 'Gene', (26, 30))	('CD19', 'Gene', '930', (26, 30))	('CD28.41BB.zeta', 'Var', (197, 211))	('41BB.zeta', 'Var', (158, 167))	('CD28.zeta', 'Var', (123, 132))
1120	29552579	CD28.zeta, 41BB.zeta, and CD28.41BB.zeta T cells also produced significant amounts of IL-2 when co-cultured with BV173-EphA2, U373, or A549 (Figure 2B), with no significant difference among constructs containing different signaling domains.	('U373', 'Var', (126, 130))	('U373', 'Chemical', '-', (126, 130))	('EphA2', 'Gene', '1969', (119, 124))	('IL-2', 'Gene', '3558', (86, 90))	('IL-2', 'Gene', (86, 90))	('EphA2', 'Gene', (119, 124))	('A549', 'CellLine', 'CVCL:0023', (135, 139))	('CD28.41BB.zeta', 'Var', (26, 40))
1124	29552579	There was no significant difference in cytokine secretion levels among CARs except for TNF-alpha, which was secreted at significantly lower levels by 41BB.zeta CAR T cells in comparison with CD28.zeta (p < 0.01) or CD28.41BB.zeta (p < 0.05) T cells (Figure S3).	('cytokine secretion levels', 'MPA', (39, 64))	('TNF-alpha', 'Gene', (87, 96))	('41BB.zeta', 'Var', (150, 159))	('TNF-alpha', 'Gene', '7124', (87, 96))
1130	29552579	There was no difference in T cell expansion after A549 stimulation between CD28.zeta, 41BB.zeta, and CD28.41BB.zeta CAR T cells.	('T cell expansion', 'CPA', (27, 43))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('CD28.41BB.zeta', 'Var', (101, 115))	('CD28.zeta', 'Var', (75, 84))	('41BB.zeta', 'Var', (86, 95))
1134	29552579	On day 0, U373.eGFP.ffLuc cells were injected stereotactically into the brains of severe combined immunodeficiency (SCID) mice, followed by CD28.zeta, 41BB.zeta, or CD28.41BB.zeta CAR T cells on day 7.	('mice', 'Species', '10090', (122, 126))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (82, 114))	('CD28.41BB.zeta', 'Var', (165, 179))	('U373', 'Chemical', '-', (10, 14))	('SCID', 'Disease', (116, 120))	('SCID', 'Disease', 'MESH:D053632', (116, 120))	('SCID', 'Phenotype', 'HP:0004430', (116, 120))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (89, 114))	('immunodeficiency', 'Phenotype', 'HP:0002721', (98, 114))	('immunodeficiency', 'Disease', (98, 114))	('immunodeficiency', 'Disease', 'MESH:D007153', (98, 114))	('CD28.zeta', 'Var', (140, 149))
1138	29552579	Mice were followed for up to 100 days after tumor cell injection, and although CD28.zeta or 41BB.zeta CAR T cell-treated mice had a significant survival advantage (p < 0.05) in comparison with CH2CH3.CD28.zeta CAR T cell-treated mice, CD28.41BB.zeta CAR T cell-treated mice did not (Figure 4B).	('survival advantage', 'CPA', (144, 162))	('CD28.zeta', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mice', 'Species', '10090', (121, 125))	('mice', 'Species', '10090', (269, 273))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Mice', 'Species', '10090', (0, 4))	('mice', 'Species', '10090', (229, 233))	('CH2CH3', 'Chemical', '-', (193, 199))	('tumor', 'Disease', (44, 49))
1141	29552579	CAR T cells sustained their potent anti-glioma activity at cell doses as low as 1 x 105 T cells with three out of five (CD28.zeta CAR) and two out of five (41BB.zeta and CD28.41BB.zeta CARs) mice surviving long term (Figure 5).	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('41BB.zeta', 'Var', (156, 165))	('glioma', 'Disease', (40, 46))	('CD28.41BB.zeta', 'Var', (170, 184))	('mice', 'Species', '10090', (191, 195))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
1146	29552579	To determine T cell persistence, we injected 1 x 105 CD28.zeta or 41BB.zeta CAR T cells, which were also genetically modified to express eGFP.ffLuc, into U373 glioma-bearing mice.	('glioma', 'Disease', (159, 165))	('U373', 'Chemical', '-', (154, 158))	('mice', 'Species', '10090', (174, 178))	('eGFP.ffLuc', 'Gene', (137, 147))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('41BB.zeta', 'Var', (66, 75))
1151	29552579	In addition, long spacers that are based on CH2CH3 domains have been shown to render CAR T cells sensitive to innate immune cells, or can induce baseline (tonic) CAR signaling.	('induce', 'Reg', (138, 144))	('render', 'Reg', (78, 84))	('CH2CH3', 'Chemical', '-', (44, 50))	('CH2CH3', 'Var', (44, 50))
1159	29552579	Another group reported that CD28.zeta have greater functionality as judged by rapid tumor eradication, while 41BB.zeta mediates slower tumor killing but attains complete tumor eradication because of better persistence.	('CD28.zeta', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('better', 'PosReg', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (135, 140))	('persistence', 'MPA', (206, 217))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
1165	29552579	Besides transgenic expression of 'immune stimulatory genes', silencing negative regulators in CAR T cells is another promising strategy to render them resistant to the immunosuppressive (TME) glioma microenvironment.	('glioma', 'Disease', (192, 198))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('silencing', 'Var', (61, 70))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))
1176	29552579	T cells expressing CD28.zeta CAR and CD20 had similar effector function as CD28.zeta CAR T cells and were readily eliminated in the presence of Rituxan and complement (Figures S6B-S6D).	('CD20', 'Gene', '54474', (37, 41))	('CD20', 'Gene', (37, 41))	('Rituxan', 'Chemical', 'MESH:D000069283', (144, 151))	('CD28.zeta', 'Var', (19, 28))
1186	29552579	This mini gene was subcloned into SFG retroviral vector containing human IgG1 hinge and CD28.zeta, 41BB.zeta, or CD28.41BB.zeta endodomains.	('CD28.41BB.zeta', 'Var', (113, 127))	('G1', 'Chemical', 'MESH:C104227', (75, 77))	('CD28.zeta', 'Var', (88, 97))	('human', 'Species', '9606', (67, 72))
1233	27965469	Mutated epithelial growth factor receptor (EGFR), ras oncogenes, p53, and c-myc have been targets of molecularly targeted therapies.	('epithelial growth factor receptor', 'Gene', '1956', (8, 41))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('Mutated', 'Var', (0, 7))	('epithelial growth factor receptor', 'Gene', (8, 41))	('c-myc', 'Gene', '4609', (74, 79))	('EGFR', 'Gene', '1956', (43, 47))	('c-myc', 'Gene', (74, 79))	('EGFR', 'Gene', (43, 47))
1238	27965469	For example, FLT3 gene mutations have an internal tandem duplication of the juxta-membrane domain (FLT3/ITD), which results in chemotherapeutic resistance in acute myeloid leukemia and subsequent decreases in the progression-free survival of patients at 4 years relative to FLT3/wild-type patients (31% versus 55%).	('patients', 'Species', '9606', (242, 250))	('decreases', 'NegReg', (196, 205))	('FLT3', 'Gene', '2322', (274, 278))	('internal tandem duplication', 'Var', (41, 68))	('progression-free survival', 'CPA', (213, 238))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (158, 180))	('FLT3', 'Gene', '2322', (99, 103))	('FLT3', 'Gene', '2322', (13, 17))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (164, 180))	('mutations', 'Var', (23, 32))	('FLT3', 'Gene', (274, 278))	('acute myeloid leukemia', 'Disease', (158, 180))	('chemotherapeutic resistance', 'MPA', (127, 154))	('FLT3', 'Gene', (99, 103))	('FLT3', 'Gene', (13, 17))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (158, 180))	('patients', 'Species', '9606', (289, 297))
1253	27965469	Many studies have suggested that TAMs secreted proteins, including MMPs, plasmin, urokinase-type plasminogen activator, vascular endothelial growth factor (VEGF), interleukin (IL)-8, basic fibroblast growth factor (bFGF), thymidine phosphorylates, phosphatidylinositol-glycan biosynthesis class F protein, and gastrin-releasing peptide that can cause angiogenesis in tumor tissue.	('vascular endothelial growth factor', 'Gene', (120, 154))	('basic fibroblast growth factor', 'Gene', (183, 213))	('VEGF', 'Gene', (156, 160))	('MMPs', 'Gene', '4313;4318;4323', (67, 71))	('gastrin-releasing peptide', 'Gene', (310, 335))	('gastrin-releasing peptide', 'Gene', '2922', (310, 335))	('angiogenesis', 'CPA', (351, 363))	('interleukin (IL)-8', 'Gene', '3576', (163, 181))	('phosphatidylinositol-glycan', 'Var', (248, 275))	('urokinase-type plasminogen activator', 'Gene', (82, 118))	('bFGF', 'Gene', '2247', (215, 219))	('plasmin', 'Gene', (73, 80))	('thymidine', 'Chemical', 'MESH:D013936', (222, 231))	('plasmin', 'Gene', (97, 104))	('tumor', 'Disease', (367, 372))	('urokinase-type plasminogen activator', 'Gene', '5328', (82, 118))	('plasmin', 'Gene', '5340', (73, 80))	('plasmin', 'Gene', '5340', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('cause', 'Reg', (345, 350))	('interleukin (IL)-8', 'Gene', (163, 181))	('bFGF', 'Gene', (215, 219))	('MMPs', 'Gene', (67, 71))	('vascular endothelial growth factor', 'Gene', '7422', (120, 154))	('basic fibroblast growth factor', 'Gene', '2247', (183, 213))	('glycan', 'Chemical', 'MESH:D011134', (269, 275))	('TAMs', 'Chemical', '-', (33, 37))	('VEGF', 'Gene', '7422', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))
1286	27965469	Overexpression of Wnt ligands has also been reported to result in a feed forward cycle of the Wnt-FGF signaling pathway, which likely induces EMT and invasion by controlling SNAI1, SNAI2, ZEB1, and ZEB2 at the transcriptional or posttranslational level.	('EMT', 'CPA', (142, 145))	('SNAI2', 'Gene', '6591', (181, 186))	('Wnt-FGF signaling pathway', 'Pathway', (94, 119))	('SNAI2', 'Gene', (181, 186))	('ZEB2', 'Gene', (198, 202))	('ZEB1', 'Gene', (188, 192))	('SNAI1', 'Gene', '6615', (174, 179))	('invasion', 'CPA', (150, 158))	('ZEB1', 'Gene', '6935', (188, 192))	('Overexpression', 'Var', (0, 14))	('feed forward cycle', 'MPA', (68, 86))	('SNAI1', 'Gene', (174, 179))	('ZEB2', 'Gene', '9839', (198, 202))	('induces', 'PosReg', (134, 141))	('result in', 'Reg', (56, 65))
1288	27965469	Although many therapeutic approaches have focused on inhibition of secretory proteins to reduce resistance of cancer cells, it is necessary to understand the crosstalk between downstream signaling pathways and functionally active factors to fundamentally overcome the occurrence of resistance.	('inhibition', 'Var', (53, 63))	('cancer', 'Disease', (110, 116))	('secretory', 'Protein', (67, 76))	('reduce', 'NegReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
1314	27965469	For example, preclinical models of melanoma revealed that loss of PTEN promoted immune resistance, while combinational treatment with PI3K-AKT pathway inhibitors alleviated the resistance.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('immune resistance', 'CPA', (80, 97))	('PTEN', 'Gene', (66, 70))	('promoted', 'PosReg', (71, 79))	('loss', 'Var', (58, 62))	('PTEN', 'Gene', '5728', (66, 70))	('AKT', 'Gene', '207', (139, 142))	('AKT', 'Gene', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
1324	27965469	Moreover, MSCs infiltrating into prostate cancer were found to increase the cancer stem cell population and metastasis through upregulation of zinc finger E-box binding homeobox 1, Snail, CXC chemokine receptor 4, and MMP9 via the CCL5-androgen receptor signaling pathway.	('increase', 'PosReg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('upregulation', 'PosReg', (127, 139))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('CCL5', 'Gene', '6352', (231, 235))	('zinc finger E-box binding homeobox 1', 'Gene', '6935', (143, 179))	('zinc finger E-box binding homeobox 1', 'Gene', (143, 179))	('Snail', 'Gene', '6615', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('prostate cancer', 'Disease', (33, 48))	('CCL5', 'Gene', (231, 235))	('MMP9', 'Gene', '4318', (218, 222))	('MMP9', 'Gene', (218, 222))	('cancer', 'Disease', (76, 82))	('CXC chemokine receptor 4', 'MPA', (188, 212))	('Snail', 'Gene', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MSCs', 'Var', (10, 14))	('cancer', 'Disease', (42, 48))
1325	27965469	MSCs were also shown to influence the characteristics of the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('influence', 'Reg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MSCs', 'Var', (0, 4))	('tumor', 'Disease', (61, 66))
1338	27965469	A previous study demonstrated that a small portion of cells in glioblastoma multiforme expressing mutated EGFR were able to expand the entire tumor cell population via a paracrine mechanism to eventually maintain tumor heterogeneity.	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (63, 86))	('maintain', 'Reg', (204, 212))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('glioblastoma multiforme', 'Disease', (63, 86))	('EGFR', 'Gene', '1956', (106, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('mutated', 'Var', (98, 105))	('expand', 'PosReg', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('EGFR', 'Gene', (106, 110))
1343	27965469	It has been reported that some human gastric carcinoma cells express VEGF-C, and that cells treated with recombinant VEGF-C showed increased expression of placental growth factor and autocrine motility factor.	('gastric carcinoma', 'Disease', (37, 54))	('VEGF-C', 'Gene', (69, 75))	('increased', 'PosReg', (131, 140))	('human', 'Species', '9606', (31, 36))	('placental', 'Protein', (155, 164))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (37, 54))	('expression', 'MPA', (141, 151))	('gastric carcinoma', 'Disease', 'MESH:D013274', (37, 54))	('VEGF-C', 'Var', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
1382	27965469	Moreover, inhibitors of Raf, MEK, and ERK effectively downregulated expression of multiple drug resistance protein, multidrug resistance-related protein, and lung resistance protein.	('MEK', 'Gene', '5609', (29, 32))	('ERK', 'Gene', '5594', (38, 41))	('multidrug resistance-related protein', 'Gene', (116, 152))	('expression', 'MPA', (68, 78))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('multidrug resistance-related protein', 'Gene', '84798', (116, 152))	('multiple drug', 'MPA', (82, 95))	('Raf', 'Gene', (24, 27))	('lung', 'MPA', (158, 162))	('inhibitors', 'Var', (10, 20))	('drug resistance', 'Phenotype', 'HP:0020174', (91, 106))	('downregulated', 'NegReg', (54, 67))	('ERK', 'Gene', (38, 41))	('MEK', 'Gene', (29, 32))
1400	27148534	Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('resveratrol', 'Chemical', 'MESH:D000077185', (143, 154))	('5-fluoruracyl', 'Chemical', '-', (114, 127))	('Resveratrol', 'Chemical', 'MESH:D000077185', (0, 11))	('cancer', 'Disease', (232, 238))	('increasing', 'PosReg', (195, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('resveratrol', 'Var', (143, 154))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))
1430	27148534	When tested on the positive ovarian cell line and at high concentrations, in particular, resveratrol and polydatin (but not acetyl-resveratrol) significantly reduced the phosphorylation of Her-2 and EGF-R, and decreased the expression of extracellular-signal-regulated kinases (ERK) and vascular endothelial growth factor (VEGF).	('resveratrol', 'Chemical', 'MESH:D000077185', (89, 100))	('Her-2', 'Gene', (189, 194))	('polydatin', 'Chemical', 'MESH:C058229', (105, 114))	('rat', 'Species', '10116', (94, 97))	('vascular endothelial growth factor', 'Pathway', (287, 321))	('EGF-R', 'Gene', '1956', (199, 204))	('decreased', 'NegReg', (210, 219))	('Her-2', 'Gene', '2064', (189, 194))	('expression', 'MPA', (224, 234))	('resveratrol', 'Chemical', 'MESH:D000077185', (131, 142))	('acetyl-resveratrol', 'Chemical', '-', (124, 142))	('polydatin', 'Var', (105, 114))	('EGF-R', 'Gene', (199, 204))	('rat', 'Species', '10116', (136, 139))	('ases', 'Chemical', '-', (272, 276))	('reduced', 'NegReg', (158, 165))	('phosphorylation', 'MPA', (170, 185))	('rat', 'Species', '10116', (65, 68))
1506	27148534	Taken together, findings suggest that the modulation of p53 by SIRT1 could be a possible target to attenuate cisplatin-induced kidney injury.	('p53', 'Protein', (56, 59))	('modulation', 'Var', (42, 52))	('kidney injury', 'Disease', 'MESH:D058186', (127, 140))	('kidney injury', 'Disease', (127, 140))	('cisplatin-induced', 'MPA', (109, 126))	('SIRT1', 'Gene', (63, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('attenuate', 'NegReg', (99, 108))
1513	27148534	When tested on osteosarcoma cells, resveratrol reduced their in vitro migration and invasion through transcriptional and epigenetic regulation of MMP-2; this finding was corroborated by in vivo experiments, which observed a decreased incidence of lung metastasis.	('invasion', 'CPA', (84, 92))	('MMP-2', 'Gene', '4313', (146, 151))	('rat', 'Species', '10116', (177, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (20, 27))	('in vitro migration', 'CPA', (61, 79))	('resveratrol', 'Chemical', 'MESH:D000077185', (35, 46))	('MMP-2', 'Gene', (146, 151))	('rat', 'Species', '10116', (40, 43))	('rat', 'Species', '10116', (73, 76))	('men', 'Species', '9606', (200, 203))	('lung metastasis', 'Disease', (247, 262))	('osteosarcoma', 'Disease', (15, 27))	('lung metastasis', 'Disease', 'MESH:D009362', (247, 262))	('osteosarcoma', 'Phenotype', 'HP:0002669', (15, 27))	('reduced', 'NegReg', (47, 54))	('epigenetic regulation', 'Var', (121, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (15, 27))
1528	27148534	Considering human biopsies of cervical cancer, the immunohistochemical staining on tissue microarrays revealed significantly higher frequencies of Notch1, Notch2, Hes1, Wnt2, Wnt5a, p-STAT3, and beta-catenin nuclear translocation than in healthy controls.	('Notch2', 'Gene', '4853', (155, 161))	('Wnt2', 'Gene', (169, 173))	('Notch1', 'Gene', (147, 153))	('cervical cancer', 'Disease', (30, 45))	('cervical cancer', 'Disease', 'MESH:D002583', (30, 45))	('Wnt5a', 'Gene', (175, 180))	('Hes1', 'Gene', '3280', (163, 167))	('beta-catenin', 'Gene', '1499', (195, 207))	('Wnt5a', 'Gene', '7474', (175, 180))	('Notch1', 'Gene', '4851', (147, 153))	('p-STAT3', 'Var', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Wnt2', 'Gene', '7472', (169, 173))	('higher', 'PosReg', (125, 131))	('human', 'Species', '9606', (12, 17))	('Notch2', 'Gene', (155, 161))	('beta-catenin', 'Gene', (195, 207))	('Hes1', 'Gene', (163, 167))
1552	27148534	Over-expression of Bcl-2 family proteins inhibits the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, which is a decisive event triggering apoptosis.	('inhibits', 'NegReg', (41, 49))	('cytochrome c', 'Gene', '54205', (65, 77))	('Bcl-2', 'Gene', '596', (19, 24))	('Bcl-2', 'Gene', (19, 24))	('Over-expression', 'Var', (0, 15))	('Bcl', 'Phenotype', 'HP:0012191', (19, 22))	('cytochrome c', 'Gene', (65, 77))
1563	27148534	Conversely, resveratrol downregulated the expression of antiapoptotic proteins, including Bcl-2, Bcl-XL, survivin, and XIAP Resveratrol had no effect, instead, on normal human prostate epithelial cells and also the ability of the phytochemical to sensitize TRAIL-resistant LNCaP cells was inhibited by the presence of dominant negative FADD, CASP-8 siRNA, or N-acetylcysteine.	('expression', 'MPA', (42, 52))	('Bcl-XL', 'Gene', '598', (97, 103))	('FADD', 'Gene', '8772', (336, 340))	('N-acetylcysteine', 'Var', (359, 375))	('Bcl-XL', 'Gene', (97, 103))	('downregulated', 'NegReg', (24, 37))	('Bcl', 'Phenotype', 'HP:0012191', (90, 93))	('Resveratrol', 'Chemical', 'MESH:D000077185', (124, 135))	('inhibited', 'NegReg', (289, 298))	('CASP-8', 'Gene', (342, 348))	('Bcl-2', 'Gene', (90, 95))	('LNCaP', 'CellLine', 'CVCL:0395', (273, 278))	('Bcl', 'Phenotype', 'HP:0012191', (97, 100))	('FADD', 'Gene', (336, 340))	('Bcl-2', 'Gene', '596', (90, 95))	('resveratrol', 'Chemical', 'MESH:D000077185', (12, 23))	('human', 'Species', '9606', (170, 175))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (359, 375))	('CASP-8', 'Gene', '841', (342, 348))
1601	27148534	Therefore, resveratrol and DHT are both transducer, following the pathway of activated MAPK ERK1/2, but DHT enhances cell proliferation in cancer cells, while resveratrol promotes apoptosis.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('DHT', 'Chemical', 'MESH:D013196', (104, 107))	('resveratrol', 'Chemical', 'MESH:D000077185', (11, 22))	('rat', 'Species', '10116', (16, 19))	('rat', 'Species', '10116', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('MAPK', 'Gene', '5595;5594;5595', (87, 91))	('resveratrol', 'Chemical', 'MESH:D000077185', (159, 170))	('MAPK', 'Gene', (87, 91))	('ERK1/2', 'Gene', (92, 98))	('DHT', 'Var', (104, 107))	('rat', 'Species', '10116', (164, 167))	('ERK1/2', 'Gene', '5595;5594', (92, 98))	('apoptosis', 'CPA', (180, 189))	('enhances', 'PosReg', (108, 116))	('DHT', 'Chemical', 'MESH:D013196', (27, 30))	('cancer', 'Disease', (139, 145))
1603	27148534	In MCF-7 breast cancer, as a result, DHT inhibited several resveratrol-stimulated effects: (i) phosphorylation of Ser-15 of p53, (ii) COX-2/p53-dependent gene expression and nuclear complex of p53-COX-2 formation, essential for p53-dependent apoptosis, and (iii) p53-directed transcriptional activity.	('DHT', 'Var', (37, 40))	('resveratrol', 'Chemical', 'MESH:D000077185', (59, 70))	('p53-directed', 'CPA', (263, 275))	('Ser', 'Chemical', 'MESH:D012694', (114, 117))	('DHT', 'Chemical', 'MESH:D013196', (37, 40))	('COX-2', 'Gene', (197, 202))	('phosphorylation of', 'MPA', (95, 113))	('COX-2', 'Gene', (134, 139))	('COX-2', 'Gene', '5743', (197, 202))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (3, 22))	('MCF-7 breast cancer', 'Disease', (3, 22))	('inhibited', 'NegReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('COX-2', 'Gene', '5743', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))
1613	27148534	Resveratrol blocked the proliferation of both parental CRC cell lines (HCT116 and SW480) and their corresponding isogenic 5-FLU-chemoresistant derived clones (HCT116R and SW480R), synergizing the inhibitory effects of 5-FLU against cell invasion.	('SW480', 'CellLine', 'CVCL:0546', (171, 176))	('SW480', 'CellLine', 'CVCL:0546', (82, 87))	('proliferation', 'CPA', (24, 37))	('5-FLU', 'Chemical', '-', (218, 223))	('blocked', 'NegReg', (12, 19))	('Resveratrol', 'Chemical', 'MESH:D000077185', (0, 11))	('SW480R', 'Var', (171, 177))	('HCT116R', 'Var', (159, 166))	('rat', 'Species', '10116', (5, 8))	('5-FLU', 'Chemical', '-', (122, 127))	('HCT116', 'CellLine', 'CVCL:0291', (159, 165))	('cell invasion', 'CPA', (232, 245))	('rat', 'Species', '10116', (31, 34))	('HCT116', 'CellLine', 'CVCL:0291', (71, 77))
1625	27148534	Resveratrol and As2O3 caused more genotoxicity and oxidative stress than the single agent, synergistically increasing the release of cytochrome c, the expressions of Fas and FasL, and apoptotic cell death via the induction of oxidative stress.	('Fas', 'Protein', (166, 169))	('apoptotic cell death', 'CPA', (184, 204))	('Resveratrol', 'Chemical', 'MESH:D000077185', (0, 11))	('FasL', 'Gene', (174, 178))	('FasL', 'Gene', '356', (174, 178))	('oxidative stress', 'Phenotype', 'HP:0025464', (226, 242))	('expressions', 'MPA', (151, 162))	('toxicity', 'Disease', 'MESH:D064420', (38, 46))	('toxicity', 'Disease', (38, 46))	('As2O3', 'Var', (16, 21))	('As2O3', 'Chemical', 'MESH:D000077237', (16, 21))	('cytochrome c', 'Gene', (133, 145))	('oxidative stress', 'Phenotype', 'HP:0025464', (51, 67))	('increasing', 'PosReg', (107, 117))	('oxidative stress', 'CPA', (51, 67))	('cytochrome c', 'Gene', '54205', (133, 145))
1718	27047250	miR-21 and miR15b may represent an therapeutic target to control multiple steps of pathogenesis; for example, the inhibition of miR-21 in glioblastoma cells increased apoptosis, while in cultured hepatocellular carcinoma cells significantly led to decrease of tumor cell proliferation, migration and invasion.	('tumor', 'Disease', (260, 265))	('migration', 'CPA', (286, 295))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('miR-21', 'Gene', (0, 6))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('inhibition', 'Var', (114, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (196, 220))	('glioblastoma', 'Disease', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('miR-21', 'Gene', '406991', (128, 134))	('hepatocellular carcinoma', 'Disease', (196, 220))	('decrease', 'NegReg', (248, 256))	('miR-21', 'Gene', '406991', (0, 6))	('miR15b', 'Gene', '406949', (11, 17))	('apoptosis', 'CPA', (167, 176))	('miR15b', 'Gene', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('miR-21', 'Gene', (128, 134))	('increased', 'PosReg', (157, 166))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (196, 220))	('invasion', 'CPA', (300, 308))
1732	27047250	In the gut mucosa homeostasis, comparative analysis of miRNA expression of germ-free mice and mice colonized with the microbiota from pathogen-free mice identified 9 miRNAs differentially expressed: miR-298 (ileum) and miR-128, miR-200c, miR-665, microR-465c-5p, miR-342-5p, miR-466d-3p, miR-466d- 5p and miR-68 (colon).	('miR-68', 'Var', (305, 311))	('mice', 'Species', '10090', (148, 152))	('colon', 'Disease', (313, 318))	('mice', 'Species', '10090', (94, 98))	('colon', 'Disease', 'MESH:D015179', (99, 104))	('mice', 'Species', '10090', (85, 89))	('colon', 'Disease', (99, 104))	('miR-200c', 'Gene', (228, 236))	('miR-665', 'Gene', '751555', (238, 245))	('miR-466d- 5p', 'Var', (288, 300))	('miR-665', 'Gene', (238, 245))	('miR-298', 'Gene', '723832', (199, 206))	('miR-342-5p', 'Var', (263, 273))	('miR-298', 'Gene', (199, 206))	('miR-128', 'Var', (219, 226))	('microR-465c-5p', 'Var', (247, 261))	('miR-200c', 'Gene', '723944', (228, 236))	('miR-466d-3p', 'Var', (275, 286))	('colon', 'Disease', 'MESH:D015179', (313, 318))
1837	23857604	We tested the preclinical efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt (583-637 AAs) and EGFRvIII (292-346 AAs) proteins.	('D2C7', 'Chemical', '-', (67, 71))	('D2C7-', 'Var', (67, 72))	('tested', 'Reg', (3, 9))
1839	23857604	In vitro cytotoxicity of D2C7-(scdsFv)-PE38KDEL was measured by protein synthesis inhibition in human EGFRwt-transfected NR6 (NR6W), human EGFRvIII-transfected NR6 (NR6M), EGFRwt-overexpressing A431-epidermoid-carcinoma, and glioblastoma xenograft cells (43, D08-0493MG, D2159MG and D270MG).	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('D2159MG', 'Var', (271, 278))	('D270MG', 'Var', (283, 289))	('glioblastoma', 'Phenotype', 'HP:0012174', (225, 237))	('human', 'Species', '9606', (96, 101))	('A431-epidermoid-carcinoma', 'Disease', 'MESH:D002294', (194, 219))	('D2C7', 'Chemical', '-', (25, 29))	('protein synthesis', 'MPA', (64, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (9, 21))	('inhibition', 'NegReg', (82, 92))	('A431-epidermoid-carcinoma', 'Disease', (194, 219))	('D2C7-', 'Var', (25, 30))	('human', 'Species', '9606', (133, 138))	('cytotoxicity', 'Disease', (9, 21))	('glioblastoma', 'Disease', (225, 237))	('glioblastoma', 'Disease', 'MESH:D005909', (225, 237))
1840	23857604	In vivo anti-tumor efficacy of D2C7-(scdsFv)-PE38KDEL was evaluated with 43, NR6M, and D270MG orthotopic tumor models.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('D2C7', 'Chemical', '-', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('D2C7-', 'Var', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (105, 110))
1843	23857604	The D2C7-(scdsFv)-PE38KDEL IC50 was 0.18-2.5 ng/ml on cells expressing EGFRwt (NR6W, A431, 43, and D08-0493MG).	('D2C7', 'Chemical', '-', (4, 8))	('A431', 'CellLine', 'CVCL:0037', (85, 89))	('D08-0493MG', 'Var', (99, 109))	('D2C7-', 'Var', (4, 9))
1844	23857604	The D2C7-(scdsFv)-PE38KDEL IC50 was  0.25 ng/ml on EGFRvIII-expressing cells (NR6M) and on EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells (D2159MG and D270MG).	('glioblastoma', 'Disease', (123, 135))	('D2C7', 'Chemical', '-', (4, 8))	('D2C7-', 'Var', (4, 9))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))
1845	23857604	Significantly, in intracranial tumor models of 43, NR6M, and D270MG, D2C7-(scdsFv)-PE38KDEL treatment by convection-enhanced delivery (CED) prolonged survival by 310% (P=0.006), 28% (P=0.002), and 166% (P=0.001), respectively.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('liver', 'Disease', 'MESH:D017093', (127, 132))	('prolonged', 'PosReg', (140, 149))	('survival', 'CPA', (150, 158))	('intracranial tumor', 'Disease', (18, 36))	('D270MG', 'Var', (61, 67))	('liver', 'Disease', (127, 132))	('D2C7', 'Chemical', '-', (69, 73))	('intracranial tumor', 'Disease', 'MESH:D001932', (18, 36))
1859	23857604	Several EGFR deletion mutants have been identified, the most common being EGFRvIII, which is present in 67% of glioblastomas with EGFRwt amplification.	('glioblastomas', 'Disease', (111, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('EGFRvIII', 'Gene', (74, 82))	('deletion', 'Var', (13, 21))	('glioblastomas', 'Phenotype', 'HP:0012174', (111, 124))	('EGFR', 'Gene', (8, 12))	('glioblastomas', 'Disease', 'MESH:D005909', (111, 124))
1860	23857604	EGFRvIII contains a deletion of exons 2-7 of the EGFR gene, and this in-frame deletion creates a novel glycine residue at the fusion junction at position 6, between amino acid residues 5 and 274, generating a tumor-specific epitope that is expressed specifically on tumor cells, but not on normal tissues.	('tumor', 'Disease', (209, 214))	('EGFR', 'Gene', (49, 53))	('glycine', 'Chemical', 'MESH:D005998', (103, 110))	('deletion', 'Var', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('deletion', 'Var', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('epitope', 'MPA', (224, 231))	('tumor', 'Disease', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
1870	23857604	Due to the high prevalence of EGFRvIII mutation in tumors that have EGFRwt amplification, it would be advantageous to have antibodies that could target both antigens for glioblastoma therapy.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutation', 'Var', (39, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('EGFRvIII', 'Gene', (30, 38))	('glioblastoma', 'Disease', (170, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (170, 182))
1871	23857604	Co-targeting these two antigens could promote greater killing of tumor cells than that which is achieved by antibodies specific for a single antigen.	('tumor', 'Disease', (65, 70))	('killing', 'CPA', (54, 61))	('Co-targeting', 'Var', (0, 12))	('promote', 'PosReg', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
1874	23857604	In comparison to the established specific mAbs (anti-EGFRwt mAb, EGFR1 or anti-EGFRvIII mAb, L8A4), D2C7 demonstrated a significantly higher tumor localization in tumors expressing EGFRwt or EGFRvIII proteins.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('higher', 'PosReg', (134, 140))	('D2C7', 'Chemical', '-', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('D2C7', 'Var', (100, 104))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))
1875	23857604	Significantly, in immunohistochemical analysis of 101 adult glioblastoma samples, the D2C7 mAb positively stained virtually all cells in 100% (50/50) of the samples that had amplification of the EGFRwt gene and in 76% (39/51) of the cases without this amplification.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('amplification', 'Var', (174, 187))	('D2C7', 'Chemical', '-', (86, 90))	('EGFRwt', 'Gene', (195, 201))
1876	23857604	Here, we summarize the in vitro and in vivo results of our investigation of D2C7-(scdsFv)-PE38KDEL, a recombinant scFv IT that binds to both EGFRwt and EGFRvIII and has potential clinical application for the therapy of brain tumors expressing these proteins.	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('brain tumors', 'Disease', 'MESH:D001932', (219, 231))	('brain tumors', 'Phenotype', 'HP:0030692', (219, 231))	('scFv', 'Gene', '652070', (114, 118))	('D2C7', 'Chemical', '-', (76, 80))	('brain tumor', 'Phenotype', 'HP:0030692', (219, 230))	('D2C7-', 'Var', (76, 81))	('scFv', 'Gene', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('brain tumors', 'Disease', (219, 231))	('binds', 'Interaction', (127, 132))
1883	23857604	Xenograft tissue derived from glioblastoma samples D270MG (expressing EGFRwt and EGFRvIII), D2159MG (expressing EGFRwt and EGFRvIII), 43 (expressing EGFRwt) (kindly provided by Dr. C. David James, University of California, San Francisco), and D08-0493MG (expressing EGFRwt), was finely minced and digested with 100 mug Liberase (Roche, Indianapolis, IN) at 37 C for 10 min.	('glioblastoma', 'Disease', (30, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (30, 42))	('D08-0493MG', 'Var', (243, 253))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('D2159MG', 'Var', (92, 99))	('D270MG', 'Var', (51, 57))
1886	23857604	D2C7 and P588 ITs were generated by fusing the specific scFv with the sequences for domains II and III of Pseudomonas exotoxin A (PE38) according to the protocol described in a previous publication.	('P588', 'Var', (9, 13))	('scFv', 'Gene', '652070', (56, 60))	('scFv', 'Gene', (56, 60))	('D2C7', 'Chemical', '-', (0, 4))
1894	23857604	The cytotoxicity of the ITs on cultured cell lines (NR6W, NR6M, and A431) and cells freshly isolated from glioblastoma xenografts (43, D08-0493MG, D270MG, and D2159MG) was assayed by inhibition of protein synthesis as described in an earlier study.	('inhibition', 'NegReg', (183, 193))	('protein synthesis', 'MPA', (197, 214))	('D2159MG', 'Var', (159, 166))	('cytotoxicity', 'Disease', (4, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('glioblastoma xenografts', 'Disease', (106, 129))	('glioblastoma xenografts', 'Disease', 'MESH:D005909', (106, 129))	('A431', 'CellLine', 'CVCL:0037', (68, 72))	('D270MG', 'Var', (147, 153))	('43', 'Var', (131, 133))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
1898	23857604	One microgram of D2C7-(scdsFv)-PE38KDEL or P588-(scdsFv)-PE38KDEL diluted in 100 mul of 0.2% PBS-HSA was delivered via alzet osmotic mini pumps (Durect Corporation, Cupertino, California) over a three day (43 xenograft) or seven day (NR6M and D270MG) period.	('D2C7', 'Chemical', '-', (17, 21))	('liver', 'Disease', 'MESH:D017093', (107, 112))	('D2C7-', 'Var', (17, 22))	('liver', 'Disease', (107, 112))	('HSA', 'Chemical', 'MESH:D006585', (97, 100))	('PBS', 'Chemical', 'MESH:D007854', (93, 96))
1902	23857604	Since several EGFR deletion mutants have been described in gliomas, determining the epitope of D2C7 on EGFRwt/EGFRvIII will aid in the identification of specific EGFR mutations that could be therapeutically targeted with the D2C7 mAb.	('mutants', 'Var', (28, 35))	('deletion mutants', 'Var', (19, 35))	('EGFR', 'Gene', (14, 18))	('D2C7', 'Chemical', '-', (95, 99))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('D2C7', 'Chemical', '-', (225, 229))	('gliomas', 'Disease', (59, 66))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
1903	23857604	Accordingly, several deletion mutants of human EGFRvIII extracellular domain (ECD) were generated.	('EGFRvIII', 'Gene', (47, 55))	('human', 'Species', '9606', (41, 46))	('deletion mutants', 'Var', (21, 37))
1905	23857604	Further deletions of the EGFRvIII ECD peptide fragment CT 287-356 amino acids demonstrated strong reactivity of D2C7 to CT 292-346 amino acids and a weak reactivity to CT 295-345 amino acids (Fig.	('D2C7', 'Chemical', '-', (112, 116))	('reactivity', 'MPA', (98, 108))	('EGFRvIII', 'Gene', (25, 33))	('deletions', 'Var', (8, 17))	('reactivity', 'MPA', (154, 164))
1910	23857604	This was achieved by mutating a single key residue in each chain to cysteine for the stabilizing disulfide bond to form.	('disulfide', 'Chemical', 'MESH:D004220', (97, 106))	('mutating', 'Var', (21, 29))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('stabilizing disulfide bond', 'MPA', (85, 111))
1912	23857604	Thus, we prepared an Fv containing both a peptide linker and a disulfide bond generated by cysteine residues that replace Ser44 of VH and Gly100 of VL.	('disulfide', 'Chemical', 'MESH:D004220', (63, 72))	('Ser44', 'Var', (122, 127))	('cysteine', 'Chemical', 'MESH:D003545', (91, 99))	('Ser44', 'Chemical', '-', (122, 127))	('Gly100', 'Chemical', '-', (138, 144))	('Gly100', 'Var', (138, 144))
1914	23857604	The Pseudomonas exotoxin A version used here, PE38KDEL, has a modified C-terminus that increases its intracellular retention, thereby enhancing its cytotoxicity.	('enhancing', 'PosReg', (134, 143))	('increases', 'PosReg', (87, 96))	('cytotoxicity', 'Disease', 'MESH:D064420', (148, 160))	('PE38KDEL', 'Var', (46, 54))	('cytotoxicity', 'Disease', (148, 160))	('intracellular retention', 'MPA', (101, 124))
1918	23857604	The D2C7-(scdsFv)-PE38KDEL bound to both the EGFRwt- and the EGFRvIII-ECD-protein-coated chips.	('D2C7', 'Chemical', '-', (4, 8))	('bound', 'Interaction', (27, 32))	('D2C7-', 'Var', (4, 9))
1920	23857604	Thus, the cloned D2C7-(scdsFv)-PE38KDEL IT bound with similar kinetics to both the wild-type and the mutant EGFR proteins.	('D2C7-', 'Var', (17, 22))	('bound', 'Interaction', (43, 48))	('D2C7', 'Chemical', '-', (17, 21))
1922	23857604	FACS analysis revealed that the D2C7-(scdsFv)-PE38KDEL bound to both the EGFRwt-expressing NR6W cells (Fig.	('bound', 'Interaction', (55, 60))	('D2C7', 'Chemical', '-', (32, 36))	('D2C7-', 'Var', (32, 37))
1924	23857604	These results demonstrate that the D2C7-(scdsFv)-PE38KDEL IT binds to both purified EGFRwt and EGFRvIII proteins on a chip and to native protein molecules expressed on transfected cells.	('D2C7-', 'Var', (35, 40))	('binds', 'Interaction', (61, 66))	('D2C7', 'Chemical', '-', (35, 39))
1926	23857604	The ability of the D2C7-(scdsFv)-PE38KDEL to inhibit protein synthesis was used as a measure of its cytotoxic effect.	('inhibit', 'NegReg', (45, 52))	('D2C7-', 'Var', (19, 24))	('protein synthesis', 'MPA', (53, 70))	('D2C7', 'Chemical', '-', (19, 23))
1933	23857604	Freshly isolated cells from glioblastoma xenografts, 43 and D08-0493MG express EGFRwt protein and D2159MG and D270MG express both EGFRwt and EGFRvIII proteins.	('glioblastoma xenografts', 'Disease', (28, 51))	('D08-0493MG', 'Var', (60, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('D2159MG', 'Var', (98, 105))	('glioblastoma xenografts', 'Disease', 'MESH:D005909', (28, 51))	('D270MG', 'Var', (110, 116))
1934	23857604	Prominently, FACS analysis demonstrated the co-expression of cancer stem cell marker CD133 and D2C7 on 71% and 86% of cells from glioblastoma xenografts 43 and D2159MG, respectively (Supplementary Fig.	('D2C7', 'Gene', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('D2C7', 'Chemical', '-', (95, 99))	('glioblastoma xenografts', 'Disease', 'MESH:D005909', (129, 152))	('cancer', 'Disease', (61, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('glioblastoma xenografts', 'Disease', (129, 152))	('CD133', 'Gene', (85, 90))	('D2159MG', 'Var', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
1940	23857604	Since the EGFRvIII mutation is most frequently reported in glioblastomas with EGFR amplification, there is no true glioblastoma xenograft that expresses EGFRvIII only.	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('mutation', 'Var', (19, 27))	('amplification', 'Var', (83, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (59, 72))	('glioblastomas', 'Disease', 'MESH:D005909', (59, 72))	('glioblastoma', 'Disease', (59, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('EGFR', 'Gene', (78, 82))	('glioblastomas', 'Disease', (59, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))	('EGFRvIII', 'Gene', (10, 18))	('reported', 'Reg', (47, 55))	('glioblastoma', 'Disease', (115, 127))
1942	23857604	S7c) demonstrated that 100% death occurred at day 18, day 15, and day 36 post-tumor implantation for 43, NR6M, and D270MG, respectively.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('death', 'Disease', 'MESH:D003643', (28, 33))	('death', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('D270MG', 'Var', (115, 121))	('NR6M', 'Var', (105, 109))
1944	23857604	Further, toxicity studies in NSG mice with different concentrations of the D2C7-(scdsFv)-PE38KDEL (1-10 mug/100 mul) demonstrated that, 1 mug of D2C7-(scdsFv)-PE38KDEL had no toxicity-associated mortality (Supplementary Fig.	('toxicity', 'Disease', 'MESH:D064420', (175, 183))	('D2C7', 'Chemical', '-', (75, 79))	('toxicity', 'Disease', (175, 183))	('mice', 'Species', '10090', (33, 37))	('D2C7-', 'Var', (145, 150))	('toxicity', 'Disease', 'MESH:D064420', (9, 17))	('toxicity', 'Disease', (9, 17))	('D2C7', 'Chemical', '-', (145, 149))
1946	23857604	Four out of ten 43 tumor-bearing mice in the D2C7-(scdsFv)-PE38KDEL treatment group were still alive at the termination of the study.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('D2C7', 'Chemical', '-', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Disease', (19, 24))	('D2C7-', 'Var', (45, 50))
1949	23857604	Notably, 8/10 of the D270MG tumor-bearing mice in the D2C7-(scdsFv)-PE38KDEL treatment group were still healthy and alive at the termination of the study.	('tumor', 'Disease', (28, 33))	('D2C7-', 'Var', (54, 59))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('D270MG', 'Var', (21, 27))	('D2C7', 'Chemical', '-', (54, 58))
1950	23857604	Sufficiently high concentrations of D2C7-(scdsFv)-PE38KDEL in the tumor area are achieved by CED.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('D2C7-', 'Var', (36, 41))	('tumor', 'Disease', (66, 71))	('D2C7', 'Chemical', '-', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
1951	23857604	However, the anti-tumor efficacy of D2C7-(scdsFv)-PE38KDEL depends on its homogenous distribution within the tumor area.	('D2C7-', 'Var', (36, 41))	('D2C7', 'Chemical', '-', (36, 40))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
1953	23857604	Tumor sections from the D270MG-sham group and the D270MG-D2C7-(scdsFv)-PE38KDEL group were used as the negative control (Supplementary Fig.	('D270MG-sham', 'Var', (24, 35))	('D270MG-D2C7-', 'Var', (50, 62))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('D2C7', 'Chemical', '-', (57, 61))
1954	23857604	The D270MG-D2C7-(scdsFv)-PE38KDEL group, pre-stained with D2C7-(scdsFv)-PE38KDEL, served as the positive control (Supplementary Fig.	('D270MG-D2C7-', 'Var', (4, 16))	('D2C7', 'Chemical', '-', (58, 62))	('D2C7', 'Chemical', '-', (11, 15))	('D2C7-', 'Var', (58, 63))
1957	23857604	One such antibody, D2C7, recognizes both the EGFRwt and the mutant EGFRvIII, two proteins that are overexpressed in glioblastoma.	('glioblastoma', 'Disease', (116, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('EGFRvIII', 'Gene', (67, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('mutant', 'Var', (60, 66))	('D2C7', 'Chemical', '-', (19, 23))
1960	23857604	Due to the prevalence of different EGFR deletion mutants in glioblastoma, we deemed it necessary to identify the epitope for D2C7 on its target EGFRwt/EGFRvIII proteins.	('glioblastoma', 'Disease', (60, 72))	('deletion mutants', 'Var', (40, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('mutants', 'Var', (49, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('EGFR', 'Gene', (35, 39))	('D2C7', 'Chemical', '-', (125, 129))
1961	23857604	The 55 amino acid D2C7 epitope (EGFRwt 583-637 amino acids) is known to be present in EGFR deletion mutants C-958, Delta959-1030, Delta6-185, I, III- VII, thereby increasing the number of antigenic targets for D2C7.	('Delta959', 'Mutation', 'c.del959', (115, 123))	('D2C7', 'Chemical', '-', (18, 22))	('D2C7', 'Gene', (18, 22))	('EGFR', 'Gene', (86, 90))	('D2C7', 'Chemical', '-', (210, 214))	('Delta959-1030', 'Var', (115, 128))	('deletion mutants C-958', 'Var', (91, 113))	('C-958', 'Var', (108, 113))	('increasing', 'PosReg', (163, 173))	('Delta6-185', 'Var', (130, 140))
1963	23857604	The in vitro cytotoxicity data showed that D2C7-(scdsFv)-PE38KDEL effectively inhibits protein synthesis in a variety of EGFRwt- or EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell line.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('D2C7', 'Chemical', '-', (43, 47))	('D2C7-', 'Var', (43, 48))	('cytotoxicity', 'Disease', (13, 25))	('glioblastoma', 'Disease', (164, 176))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('human', 'Species', '9606', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cytotoxicity', 'Disease', 'MESH:D064420', (13, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('inhibits', 'NegReg', (78, 86))	('protein synthesis', 'MPA', (87, 104))
1964	23857604	Notably, in the intracranial animal models of EGFRwt-expressing glioma xenograft 43, EGFRvIII-expressing NR6M, and EGFRwt- and EGFRvIII-expressing glioblastoma xenograft D270MG, D2C7-(scdsFv)-PE38KDEL demonstrated significant increase in survival, 310% (P=0.006), 28% (P=0.002), and 166% (P=0.001), respectively.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('D270MG', 'Var', (170, 176))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('D2C7', 'Chemical', '-', (178, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('survival', 'CPA', (238, 246))	('glioma', 'Disease', (64, 70))	('increase', 'PosReg', (226, 234))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
1965	23857604	To the best of our knowledge, this is the first report demonstrating that an IT can target both the wild-type EGFR and the mutant EGFRvIII in glioma models.	('glioma', 'Disease', (142, 148))	('EGFR', 'Gene', (110, 114))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('EGFRvIII', 'Gene', (130, 138))	('mutant', 'Var', (123, 129))
1970	23857604	Further, D2C7-(scdsFv)-PE38KDEL inhibited protein synthesis at a concentration 160 times lower than MR1-1, an EGFRvIII-specific IT, in EGFRwt-expressing NR6W cells.	('inhibited', 'NegReg', (32, 41))	('D2C7', 'Chemical', '-', (9, 13))	('protein synthesis', 'MPA', (42, 59))	('D2C7-', 'Var', (9, 14))
1974	23857604	Further, the D2C7-(scdsFv)-PE38KDEL IT prolonged survival in in vivo tumor models with the 43 xenograft, NR6M, and D270MG xenograft.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('D2C7', 'Chemical', '-', (13, 17))	('tumor', 'Disease', (69, 74))	('survival', 'CPA', (49, 57))	('D2C7-', 'Var', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('D270MG', 'Var', (115, 121))	('prolonged', 'PosReg', (39, 48))
1975	23857604	Examination of brain sections from the 8 euthanized mice from the D270MG-D2C7-(scdsFv)-PE38KDEL treatment group by hematoxylin and eosin staining revealed no tumor cells in 8/8 mice.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('eosin', 'Chemical', 'MESH:D004801', (131, 136))	('mice', 'Species', '10090', (52, 56))	('D2C7', 'Chemical', '-', (73, 77))	('D270MG-D2C7-', 'Var', (66, 78))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mice', 'Species', '10090', (177, 181))	('hematoxylin', 'Chemical', 'MESH:D006416', (115, 126))
1979	23857604	Further, EGFR mutants form homo/heterodimers and currently available EGFR mAbs cetuximab, matuzumab, and panitumumab are unable to block activation of these dimers.	('mutants', 'Var', (14, 21))	('panitumumab', 'Chemical', 'MESH:D000077544', (105, 116))	('homo/heterodimers', 'MPA', (27, 44))	('EGFR', 'Gene', (9, 13))	('matuzumab', 'Chemical', 'MESH:C520777', (90, 99))	('form', 'Reg', (22, 26))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))
1980	23857604	Since the D2C7 epitope is present on a wide variety of these EGFR deletion mutants, D2C7-(scdsFv)-PE38KDEL treatment should prove efficacious for glioblastoma patients harboring these mutations.	('D2C7', 'Chemical', '-', (84, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('D2C7', 'Chemical', '-', (10, 14))	('glioblastoma', 'Disease', (146, 158))	('patients', 'Species', '9606', (159, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('deletion mutants', 'Var', (66, 82))	('EGFR', 'Gene', (61, 65))
1982	23857604	In the 43, NR6M, and D270MG models, D2C7-(scdsFv)-PE38KDEL was administered by continuous intracranial delivery through osmotic mini-pumps.	('liver', 'Disease', 'MESH:D017093', (105, 110))	('D2C7-', 'Var', (36, 41))	('liver', 'Disease', (105, 110))	('D270MG', 'Var', (21, 27))	('D2C7', 'Chemical', '-', (36, 40))
1985	23857604	D2C7-(scdsFv)-PE38KDEL might cause human skin and liver toxicity if the immunotoxin were administered by systemic injection.	('human skin', 'Disease', (35, 45))	('D2C7-', 'Var', (0, 5))	('human', 'Species', '9606', (35, 40))	('D2C7', 'Chemical', '-', (0, 4))	('liver toxicity', 'Disease', 'MESH:D056486', (50, 64))	('liver toxicity', 'Disease', (50, 64))	('cause', 'Reg', (29, 34))
1988	23857604	The in vitro internalization studies demonstrated rapid uptake of D2C7-(scdsFv)-PE38KDEL by NR6W and NR6M cells within 1-2 hours of treatment (data not shown).	('D2C7', 'Chemical', '-', (66, 70))	('D2C7-', 'Var', (66, 71))	('uptake', 'MPA', (56, 62))
1990	23857604	Moreover, our immunohistochemistry studies in the D270MG orthotopic model clearly demonstrate that homogenous distribution of the D2C7-(scdsFv)-PE38KDEL is essential to generating a significant anti-tumor response.	('tumor', 'Disease', (199, 204))	('D2C7', 'Chemical', '-', (130, 134))	('D2C7-', 'Var', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
1991	23857604	Consequently, tumor cells that failed to encounter D2C7-(scdsFv)-PE38KDEL might regrow and repopulate the tumor area.	('tumor', 'Disease', (14, 19))	('regrow', 'CPA', (80, 86))	('D2C7', 'Chemical', '-', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('D2C7-', 'Var', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (106, 111))
1997	23857604	In this regard, D2C7-(scdsFv)-PE38KDEL is a novel IT that can target both the EGFRwt and the EGFRvIII proteins that are frequently overexpressed in malignant gliomas.	('D2C7-', 'Var', (16, 21))	('D2C7', 'Chemical', '-', (16, 20))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('malignant gliomas', 'Disease', (148, 165))	('malignant gliomas', 'Disease', 'MESH:D005910', (148, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))
1998	23857604	Combination therapy using mAbs 528 and 806 demonstrated a significant decrease in tumor volume of xenografts expressing EGFRwt or EGFRvIII _ENREF_43.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('decrease', 'NegReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('EGFRvIII', 'Var', (130, 138))	('tumor', 'Disease', (82, 87))
2011	23857604	Successful imaging of the delivery of D2C7-(scdsFv)-PE38KDEL will greatly improve treatment efficacy.	('improve', 'PosReg', (74, 81))	('liver', 'Disease', 'MESH:D017093', (28, 33))	('D2C7', 'Chemical', '-', (38, 42))	('D2C7-', 'Var', (38, 43))	('treatment efficacy', 'CPA', (82, 100))	('liver', 'Disease', (28, 33))
2012	23857604	As discussed above, the high levels of homogeneous expression of the D2C7-(scdsFv)-PE38KDEL molecular targets, wild-type EGFR and EGFRvIII (both of which are major glioblastoma driver oncogenes), in more than 95% of newly diagnosed glioblastoma tumors also will improve D2C7-(scdsFv)-PE38KDEL efficacy over other immunotoxins previously used in glioblastoma clinical trials.	('D2C7-', 'Var', (270, 275))	('glioblastoma', 'Disease', (232, 244))	('glioblastoma', 'Phenotype', 'HP:0012174', (345, 357))	('glioblastoma tumors', 'Disease', (232, 251))	('glioblastoma', 'Disease', 'MESH:D005909', (232, 244))	('glioblastoma', 'Phenotype', 'HP:0012174', (232, 244))	('glioblastoma', 'Disease', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('D2C7', 'Chemical', '-', (69, 73))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (232, 251))	('improve', 'PosReg', (262, 269))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('D2C7', 'Chemical', '-', (270, 274))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('glioblastoma', 'Disease', (345, 357))	('glioblastoma', 'Disease', 'MESH:D005909', (345, 357))
2015	23857604	D2C7-(scdsFv)-PE38KDEL is a recombinant immunotoxin (IT), targeting both EGFRwt and the tumor-specific EGFRvIII.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('D2C7-', 'Var', (0, 5))	('D2C7', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
2016	23857604	We show that D2C7-(scdsFv)-PE38KDEL has significant anti-tumor activity due to its affinity for EGFRwt and EGFRvIII.	('D2C7', 'Chemical', '-', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('D2C7-', 'Var', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
2017	23857604	This IT is efficacious in in vitro cytotoxicity assays and in in vivo orthotopic models of glioblastoma xenograft cells that express EGFRwt, EGFRvIII, or both EGFRwt and EGFRvIII.	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('cytotoxicity', 'Disease', (35, 47))	('EGFRwt', 'Var', (133, 139))	('glioblastoma', 'Disease', (91, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (35, 47))
2018	23857604	The specificity and high binding affinity toward both targets indicate that D2C7-(scdsFv)-PE38KDEL is likely to show greater efficiency in treating brain tumors than monospecific therapeutics.	('brain tumors', 'Disease', (148, 160))	('brain tumor', 'Phenotype', 'HP:0030692', (148, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('binding', 'Interaction', (25, 32))	('brain tumors', 'Phenotype', 'HP:0030692', (148, 160))	('D2C7', 'Chemical', '-', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('D2C7-', 'Var', (76, 81))	('brain tumors', 'Disease', 'MESH:D001932', (148, 160))
2019	23857604	Funding has been awarded for Phase I and II clinical trials of D2C7-(scdsFv)-PE38KDEL in glioblastoma patients.	('glioblastoma', 'Disease', (89, 101))	('patients', 'Species', '9606', (102, 110))	('D2C7-', 'Var', (63, 68))	('D2C7', 'Chemical', '-', (63, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))
2022	23047291	Genome-wide association analysis using approximately 2.1 million quality controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (p < 10-8) with SNPs in the O6-methylguanine-DNA methyltransferase (MGMT) gene.	('O6-methylguanine-DNA methyltransferase', 'Gene', (202, 240))	('significant association', 'Reg', (150, 173))	('MGMT', 'Gene', '4255', (242, 246))	('MGMT', 'Gene', (242, 246))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (202, 240))	('SNPs', 'Var', (190, 194))
2023	23047291	We also demonstrate that the primary SNP in this region is significantly associated with differential gene expression of MGMT (p< 10-26) in LCLs, and differential methylation in glioblastoma samples from The Cancer Genome Atlas.	('differential', 'Var', (150, 162))	('MGMT', 'Gene', '4255', (121, 125))	('glioblastoma', 'Disease', (178, 190))	('MGMT', 'Gene', (121, 125))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('methylation', 'MPA', (163, 174))	('associated', 'Reg', (73, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('differential gene expression', 'MPA', (89, 117))	('LCL', 'Chemical', '-', (140, 143))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))
2058	23047291	Rs531572 was highly significantly associated with both IC50 values (p<10-6,4, Figure 3A) and MGMT transcript levels (p<10-25, Figure 3B) with the A allele associated with that higher IC50 values and greater MGMT transcript levels.	('associated', 'Reg', (34, 44))	('greater', 'PosReg', (199, 206))	('MGMT', 'Gene', '4255', (93, 97))	('Rs531572', 'Mutation', 'Rs531572', (0, 8))	('MGMT', 'Gene', (207, 211))	('MGMT', 'Gene', (93, 97))	('Rs531572', 'Var', (0, 8))	('MGMT', 'Gene', '4255', (207, 211))	('IC50 values', 'MPA', (55, 66))	('IC50 values', 'MPA', (183, 194))	('higher', 'PosReg', (176, 182))
2063	23047291	Association of the rs531572 SNP with the beta values over the first 4 methylation probes (A-D) indicate that this SNP is not associated with alteration of methylation in the promoter region of MGMT (p>0.05).	('MGMT', 'Gene', (193, 197))	('rs531572', 'Mutation', 'rs531572', (19, 27))	('MGMT', 'Gene', '4255', (193, 197))	('rs531572', 'Var', (19, 27))
2069	23047291	While the impact of SNPs has not been thoroughly examined, altered MGMT expression via promoter silencing has been observed.	('MGMT', 'Gene', '4255', (67, 71))	('MGMT', 'Gene', (67, 71))	('promoter silencing', 'Var', (87, 105))
2070	23047291	Methylation of CpG islands in MGMT has been associated with reduced DNA repair capacity.	('Methylation', 'Var', (0, 11))	('reduced', 'NegReg', (60, 67))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))	('DNA repair capacity', 'CPA', (68, 87))
2075	23047291	While these SNPs are not found in known MGMT promoter regions, these variants may be tagging a variant with direct functional effect on MGMT mRNA expression.	('variants', 'Var', (69, 77))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('MGMT', 'Gene', '4255', (136, 140))	('MGMT', 'Gene', (136, 140))
2077	23047291	However, when examined in a set of glioblastoma samples made available through the TCGA project, we found no association with SNP genotype and methylation of the promoter region of MGMT, thus providing further evidence that the variant tagged by these SNPs has a direct functional effect on MGMT expression.	('variant', 'Var', (228, 235))	('glioblastoma', 'Disease', (35, 47))	('effect', 'Reg', (281, 287))	('MGMT', 'Gene', (291, 295))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('MGMT', 'Gene', (181, 185))	('MGMT', 'Gene', '4255', (291, 295))	('MGMT', 'Gene', '4255', (181, 185))
2190	23646114	Interestingly, a variant of this gene with a deletion of 10 amino acids at exon10/11 with a deficient GEF activity that was found overexpressed in normal brain is downregulated in GBMs.	('GEF', 'Gene', (102, 105))	('downregulated', 'NegReg', (163, 176))	('deletion of', 'Var', (45, 56))	('GEF', 'Gene', '5923', (102, 105))
2221	32411609	MTHFD2 (350 amino acids, 37kDa) is one of the major enzymes involved in mitochondrial folate one-carbon metabolism and is also known as NMDMC (NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase).	('NMDMC', 'Gene', '10797', (136, 141))	('NMDMC', 'Gene', (136, 141))	('folate', 'Chemical', 'MESH:D005492', (86, 92))	('folate', 'Chemical', 'MESH:D005492', (190, 196))	('carbon', 'Chemical', 'MESH:D002244', (97, 103))	('NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase', 'Gene', '10797', (143, 225))	('350', 'Var', (8, 11))	('MTHFD2', 'Gene', (0, 6))
2226	32411609	Thirdly, depletion of MTHFD2 may impair aggressive phenotypes and cause cell death in multiple cancers.	('multiple cancers', 'Disease', (86, 102))	('aggressive phenotypes', 'CPA', (40, 61))	('death', 'Disease', 'MESH:D003643', (77, 82))	('death', 'Disease', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('multiple cancers', 'Disease', 'MESH:D009369', (86, 102))	('MTHFD2', 'Gene', (22, 28))	('cause', 'Reg', (66, 71))	('impair', 'NegReg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('depletion', 'Var', (9, 18))
2243	32411609	Compared with MTHFD2L isozyme, MTHFD2 was reported to have much higher expression and displayed a more predominant role in maintaining mitochondrial folate pathway function as well as responding to growth factor stimulation.	('expression', 'MPA', (71, 81))	('MTHFD2L', 'Gene', '441024', (14, 21))	('MTHFD2L', 'Gene', (14, 21))	('mitochondrial', 'MPA', (135, 148))	('function', 'MPA', (164, 172))	('higher', 'PosReg', (64, 70))	('folate', 'Chemical', 'MESH:D005492', (149, 155))	('maintaining', 'PosReg', (123, 134))	('MTHFD2', 'Var', (31, 37))
2246	32411609	MTHFD2 knockout caused embryonic deaths at 12.5 days gestation in mice, suggesting its indispensable role in normal embryonic development.	('MTHFD2', 'Gene', (0, 6))	('embryonic deaths', 'Disease', 'MESH:D003643', (23, 39))	('mice', 'Species', '10090', (66, 70))	('knockout', 'Var', (7, 15))	('embryonic deaths', 'Disease', (23, 39))
2259	32411609	Patients with highly expressed MTHFD2 may have a longer survival period.	('Patients', 'Species', '9606', (0, 8))	('survival period', 'CPA', (56, 71))	('highly expressed', 'Var', (14, 30))	('MTHFD2', 'Gene', (31, 37))
2266	32411609	For instance, in breast cancer, MTHFD2 knockdown suppressed cell migration and invasion.	('cell migration', 'CPA', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('knockdown', 'Var', (39, 48))	('breast cancer', 'Disease', (17, 30))	('MTHFD2', 'Gene', (32, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('suppressed', 'NegReg', (49, 59))	('invasion', 'CPA', (79, 87))
2269	32411609	In HCC cells, siRNA-mediated silencing of MTHFD2 inhibited cellular features associated with cancer metastasis, including cell migration, invasion, and epithelial-mesenchymal transition but no significant difference was observed on cell proliferation, apoptosis, or cell cycle distribution.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cell migration', 'CPA', (122, 136))	('apoptosis', 'CPA', (252, 261))	('silencing', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cellular features', 'CPA', (59, 76))	('epithelial-mesenchymal transition', 'CPA', (152, 185))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('invasion', 'CPA', (138, 146))	('inhibited', 'NegReg', (49, 58))	('MTHFD2', 'Gene', (42, 48))
2271	32411609	described decreased cell proliferation, migration, and invasion after MTHFD2 knockdown in 786-O cells, possibly through a reduction in vimentin expression.	('decreased', 'NegReg', (10, 19))	('cell proliferation', 'CPA', (20, 38))	('expression', 'MPA', (144, 154))	('vimentin', 'Gene', '7431', (135, 143))	('knockdown', 'Var', (77, 86))	('vimentin', 'Gene', (135, 143))	('reduction', 'NegReg', (122, 131))	('invasion', 'CPA', (55, 63))	('migration', 'CPA', (40, 49))	('MTHFD2', 'Gene', (70, 76))
2273	32411609	In CRC, MTHFD2 knockdown caused cell death under hypoxia and decreased cell growth and sphere formation ability.	('death', 'Disease', (37, 42))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('knockdown', 'Var', (15, 24))	('MTHFD2', 'Gene', (8, 14))	('decreased', 'NegReg', (61, 70))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('hypoxia', 'Disease', (49, 56))	('death', 'Disease', 'MESH:D003643', (37, 42))
2276	32411609	In sum, MTHFD2 depletion could result in cancer cell death and impair key features associated with cancer progressions, such as proliferation, invasion, migration, and metastasis.	('depletion', 'Var', (15, 24))	('death', 'Disease', 'MESH:D003643', (53, 58))	('death', 'Disease', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('MTHFD2', 'Gene', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('invasion', 'CPA', (143, 151))	('migration', 'CPA', (153, 162))	('impair', 'NegReg', (63, 69))	('cancer', 'Disease', (99, 105))	('proliferation', 'CPA', (128, 141))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('metastasis', 'CPA', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('result in', 'Reg', (31, 40))
2290	32411609	Besides, MTHFD2 was speculated as one of the regulatory targets of Nrf2, as MTHFD2 mRNA was decreased by Nrf2 knockdown in A549 lung cancer cells.	('knockdown', 'Var', (110, 119))	('Nrf2', 'Gene', (105, 109))	('Nrf2', 'Gene', (67, 71))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('Nrf2', 'Gene', '4780', (105, 109))	('Nrf2', 'Gene', '4780', (67, 71))	('decreased', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mRNA', 'MPA', (83, 87))	('MTHFD2', 'Gene', (76, 82))
2292	32411609	In AML cells, miR-92a inhibited cell proliferation and promoted apoptosis by directly downregulating MTHFD2.	('inhibited', 'NegReg', (22, 31))	('downregulating', 'NegReg', (86, 100))	('miR-92a', 'Var', (14, 21))	('apoptosis', 'CPA', (64, 73))	('MTHFD2', 'Gene', (101, 107))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('promoted', 'PosReg', (55, 63))	('cell proliferation', 'CPA', (32, 50))	('miR-92a', 'Chemical', '-', (14, 21))	('AML', 'Disease', (3, 6))
2301	32411609	In AML cells, knockdown of MTHFD2 resulted in morphological shift including nuclear condensation and cytoplasmic ruffling.	('cytoplasmic ruffling', 'CPA', (101, 121))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('nuclear condensation', 'CPA', (76, 96))	('knockdown', 'Var', (14, 23))	('MTHFD2', 'Gene', (27, 33))	('AML', 'Disease', (3, 6))
2302	32411609	In breast cancer cells, MTHFD2 depletion caused a weaker and deformed vimentin network, indicating the impairment of cell motility.	('vimentin', 'Gene', '7431', (70, 78))	('weaker', 'NegReg', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('vimentin', 'Gene', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cell motility', 'CPA', (117, 130))	('MTHFD2', 'Gene', (24, 30))	('depletion', 'Var', (31, 40))	('deformed', 'NegReg', (61, 69))
2308	32411609	Suppression of MTHFD2 disturbed NADPH production and redox homeostasis, rendering CRC cells more vulnerable to oxidative stress such as hypoxia.	('rendering', 'Reg', (72, 81))	('redox homeostasis', 'MPA', (53, 70))	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('hypoxia', 'Disease', (136, 143))	('hypoxia', 'Disease', 'MESH:D000860', (136, 143))	('NADPH production', 'MPA', (32, 48))	('Suppression', 'Var', (0, 11))	('MTHFD2', 'Gene', (15, 21))	('vulnerable', 'MPA', (97, 107))	('oxidative stress', 'Phenotype', 'HP:0025464', (111, 127))	('disturbed', 'Reg', (22, 31))
2309	32411609	Histidine-induced filament formation required GCN2/ATF4/MTHFD2 axis-maintained redox homeostasis, and knockdown of MTHFD2 would affect the cytidine triphosphate (CTP) synthase filament formation due to redox imbalance.	('ATF4', 'Gene', '468', (51, 55))	('affect', 'Reg', (128, 134))	('MTHFD2', 'Gene', (115, 121))	('CTP', 'Chemical', 'MESH:D003570', (162, 165))	('GCN2', 'Gene', (46, 50))	('cytidine triphosphate', 'Chemical', 'MESH:D003570', (139, 160))	('Histidine', 'Chemical', 'MESH:D006639', (0, 9))	('redox imbalance', 'MPA', (202, 217))	('knockdown', 'Var', (102, 111))	('imbalance', 'Phenotype', 'HP:0002172', (208, 217))	('ATF4', 'Gene', (51, 55))	('redox imbalance', 'Phenotype', 'HP:0025463', (202, 217))	('GCN2', 'Gene', '440275', (46, 50))
2313	32411609	Unsurprisingly, depletion of MTHFD2 would inhibit mitochondrial 1C metabolism and disturb purine synthesis.	('purine synthesis', 'MPA', (90, 106))	('purine', 'Chemical', 'MESH:C030985', (90, 96))	('MTHFD2', 'Gene', (29, 35))	('depletion', 'Var', (16, 25))	('disturb purine synthesis', 'Phenotype', 'HP:0003142', (82, 106))	('disturb', 'Reg', (82, 89))	('mitochondrial 1C metabolism', 'MPA', (50, 77))	('inhibit', 'NegReg', (42, 49))
2314	32411609	For instance, loss of MTHFD2 led to glycine auxotrophs (i.e., a reliance on exogenous glycine) in mammalian fibroblasts, breast cancer, and AML.	('loss', 'Var', (14, 18))	('glycine', 'Chemical', 'MESH:D005998', (86, 93))	('led to', 'Reg', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('AML', 'Disease', 'MESH:D015470', (140, 143))	('MTHFD2', 'Gene', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mammalian', 'Species', '9606', (98, 107))	('breast cancer', 'Disease', (121, 134))	('glycine', 'Chemical', 'MESH:D005998', (36, 43))	('AML', 'Disease', (140, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('glycine auxotrophs', 'MPA', (36, 54))
2315	32411609	In mammalian fibroblasts, knockout of NMDMC(MTHFD2) completely blocked 1-C unit generation in mitochondria, and the cytoplasmic folate pathways were insufficient to compensate for the optimal purine synthesis.	('NMDMC', 'Gene', '10797', (38, 43))	('folate', 'Chemical', 'MESH:D005492', (128, 134))	('1-C unit generation in mitochondria', 'MPA', (71, 106))	('knockout', 'Var', (26, 34))	('purine', 'Chemical', 'MESH:C030985', (192, 198))	('NMDMC', 'Gene', (38, 43))	('blocked', 'NegReg', (63, 70))	('mammalian', 'Species', '9606', (3, 12))
2318	32411609	demonstrated that depletion of MTHFD2 decreased de novo purine synthesis and was associated with reduced formate production.	('formate production', 'MPA', (105, 123))	('decreased', 'NegReg', (38, 47))	('formate', 'Chemical', 'MESH:C030544', (105, 112))	('reduced', 'NegReg', (97, 104))	('de novo purine synthesis', 'MPA', (48, 72))	('depletion', 'Var', (18, 27))	('MTHFD2', 'Gene', (31, 37))	('purine', 'Chemical', 'MESH:C030985', (56, 62))
2322	32411609	MTHFD2 knockdown (or AICAR rescue) was found to reduce stem-like properties and restore sensitivity to gefitinib in gefitinib-resistant lung cancer cells.	('MTHFD2', 'Gene', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('gefitinib', 'Chemical', 'MESH:D000077156', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('lung cancer', 'Disease', (136, 147))	('reduce', 'NegReg', (48, 54))	('gefitinib', 'Chemical', 'MESH:D000077156', (116, 125))	('restore', 'PosReg', (80, 87))	('knockdown', 'Var', (7, 16))	('sensitivity to gefitinib', 'MPA', (88, 112))	('stem-like properties', 'CPA', (55, 75))	('AICAR', 'Gene', '471', (21, 26))	('AICAR', 'Gene', (21, 26))
2327	32411609	Since abnormal angiogenesis is an important hallmark in GBM, targeting MTHFD2 may halt the progression of GBM by either slowing cancer cell proliferation or inhibiting abnormal angiogenesis, or both.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('GBM', 'Disease', (106, 109))	('targeting', 'Var', (61, 70))	('inhibiting', 'NegReg', (157, 167))	('MTHFD2', 'Gene', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('abnormal angiogenesis', 'CPA', (168, 189))	('slowing', 'NegReg', (120, 127))	('cancer', 'Disease', (128, 134))
2330	32411609	They generated HCT-116 CRC cell lines expressing either the wild-type MTHFD2 protein or a mutant MTHFD2DeltaNAD, which lacks the dehydrogenase activity due to a mutation in the NAD-binding site.	('MTHFD2DeltaNAD', 'Gene', (97, 111))	('lacks', 'NegReg', (119, 124))	('mutation', 'Var', (161, 169))	('mutant', 'Var', (90, 96))	('NAD', 'Chemical', 'MESH:D009243', (108, 111))	('NAD', 'Chemical', 'MESH:D009243', (177, 180))	('HCT-116 CRC', 'CellLine', 'CVCL:0291', (15, 26))	('CRC', 'Phenotype', 'HP:0003003', (23, 26))	('MTHFD2', 'Gene', (70, 76))
2340	32411609	Interestingly, MTHFD2 depletion could decrease the alpha-ketoglutarate to succinate ratio in AML cells and thus reduced their stem cell signatures, suggesting its potential role in epigenetic modulation.	('alpha-ketoglutarate to succinate ratio', 'MPA', (51, 89))	('AML', 'Disease', (93, 96))	('depletion', 'Var', (22, 31))	('MTHFD2', 'Gene', (15, 21))	('decrease', 'NegReg', (38, 46))	('succinate', 'Chemical', 'MESH:D019802', (74, 83))	('reduced', 'NegReg', (112, 119))	('stem cell signatures', 'CPA', (126, 146))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (51, 70))
2345	32411609	The crystal structure of the first inhibitor of human MTHFD2, LY345899, was disclosed in 2017.	('human', 'Species', '9606', (48, 53))	('MTHFD2', 'Gene', (54, 60))	('LY345899', 'Chemical', '-', (62, 70))	('LY345899', 'Var', (62, 70))
2347	32411609	Notwithstanding, LY345899 treatment significantly inhibited CRC tumor growth in both cell lines and patient-derived xenograft (PDX) model.	('CRC tumor', 'Disease', (60, 69))	('CRC tumor', 'Disease', 'MESH:D015179', (60, 69))	('patient', 'Species', '9606', (100, 107))	('LY345899', 'Chemical', '-', (17, 25))	('LY345899', 'Var', (17, 25))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('inhibited', 'NegReg', (50, 59))
2348	32411609	recently disclosed a novel isozyme-selective MTHFD2 inhibitor, DS44960156, with a tricyclic coumarin scaffold.	('DS44960156', 'Var', (63, 73))	('coumarin', 'Chemical', 'MESH:C030123', (92, 100))	('DS44960156', 'Chemical', '-', (63, 73))	('MTHFD2', 'Gene', (45, 51))
2349	32411609	It is characterized by several superior features, including remarkable selectivity (>18 fold) for MTHFD2 over MTHFD1, a low molecular weight (<400), and a good ligand efficiency (LE, a metric of binder).	('MTHFD2', 'Var', (98, 104))	('ligand', 'Interaction', (160, 166))	('MTHFD1', 'Gene', '4522', (110, 116))	('MTHFD1', 'Gene', (110, 116))
2350	32411609	The upgraded compound DS18561882 showed a strong cell-based activity and a good oral pharmacokinetic profile which inhibited tumor growth in mouse xenograft breast cancer model upon oral administration.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('DS18561882', 'Chemical', '-', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('DS18561882', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('mouse', 'Species', '10090', (141, 146))	('tumor', 'Disease', (125, 130))	('inhibited', 'NegReg', (115, 124))
2358	32411609	Depletion of MTHDF2 may abrogate malignant phenotypes, such as proliferation, migration, invasion, and metastasis.	('proliferation', 'CPA', (63, 76))	('MTHDF2', 'Gene', (13, 19))	('invasion', 'CPA', (89, 97))	('malignant', 'CPA', (33, 42))	('Depletion', 'Var', (0, 9))	('migration', 'CPA', (78, 87))	('abrogate', 'NegReg', (24, 32))	('MTHDF2', 'Chemical', '-', (13, 19))	('metastasis', 'CPA', (103, 113))
2359	32411609	Cell line-derived xenograft and PDX-based studies further supported the anti-cancer effects of MTHFD2 knockdown in vivo.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('knockdown', 'Var', (102, 111))	('MTHFD2', 'Gene', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
2361	32411609	It remains unknown whether inhibiting MTHFD2 in these cancers would significantly suppress tumor growth.	('inhibiting', 'Var', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('suppress', 'NegReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (91, 96))	('MTHFD2', 'Gene', (38, 44))
2365	32411609	The first synthetic MTHFD2 inhibitor LY345899 has shown potent anti-tumor activity in CRC while the research and development of inhibitors with higher affinity and selectivity is still ongoing.	('tumor', 'Disease', (68, 73))	('CRC while', 'Disease', (86, 95))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('LY345899', 'Chemical', '-', (37, 45))	('LY345899', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MTHFD2', 'Gene', (20, 26))
2394	31466397	The long structures of repeated disaccharide units are implicated in the regulation of many oncogenic processes and CS up-regulation or modifications have been associated with cancer progression.	('disaccharide', 'Chemical', 'MESH:D004187', (32, 44))	('associated', 'Reg', (160, 170))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('modifications', 'Var', (136, 149))	('oncogenic processes', 'CPA', (92, 111))	('cancer', 'Disease', (176, 182))	('up-regulation', 'PosReg', (119, 132))	('implicated', 'Reg', (55, 65))
2406	31466397	Finally, CTCs from three patient samples are analyzed by whole exome sequencing (WES), which confirms the presence of glioma-associated mutations.	('glioma', 'Disease', (118, 124))	('patient', 'Species', '9606', (25, 32))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('mutations', 'Var', (136, 145))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
2426	31466397	T7039, Sigma-Aldrich) at a concentration of 20 ng/mL or equal volumes of TGF-beta suspension buffer as control (0.2 microm filtered distilled water) for 72 h to induce the mesenchymal transition.	('TGF-beta', 'Gene', '7040', (73, 81))	('mesenchymal transition', 'CPA', (172, 194))	('induce', 'PosReg', (161, 167))	('TGF-beta', 'Gene', (73, 81))	('T7039', 'Var', (0, 5))
2437	31466397	The samples were incubated with primary antibodies together with rVAR2 or rDBL4 over night at 4  C in the following concentrations: rVAR2 (50 nM), rDBL4 (50 nM), anti-NRP1 (Cat.	('NRP1', 'Gene', (167, 171))	('NRP1', 'Gene', '8829', (167, 171))	('rVAR2 (50 nM', 'Var', (132, 144))	('rDBL4 (50 nM', 'Var', (147, 159))
2453	31466397	The blood sample was diluted 10 times in Red Blood Cell (RBC) lysis buffer resulting in a final concentration of 0.155M ammonium chloride, 0.01M potassium hydrogen carbonate and 0.1 mM EDTA, and incubated for 13 min.	('EDTA', 'Chemical', 'MESH:D004492', (185, 189))	('0.01M', 'Var', (139, 144))	('0.155M', 'Var', (113, 119))	('potassium hydrogen carbonate', 'Chemical', 'MESH:D001639', (145, 173))	('ammonium chloride', 'Chemical', 'MESH:D000643', (120, 137))
2489	31466397	Variants outside a selected glioblastoma-related target region containing 95 candidate genes were excluded from the call set.	('glioblastoma', 'Disease', (28, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('Variants', 'Var', (0, 8))
2492	31466397	We tested rVAR2 binding to a panel of cell lines, including low-grade (WHO grade II) diffuse glioma (Res259) as well as high-grade (WHO grade IV) GBM (U87mg, KNS-42, and U118mg), to test for the presence of ofCS in glioma.	('U87mg', 'Var', (151, 156))	('glioma', 'Disease', (93, 99))	('Res259', 'Chemical', 'MESH:C570647', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('tested', 'Reg', (3, 9))	('glioma', 'Disease', (215, 221))	('U118mg', 'Var', (170, 176))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('binding', 'Interaction', (16, 23))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('rVAR2', 'Protein', (10, 15))
2505	31466397	By this procedure, we achieved an average recovery of 76%, 41%, 11%, and 64% for U87mg, Res259, KNS-42, and U118mg cells, respectively (Figure 2D).	('Res259', 'Chemical', 'MESH:C570647', (88, 94))	('U118mg', 'Var', (108, 114))	('U87mg', 'Var', (81, 86))
2507	31466397	We have previously described that single cancer cells simultaneously display the ofCS modification on several proteoglycans.	('proteoglycans', 'Protein', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ofCS modification', 'Var', (81, 98))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
2514	31466397	Similarly, ofCS and CSPG4 were clearly co-localizing on U87mg and U188mg cells (p < 0.001, one-way ANOVA) (Figure 3B).	('U87mg', 'Var', (56, 61))	('ofCS', 'Gene', (11, 15))	('co-localizing', 'Reg', (39, 52))	('U188mg', 'Var', (66, 72))	('CSPG4', 'Gene', '1464', (20, 25))	('CSPG4', 'Gene', (20, 25))
2524	31466397	However, it was noticed that rVAR2-staining of U87mg after magnetic capture was somewhat reduced compared to the Res259 and KNS-42 cells.	('Res259', 'Chemical', 'MESH:C570647', (113, 119))	('rVAR2-staining', 'CPA', (29, 43))	('U87mg', 'Var', (47, 52))	('reduced', 'NegReg', (89, 96))
2526	31466397	The rVAR2 staining enabled detection of U87mg cells and their separation from CD45- and/or CD66b-positive WBCs (Figure 4B).	('CD66b', 'Gene', '1088', (91, 96))	('CD45', 'Gene', (78, 82))	('CD66b', 'Gene', (91, 96))	('U87mg cells', 'Var', (40, 51))	('CD45', 'Gene', '5788', (78, 82))
2534	31466397	To confirm that the VAR2+, CD45- cells detected in the patient blood samples were indeed glioma-derived CTCs, we performed targeted whole exome sequencing (WES) searching for glioma relevant mutations.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('CD45', 'Gene', '5788', (27, 31))	('glioma', 'Disease', (175, 181))	('glioma', 'Disease', (89, 95))	('patient', 'Species', '9606', (55, 62))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('VAR2+', 'Var', (20, 25))	('CD45', 'Gene', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
2538	31466397	Indeed, we identified genes with cancer-indicative mutations in all CTC samples: RB1, TP53/EPM2AIP1, and TP53/ALK for patient 1, 3, and 4, respectively (Table 2).	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('EPM2AIP1', 'Gene', (91, 99))	('TP53', 'Gene', '7157', (86, 90))	('ALK', 'Gene', '238', (110, 113))	('RB1', 'Gene', (81, 84))	('TP53', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('RB1', 'Gene', '5925', (81, 84))	('TP53', 'Gene', '7157', (105, 109))	('ALK', 'Gene', (110, 113))	('TP53', 'Gene', (105, 109))	('patient', 'Species', '9606', (118, 125))	('EPM2AIP1', 'Gene', '9852', (91, 99))
2564	31466397	In this study, we sought to identify ofCS-modified proteoglycans in glioma by using rVAR2-based protein pull-down of lysates from KNS-42, U118mg, and U87mg cell lines.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('U118mg', 'Var', (138, 144))	('glioma', 'Disease', (68, 74))	('U87mg', 'Var', (150, 155))
2570	31466397	High CD44 expression is common in GBM and is used to identify GBM with particular poor survival chance.	('expression', 'MPA', (10, 20))	('CD44', 'Gene', '960', (5, 9))	('High', 'Var', (0, 4))	('CD44', 'Gene', (5, 9))
2575	31466397	We picked CTCs and performed WGA followed by WES against a panel of known glioma mutations to confirm that the detected rVAR2+, CD45-, and DAPI+ cells were actual CTCs derived from the brain tumors.	('brain tumor', 'Phenotype', 'HP:0030692', (185, 196))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('CD45', 'Gene', (128, 132))	('rVAR2+', 'Var', (120, 126))	('CD45', 'Gene', '5788', (128, 132))	('glioma', 'Disease', (74, 80))	('brain tumors', 'Disease', 'MESH:D001932', (185, 197))	('brain tumors', 'Phenotype', 'HP:0030692', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('mutations', 'Var', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('brain tumors', 'Disease', (185, 197))
2577	31466397	Patient I, which was diagnosed with anaplastic oligodendroglioma, had CTCs with mutation in the RB1 gene, which results in a frameshift with premature stop codon.	('frameshift', 'Var', (125, 135))	('anaplastic oligodendroglioma', 'Disease', (36, 64))	('RB1', 'Gene', '5925', (96, 99))	('results in', 'Reg', (112, 122))	('mutation', 'Var', (80, 88))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (36, 64))	('Patient', 'Species', '9606', (0, 7))	('RB1', 'Gene', (96, 99))
2578	31466397	Alterations in genes that are associated with the retinoblastoma pathway is a predictor of poor chance of survival in gliomas.	('genes', 'Gene', (15, 20))	('gliomas', 'Disease', 'MESH:D005910', (118, 125))	('retinoblastoma', 'Phenotype', 'HP:0009919', (50, 64))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('gliomas', 'Disease', (118, 125))	('Alterations', 'Var', (0, 11))	('retinoblastoma', 'Disease', 'MESH:D012175', (50, 64))	('retinoblastoma', 'Disease', (50, 64))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
2579	31466397	Interestingly, the somatic mutation pattern found in the tumor biopsy from this patient showed mutation of the IDH1 gene, a common feature of lower grade gliomas, which was not detected in the CTC sample.	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('IDH1', 'Gene', '3417', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('gliomas', 'Phenotype', 'HP:0009733', (154, 161))	('gliomas', 'Disease', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('gliomas', 'Disease', 'MESH:D005910', (154, 161))	('tumor', 'Disease', (57, 62))	('patient', 'Species', '9606', (80, 87))	('IDH1', 'Gene', (111, 115))	('mutation', 'Var', (95, 103))
2581	31466397	A TP53 mutation was found in the CTCs from both patient 3 (GBM) and 4 (anaplastic oligodendroglioma).	('anaplastic oligodendroglioma', 'Disease', (71, 99))	('patient', 'Species', '9606', (48, 55))	('TP53', 'Gene', '7157', (2, 6))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (71, 99))	('mutation', 'Var', (7, 15))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('TP53', 'Gene', (2, 6))
2583	31466397	Another detected mutation in patient 3 was a missense mutation in the EPM2AIP1 gene.	('missense mutation', 'Var', (45, 62))	('EPM2AIP1', 'Gene', '9852', (70, 78))	('EPM2AIP1', 'Gene', (70, 78))	('patient', 'Species', '9606', (29, 36))
2584	31466397	The EPM2AIP1 mutations have previously been described in different gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', (67, 91))	('EPM2AIP1', 'Gene', '9852', (4, 12))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (67, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('EPM2AIP1', 'Gene', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (13, 22))	('described', 'Reg', (44, 53))
2585	31466397	Interestingly, EPM2AIP1 is part of a bidirectional promotor with MLH1 and epimutations causing hypermethylation has been linked to hereditary colorectal cancers.	('hereditary colorectal cancers', 'Disease', (131, 160))	('EPM2AIP1', 'Gene', (15, 23))	('linked', 'Reg', (121, 127))	('hereditary colorectal cancers', 'Disease', 'MESH:D015179', (131, 160))	('MLH1', 'Gene', '4292', (65, 69))	('MLH1', 'Gene', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hypermethylation', 'Var', (95, 111))	('EPM2AIP1', 'Gene', '9852', (15, 23))	('epimutations', 'Var', (74, 86))
2587	31466397	In patient 4 the WES analysis also detected mutations in the ALK gene, which encodes a receptor tyrisone kinase.	('detected', 'Reg', (35, 43))	('ALK', 'Gene', (61, 64))	('patient', 'Species', '9606', (3, 10))	('mutations', 'Var', (44, 53))	('ALK', 'Gene', '238', (61, 64))	('tyrisone', 'Chemical', 'None', (96, 104))
2588	31466397	ALK is frequently mutated in neuroblastoma and indeed the detected NM_004304.4_p.R1275L variant is a described hot spot locus within the kinase domain.	('neuroblastoma', 'Disease', (29, 42))	('p.R1275L', 'Mutation', 'p.R1275L', (79, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (29, 42))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('NM_004304.4_p.R1275L', 'Var', (67, 87))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', '238', (0, 3))
2589	31466397	This hotspot mutation hinders the auto-inhibition of ALK and acts transformative.	('ALK', 'Gene', (53, 56))	('mutation', 'Var', (13, 21))	('hinders', 'NegReg', (22, 29))	('auto-inhibition', 'MPA', (34, 49))	('ALK', 'Gene', '238', (53, 56))
2590	31466397	Consequently, neuroblastoma patients with ALK mutations show poorer overall survival.	('mutations', 'Var', (46, 55))	('ALK', 'Gene', '238', (42, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (14, 27))	('ALK', 'Gene', (42, 45))	('neuroblastoma', 'Disease', 'MESH:D009447', (14, 27))	('overall', 'MPA', (68, 75))	('patients', 'Species', '9606', (28, 36))	('poorer', 'NegReg', (61, 67))	('neuroblastoma', 'Disease', (14, 27))
2591	31466397	Importantly, small molecules for targeted therapy of ALK have been developed and neuroblastoma cell lines harboring p.R1275 mutations show sensitivity towards ALK inhibitors, such as crizotinib.	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))	('ALK', 'Gene', (53, 56))	('ALK', 'Gene', '238', (159, 162))	('neuroblastoma', 'Disease', 'MESH:D009447', (81, 94))	('neuroblastoma', 'Disease', (81, 94))	('ALK', 'Gene', (159, 162))	('p.R1275 mutations', 'Var', (116, 133))	('ALK', 'Gene', '238', (53, 56))	('crizotinib', 'Chemical', 'MESH:C551994', (183, 193))	('sensitivity', 'MPA', (139, 150))
2592	31466397	Altogether, the specific detection of glioma-related mutation patterns in the CTC samples strongly indicates that the detected cells originate from a glioma site.	('mutation', 'Var', (53, 61))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', (38, 44))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
2597	31466397	; Formal analysis, S.R.B.-C., T.D.A., M.H.T., T.G.T., O.O.	('H.T', 'Disease', 'MESH:D000848', (40, 43))	('H.T', 'Disease', (40, 43))	('T.G.T.', 'Var', (46, 52))
2598	31466397	; Investigation, S.R.B.-C., R.S.P., M.A.P., T.M.C., C.L., N.T.S., T.D.A., A.M.J., M.H.T., O.O.	('N.T.S', 'Disease', (58, 63))	('T.M.C.', 'Var', (44, 50))	('T.D.A.', 'Var', (66, 72))	('H.T', 'Disease', (84, 87))	('N.T.S', 'Disease', 'MESH:D018455', (58, 63))	('H.T', 'Disease', 'MESH:D000848', (84, 87))
2613	30948495	Although GBM has been extensively characterized at the molecular level, current clinical management has limited guidance from molecular pathology, beyond mutations in isocitrate dehydrogenase 1/2 (IDH1/2) and MGMT promoter methylation.	('IDH1/2', 'Gene', (197, 203))	('mutations', 'Var', (154, 163))	('IDH1/2', 'Gene', '3417;3418', (197, 203))	('MGMT', 'Gene', (209, 213))	('MGMT', 'Gene', '4255', (209, 213))	('isocitrate', 'Chemical', 'MESH:D007523', (167, 177))
2617	30948495	Despite these challenges, transcriptional profiling of GBM lacking IDH1 or IDH2 or classic driver mutations has identified molecular subgroups that predominate among patient tumors.	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('IDH1', 'Gene', (67, 71))	('lacking', 'NegReg', (59, 66))	('IDH2', 'Gene', (75, 79))	('mutations', 'Var', (98, 107))	('IDH1', 'Gene', '3417', (67, 71))	('IDH2', 'Gene', '3418', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patient', 'Species', '9606', (166, 173))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
2632	30948495	Supporting this finding, the most frequent somatic alterations detected in GSC models included TP53 mutations, PTEN mutations, EGFR amplifications, and CDKN2A/p16 deletions, further reinforcing that our models recapitulate genetic features of primary tumors while capturing molecular features of tumor heterogeneity (Fig.	('primary tumors', 'Disease', (243, 257))	('tumor', 'Disease', (251, 256))	('PTEN', 'Gene', '5728', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('deletions', 'Var', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Disease', (296, 301))	('p16', 'Gene', (159, 162))	('TP53', 'Gene', '7157', (95, 99))	('EGFR', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('p16', 'Gene', '1029', (159, 162))	('CDKN2A', 'Gene', (152, 158))	('primary tumors', 'Disease', 'MESH:D001932', (243, 257))	('mutations', 'Var', (116, 125))	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('PTEN', 'Gene', (111, 115))	('CDKN2A', 'Gene', '1029', (152, 158))	('TP53', 'Gene', (95, 99))
2642	30948495	Patients with GBM that harbors enrichment of the core GSC SE signature have inferior survival compared with those with reduced enrichment (Fig.	('Patients', 'Species', '9606', (0, 8))	('inferior', 'NegReg', (76, 84))	('SE', 'Disease', 'None', (58, 60))	('enrichment', 'Var', (31, 41))	('survival', 'MPA', (85, 93))
2643	30948495	Patients with high expression of this core GSC SE signature have higher-grade tumor histology and are less likely to have tumors with IDH1 mutations and a glioma CpG-island methylator phenotype (; Fig.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('higher-grade', 'PosReg', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', (134, 138))	('SE', 'Disease', 'None', (47, 49))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (78, 83))	('IDH1', 'Gene', '3417', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (122, 127))	('glioma', 'Disease', (155, 161))
2661	30948495	shRNA knockdown of RUNX2, a group 2-specific TF with no prior association to GBM, was lethal in vitro and in vivo (Fig.	('RUNX2', 'Gene', (19, 24))	('knockdown', 'Var', (6, 15))	('RUNX2', 'Gene', '860', (19, 24))
2662	30948495	OLIG2, a group 1-specific TF that has been implicated in oligodendrocyte identity, showed a reciprocal pattern of dependency with its knockdown highly sensitive in group 1 but not group 2 (Fig.	('OLIG2', 'Gene', '10215', (0, 5))	('knockdown', 'Var', (134, 143))	('OLIG2', 'Gene', (0, 5))
2670	30948495	Considering significant correlations to TFs, two of the tumors contained mostly cells assigned to group 1 (MGH26 and MGH30).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('MGH30', 'Var', (117, 122))
2681	30948495	Four GSC models driven by predicted clinically actionable SE genes EGFR and CDK6 were treated with a combination of EGFR and CDK4/6 inhibitors, lapatinib, and palbociclib, revealing cellular growth inhibition by treatments (Fig.	('inhibitors', 'Var', (132, 142))	('lapatinib', 'Chemical', 'MESH:C490728', (144, 153))	('SE genes', 'Disease', 'MESH:D058495', (58, 66))	('EGFR', 'Gene', (116, 120))	('CDK4/6', 'Gene', '1019;1021', (125, 131))	('cellular growth', 'CPA', (182, 197))	('EGFR', 'Gene', (67, 71))	('CDK4/6', 'Gene', (125, 131))	('SE genes', 'Disease', (58, 66))	('CDK6', 'Gene', (76, 80))
2687	30948495	Using AZD8330, a potent and selective inhibitor to the MAPK/ERK MEK family of kinases, we observed selective effects on GSC group 1 viability at low micromolar doses with little effect in group 2 GSCs (Fig.	('AZD8330', 'Chemical', 'MESH:C581956', (6, 13))	('MEK', 'Gene', (64, 67))	('MEK', 'Gene', '5609', (64, 67))	('MAPK', 'Gene', '5594', (55, 59))	('ERK', 'Gene', '5594', (60, 63))	('MAPK', 'Gene', (55, 59))	('ERK', 'Gene', (60, 63))	('AZD8330', 'Var', (6, 13))	('effects', 'Reg', (109, 116))	('viability', 'CPA', (132, 141))
2689	30948495	Classification schemes based on these transcriptional signatures have ranged in the number of groups widely, but none has reliably informed clinical management beyond the identification of the IDH1 or IDH2 mutant tumors, which are tumors with a distinct molecular basis.	('IDH1', 'Gene', (193, 197))	('tumors', 'Disease', (231, 237))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('IDH2', 'Gene', '3418', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('mutant', 'Var', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('IDH1', 'Gene', '3417', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('IDH2', 'Gene', (201, 205))
2691	30948495	GBMs display spatial diversity of genetic events, which have not, to date, been associated with specific regional variation, but genetic analyses have suggested that tumors may accumulate mutations selectively based on heterochromatin and euchromatin states, supporting crosstalk between epigenetic and genetic tumor regulation.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('mutations', 'Var', (188, 197))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (311, 316))
2745	30948495	Lentiviral clones expressing two nonoverlapping shRNAs directed against human ASCL1 (TRCN0000235657, TRCN0000244309), human BCAN (TRCN0000151872, TRCN0000371366), human C1ORF61 (TRCN0000172451, TRCN0000167021), human CDK6 (TRCN0000196261, TRCN0000196337), human CXCL8 (TRCN0000058030, TRCN0000232050), human CXXC5 (TRCN0000139498, TRCN0000142729), EGFR (TRCN0000121329, TRCN0000121068), HMGA2 (TRCN0000342671, TRCN0000021966), MSRB3 (TRCN0000064761, TRCN0000064759), RUNX2 (TRCN0000013656, TRCN0000013655), SALL3 (TRCN0000418831, TRCN0000019755), SEPT9 (TRCN0000119069, TRCN0000445092), SOX2 (TRCN0000355694, TRCN0000231642), or a nontargeting control shRNA that has no targets in the human genome were obtained from Sigma-Aldrich.	('HMGA2', 'Gene', (387, 392))	('CXCL8', 'Gene', '3576', (262, 267))	('CXCL8', 'Gene', (262, 267))	('C1ORF61', 'Gene', '10485', (169, 176))	('BCAN', 'Gene', '63827', (124, 128))	('TRCN0000418831', 'Var', (514, 528))	('TRCN0000342671', 'Var', (394, 408))	('human', 'Species', '9606', (256, 261))	('SEPT9', 'Gene', (547, 552))	('TRCN0000445092', 'Var', (570, 584))	('C1ORF61', 'Gene', (169, 176))	('TRCN0000371366', 'Chemical', 'None', (146, 160))	('human', 'Species', '9606', (302, 307))	('SEPT9', 'Gene', '10801', (547, 552))	('SALL3', 'Gene', (507, 512))	('human', 'Species', '9606', (72, 77))	('MSRB3', 'Gene', (427, 432))	('TRCN0000064761', 'Var', (434, 448))	('SOX2', 'Gene', '6657', (587, 591))	('BCAN', 'Gene', (124, 128))	('SOX2', 'Gene', (587, 591))	('CXXC5', 'Gene', (308, 313))	('HMGA2', 'Gene', '8091', (387, 392))	('CXXC5', 'Gene', '51523', (308, 313))	('RUNX2', 'Gene', (467, 472))	('human', 'Species', '9606', (118, 123))	('MSRB3', 'Gene', '253827', (427, 432))	('ASCL1', 'Gene', '429', (78, 83))	('RUNX2', 'Gene', '860', (467, 472))	('SALL3', 'Gene', '27164', (507, 512))	('TRCN0000231642', 'Var', (609, 623))	('TRCN0000355694', 'Var', (593, 607))	('TRCN0000121329', 'Var', (354, 368))	('human', 'Species', '9606', (163, 168))	('TRCN0000119069', 'Var', (554, 568))	('TRCN0000013655', 'Var', (490, 504))	('human', 'Species', '9606', (685, 690))	('ASCL1', 'Gene', (78, 83))	('human', 'Species', '9606', (211, 216))	('TRCN0000019755', 'Var', (530, 544))	('TRCN0000355694', 'Chemical', 'None', (593, 607))	('TRCN0000013656', 'Var', (474, 488))
2754	30948495	SEs with significantly differential H3K27ac occupancy (false discovery rate [FDR]-adjusted P < 0.01) were identified by modeling H3K27ac read counts as negative binomial distribution using a generalized linear model.	('H3K27ac', 'Protein', (36, 43))	('SE', 'Disease', 'None', (0, 2))	('occupancy', 'MPA', (44, 53))	('H3K27ac', 'Var', (129, 136))
2771	28693199	Epidermal growth factor receptor in glioblastoma Mutations in the epidermal growth factor receptor (EGFR) are commonly occurring in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('epidermal growth factor receptor', 'Gene', (66, 98))	('EGFR', 'Gene', (100, 104))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('occurring', 'Reg', (119, 128))	('glioblastoma', 'Disease', (36, 48))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('epidermal growth factor receptor', 'Gene', '1956', (66, 98))	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('Mutations', 'Var', (49, 58))
2773	28693199	Additionally, recent studies have revealed that wild-type EGFR, and to a greater extent hyper-activating EGFR mutants induced a substantial upregulation of Fyn expression.	('expression', 'MPA', (160, 170))	('mutants', 'Var', (110, 117))	('Fyn', 'Gene', (156, 159))	('EGFR', 'Gene', (105, 109))	('Fyn', 'Gene', '2534', (156, 159))	('upregulation', 'PosReg', (140, 152))
2783	28693199	Gene amplification and mutation of EGFR also enhance EGFR activation and occur in upwards of 57% of glioblastomas as determined by the TCGA dataset.	('glioblastomas', 'Disease', (100, 113))	('activation', 'MPA', (58, 68))	('mutation', 'Var', (23, 31))	('enhance', 'PosReg', (45, 52))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Protein', (53, 57))	('glioblastomas', 'Phenotype', 'HP:0012174', (100, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('glioblastomas', 'Disease', 'MESH:D005909', (100, 113))
2785	28693199	Mutations of EGFR occur in roughly one-third of all classical tumors and often in mesenchymal, proneural and neural glioblastomas as well.	('classical tumors', 'Disease', 'MESH:D005693', (52, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('glioblastomas', 'Phenotype', 'HP:0012174', (116, 129))	('neural glioblastomas', 'Disease', (109, 129))	('neural glioblastomas', 'Disease', 'MESH:D005909', (109, 129))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('occur', 'Reg', (18, 23))	('classical tumors', 'Disease', (52, 68))	('proneural', 'Disease', (95, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('Mutations', 'Var', (0, 9))	('mesenchymal', 'Disease', (82, 93))	('EGFR', 'Gene', (13, 17))
2786	28693199	Of these mutations, extracellular domain EGFR mutations are most commonly observed in glioblastoma.	('mutations', 'Var', (46, 55))	('observed', 'Reg', (74, 82))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
2787	28693199	The most frequently occurring EGFR mutation in glioblastoma, EGFRDeltaIII, arises from an in-frame deletion of 801 bp in the DNA sequence encoding the extracellular domain, rendering a truncated yet constitutively active form of the receptor EGFRDeltaIII is a cancer specific mutation, as it not detected in normal tissues, making it an attractive target for therapeutic intervention.	('EGFR', 'Gene', (30, 34))	('glioblastoma', 'Disease', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('cancer', 'Disease', (260, 266))	('deletion of', 'Var', (99, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('mutation', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
2791	28693199	EGFRDeltaIII has also been associated with transformative properties, as INK4A/Arf depleted astrocytes and neural stem cells form high grade tumors in vivo when expressing EGFRDeltaIII.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('INK4A/Arf', 'Gene', (73, 82))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('INK4A/Arf', 'Gene', '1029', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('EGFRDeltaIII', 'Var', (172, 184))
2793	28693199	Not only is EGFRDeltaIII likely an important factor in gliomagenesis, but the tumorigenic potential of glioma cells in vivo are significantly increased by EGFRDeltaIII expression when compared to xenografts expressing the wild-type EGFR.	('glioma', 'Disease', (55, 61))	('increased', 'PosReg', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('EGFRDeltaIII', 'Gene', (155, 167))	('expression', 'Var', (168, 178))	('tumor', 'Disease', (78, 83))	('glioma', 'Disease', (103, 109))
2795	28693199	Interestingly, recent reports indicate that co-expression of EGFRDeltaIII and the GSC marker CD133+ defines a population of GSCs harboring the greatest tumor-initiating ability, thus further defining its importance in glioblastoma.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('glioblastoma', 'Disease', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('co-expression', 'Var', (44, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('EGFRDeltaIII', 'Gene', (61, 73))	('tumor', 'Disease', (152, 157))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('CD133+', 'Gene', (93, 99))
2799	28693199	Using missense mutants encoding R108K, T263P, A289V, G598V, and L861Q it was determined that these mutations were: i) hyper-phosphorylated receptor in the absence of ligand; ii) accompanied by an increased EGFR gene dosage; and iii) exhibited a stronger transforming phenotype relative to wild-type EGFR as determined by anchorage-independent growth in NIH-3T3 cells.	('T263P', 'Var', (39, 44))	('increased', 'PosReg', (196, 205))	('A289V', 'Mutation', 'rs149840192', (46, 51))	('A289V', 'Var', (46, 51))	('EGFR', 'Gene', (206, 210))	('T263P', 'Mutation', 'rs1057519829', (39, 44))	('R108K', 'Var', (32, 37))	('hyper-phosphorylated', 'PosReg', (118, 138))	('NIH-3T3', 'CellLine', 'CVCL:0594', (353, 360))	('R108K', 'Mutation', 'rs1057519828', (32, 37))	('L861Q', 'Mutation', 'rs121913444', (64, 69))	('G598V', 'Var', (53, 58))	('stronger', 'PosReg', (245, 253))	('L861Q', 'Var', (64, 69))	('G598V', 'Mutation', 'rs139236063', (53, 58))
2800	28693199	Importantly, of the missense mutations evaluated, EGFR-R108K shares the greatest degree of signaling and behavioral homology to EGFRDeltaIII, particularly as it relates to therapeutic resistance.	('signaling', 'MPA', (91, 100))	('EGFR-R108K', 'Var', (50, 60))	('R108K', 'Mutation', 'rs1057519828', (55, 60))
2817	28693199	The class IA PI3Ks form heterodimers that are recruited to trigger RTKs and adaptor proteins through regulatory subunits, including p85a, p55a and p50a, or PIK3R1; p85b or PIKR2; and p55y or PIKR3.	('p55y', 'Var', (183, 187))	('p85b', 'Gene', '5296', (164, 168))	('p85b', 'Gene', (164, 168))	('PIK3R1', 'Gene', '5295', (156, 162))	('p85a', 'Gene', (132, 136))	('PIK3R1', 'Gene', (156, 162))	('p50a', 'Var', (147, 151))	('p85a', 'Gene', '5295', (132, 136))	('p55a', 'Var', (138, 142))
2820	28693199	PI3K then localizes to the plasma membrane, where it functions to catalyze the formation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) via the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2).	('PI3K', 'Var', (0, 4))	('PIP3', 'Chemical', '-', (134, 138))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (167, 204))	('phosphorylation', 'MPA', (148, 163))	('phosphatidylinositol 3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (92, 132))	('PIP2', 'Chemical', 'MESH:D019269', (206, 210))
2821	28693199	The resulting PIP3 is a critical activator of Akt, which consequently phosphorylates, or inhibits, numerous target proteins involved in regulating cellular metabolism, motility and protein synthesis.	('Akt', 'Gene', '207', (46, 49))	('inhibits', 'NegReg', (89, 97))	('Akt', 'Gene', (46, 49))	('phosphorylates', 'Var', (70, 84))	('PIP3', 'Chemical', '-', (14, 18))
2823	28693199	Activation of PI3K can also arise from point mutations, of which ~15% have been catalogued in glioblastoma tumors.	('point mutations', 'Var', (39, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (94, 113))	('PI3K', 'Var', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('glioblastoma tumors', 'Disease', (94, 113))	('Activation', 'PosReg', (0, 10))
2824	28693199	These mutations occur most commonly in the adaptor-binding domain (ABD) and less frequently in the C2 helical and kinase domains of the catalytic subunit (PIK3CA).	('PIK3CA', 'Gene', (155, 161))	('mutations', 'Var', (6, 15))	('PIK3CA', 'Gene', '5290', (155, 161))
2825	28693199	Though mutations in the regulatory subunit (PI3KR1) are uncommon, prior sequencing analysis from the TCGA indicated the presence of 9 such mutations occurring among a cohort of 91 glioblastoma samples.	('glioblastoma', 'Phenotype', 'HP:0012174', (180, 192))	('mutations', 'Var', (139, 148))	('PI3KR1', 'Gene', (44, 50))	('glioblastoma', 'Disease', (180, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (180, 192))	('mutations', 'Var', (7, 16))
2827	28693199	PI3K signaling is negatively regulated by various proteins, most notably PTEN; PTEN, however, is commonly inactivated (~50%) in glioblastoma by either epigenetic silencing or deletion mutation.	('inactivated', 'NegReg', (106, 117))	('deletion mutation', 'Var', (175, 192))	('epigenetic silencing', 'Var', (151, 171))	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (73, 77))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('PTEN', 'Gene', (79, 83))	('PI3K signaling', 'Pathway', (0, 14))	('PTEN', 'Gene', '5728', (79, 83))
2828	28693199	Loss of PTEN, therefore, disrupts the PI3K:PTEN balance resulting in increased Akt activation and uncontrolled cell growth.	('increased', 'PosReg', (69, 78))	('disrupts', 'NegReg', (25, 33))	('uncontrolled cell growth', 'CPA', (98, 122))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('Akt', 'Gene', '207', (79, 82))	('Loss', 'Var', (0, 4))	('Akt', 'Gene', (79, 82))	('activation', 'PosReg', (83, 93))
2829	28693199	Given the frequency of PI3K pathway aberrations occurring in glioblastoma, inhibition of its signaling components is an important contribution for a therapeutic avenue.	('glioblastoma', 'Disease', (61, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('PI3K pathway', 'Pathway', (23, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('aberrations', 'Var', (36, 47))
2833	28693199	Following EGFR activation, the MAPK signaling pathway is triggered by the growth factor receptor-bound protein 2 (Grb2) binding directly to EGFR via Y1068 and Y1086 or indirectly by SHC binding Y1173 and Y1143.	('Y1086', 'Var', (159, 164))	('Grb2', 'Gene', '2885', (114, 118))	('binding', 'Interaction', (120, 127))	('MAPK signaling pathway', 'Pathway', (31, 53))	('growth factor receptor-bound protein 2', 'Gene', (74, 112))	('SHC', 'Gene', '6464', (182, 185))	('Y1173', 'Var', (194, 199))	('Y1143', 'Var', (204, 209))	('Grb2', 'Gene', (114, 118))	('growth factor receptor-bound protein 2', 'Gene', '2885', (74, 112))	('triggered', 'Reg', (57, 66))	('Y1068', 'Var', (149, 154))	('SHC', 'Gene', (182, 185))
2842	27486821	Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression.	('HMGA2', 'Gene', (128, 133))	('GSC', 'Gene', '14836', (71, 74))	('H19', 'Protein', (120, 123))	('HMGA2', 'Gene', '15364', (128, 133))	('abrogated', 'NegReg', (19, 28))	('let-7', 'Chemical', '-', (13, 18))	('let-7', 'Gene', (13, 18))	('GSC', 'Gene', (71, 74))	('phenformin', 'Chemical', 'MESH:D010629', (29, 39))	('inhibition', 'NegReg', (106, 116))	('Silencing', 'Var', (0, 9))
2843	27486821	Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs.	('GSC', 'Gene', (140, 143))	('mice', 'Species', '10090', (102, 106))	('phenformin', 'Chemical', 'MESH:D010629', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('prolonged', 'PosReg', (68, 77))	('tumor', 'Disease', (51, 56))	('GSC', 'Gene', '14836', (140, 143))	('inhibited', 'NegReg', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('phenformin', 'Var', (30, 40))
2854	27486821	Additional studies have shown that metformin can inhibit cancer cell proliferation and induce cell cycle arrest in multiple cancer types, including glioma.	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (94, 111))	('cancer', 'Disease', (57, 63))	('glioma', 'Disease', (148, 154))	('metformin', 'Var', (35, 44))	('induce', 'Reg', (87, 93))	('arrest', 'Disease', 'MESH:D006323', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('inhibit', 'NegReg', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('arrest', 'Disease', (105, 111))
2855	27486821	Importantly, metformin inhibits the growth of cancer stem cells (including GSCs), induces tumor regression and prolongs tumor remission in xenograft models.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('metformin', 'Var', (13, 22))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('GSC', 'Gene', '14836', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('GSC', 'Gene', (75, 78))	('prolongs', 'NegReg', (111, 119))	('inhibits', 'NegReg', (23, 31))	('induces', 'PosReg', (82, 89))	('tumor', 'Disease', (120, 125))
2863	27486821	Several miRNAs, such as miR-33a, miR-26a, miR-193, miR-221/222 and let-7, are regulated by metformin in breast, pancreatic, and lung cancer cells.	('miR-221', 'Gene', (51, 58))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('pancreatic', 'Disease', 'MESH:D010195', (112, 122))	('let-7', 'Gene', (67, 72))	('regulated', 'Reg', (78, 87))	('metformin', 'Chemical', 'MESH:D008687', (91, 100))	('let-7', 'Chemical', '-', (67, 72))	('miR-221', 'Gene', '723827', (51, 58))	('pancreatic', 'Disease', (112, 122))	('miR-26a', 'Gene', '387218', (33, 40))	('lung cancer', 'Disease', (128, 139))	('miR-33a', 'Var', (24, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('miR-193', 'Gene', (42, 49))	('miR-193', 'Gene', '387188', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('miR-26a', 'Gene', (33, 40))
2874	27486821	In addition, phenformin also inhibited the frequency of sphere formation (Figure 1B) and the self-renewal of these cells (Figure 1C).	('inhibited', 'NegReg', (29, 38))	('phenformin', 'Var', (13, 23))	('phenformin', 'Chemical', 'MESH:D010629', (13, 23))	('self-renewal of these cells', 'CPA', (93, 120))
2878	27486821	Moreover, the average sphere size of the phenformin-treated GSCs was much smaller than that of untreated spheroids or those treated with metformin (Figures 1D and Supplementary S1B).	('smaller', 'NegReg', (74, 81))	('GSC', 'Gene', '14836', (60, 63))	('metformin', 'Chemical', 'MESH:D008687', (137, 146))	('spheroids', 'Chemical', '-', (105, 114))	('phenformin', 'Chemical', 'MESH:D010629', (41, 51))	('GSC', 'Gene', (60, 63))	('phenformin-treated', 'Var', (41, 59))
2879	27486821	To further confirm that phenformin can affect GSC stemness, we analyzed the expression of the stemness markers OCT4, SOX2 and CD44 in the treated cells and found that phenformin (100 muM) inhibited the expression of these markers (Figure S1E, 1F, Supplementary Figure S1C-S1E), whereas it increased the expression of the neural markers, GFAP and MAP2 (Figures 1G and Supplementary Figure S1C).	('stemness', 'Disease', 'MESH:D020295', (94, 102))	('stemness', 'Disease', (94, 102))	('GSC', 'Gene', '14836', (46, 49))	('expression', 'MPA', (202, 212))	('inhibited', 'NegReg', (188, 197))	('GFAP', 'Gene', (337, 341))	('MAP2', 'Gene', (346, 350))	('stemness', 'Disease', 'MESH:D020295', (50, 58))	('stemness', 'Disease', (50, 58))	('OCT4', 'Gene', (111, 115))	('expression', 'MPA', (303, 313))	('phenformin', 'Chemical', 'MESH:D010629', (167, 177))	('MAP2', 'Gene', '17756', (346, 350))	('phenformin', 'Chemical', 'MESH:D010629', (24, 34))	('increased', 'PosReg', (289, 298))	('OCT4', 'Gene', '18999', (111, 115))	('SOX2', 'Gene', '20674', (117, 121))	('GFAP', 'Gene', '14580', (337, 341))	('CD44', 'Gene', (126, 130))	('phenformin', 'Var', (167, 177))	('SOX2', 'Gene', (117, 121))	('GSC', 'Gene', (46, 49))	('CD44', 'Gene', '12505', (126, 130))
2882	27486821	Phenformin at concentrations up to 500 muM did not induce significant GSC death (Figures 1H-1I), but cell apoptosis was induced by phenformin at concentrations higher than 1.0 mM already after 24 hr of treatment as documented by the increases in cleaved caspase 3 and PARP expression (Figure 1H) and using the live/dead assay (Figures 1I, 1J).	('cell apoptosis', 'CPA', (101, 115))	('GSC', 'Gene', '14836', (70, 73))	('increases', 'PosReg', (233, 242))	('Phenformin', 'Chemical', 'MESH:D010629', (0, 10))	('GSC', 'Gene', (70, 73))	('phenformin', 'Chemical', 'MESH:D010629', (131, 141))	('PARP', 'Gene', (268, 272))	('phenformin', 'Var', (131, 141))	('cleaved caspase', 'MPA', (246, 261))	('PARP', 'Gene', '11545', (268, 272))
2884	27486821	In addition, we also found that the effect of phenformin on GSCs was much more potent than its effect on glioma cell lines (Supplementary Figures S1F, S1G).	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('GSC', 'Gene', '14836', (60, 63))	('glioma', 'Disease', (105, 111))	('GSC', 'Gene', (60, 63))	('phenformin', 'Chemical', 'MESH:D010629', (46, 56))	('phenformin', 'Var', (46, 56))	('glioma', 'Disease', 'MESH:D005910', (105, 111))
2890	27486821	In contrast, phenformin did not induce any significant changes in the expression of miR-34, miR-125b, miR-197, miR-372, miR-140 and miR-210 (data not shown).	('miR-125b', 'Var', (92, 100))	('miR-210', 'Gene', (132, 139))	('miR-140', 'Gene', (120, 127))	('phenformin', 'Chemical', 'MESH:D010629', (13, 23))	('miR-34', 'Var', (84, 90))	('miR-197', 'Var', (102, 109))	('miR-372', 'Var', (111, 118))	('miR-210', 'Gene', '387206', (132, 139))	('miR-140', 'Gene', '387158', (120, 127))
2891	27486821	Using specific antagomiRs we demonstrated that inhibition of miR-124 and let-7 expression decreased some of the inhibitory effect of phenformin on GSC self-renewal, whereas inhibition of miR-137 expression did not have a significant effect (Figure 2B).	('let-7', 'Chemical', '-', (73, 78))	('phenformin', 'Chemical', 'MESH:D010629', (133, 143))	('GSC', 'Gene', (147, 150))	('miR-124', 'Gene', (61, 68))	('inhibition', 'Var', (47, 57))	('phenformin', 'MPA', (133, 143))	('decreased', 'NegReg', (90, 99))	('inhibitory effect', 'MPA', (112, 129))	('miR-137', 'Gene', (187, 194))	('GSC', 'Gene', '14836', (147, 150))	('let-7', 'Gene', (73, 78))	('miR-137', 'Gene', '387155', (187, 194))
2893	27486821	Since phenformin inhibited both the stemness and mesenchymal markers of GSCs, we further examined the effect of phenformin on HMGA2 expression and the role of let-7 in its effect.	('stemness', 'Disease', (36, 44))	('GSC', 'Gene', '14836', (72, 75))	('phenformin', 'Chemical', 'MESH:D010629', (6, 16))	('examined', 'Reg', (89, 97))	('phenformin', 'Var', (6, 16))	('GSC', 'Gene', (72, 75))	('inhibited', 'NegReg', (17, 26))	('HMGA2', 'Gene', '15364', (126, 131))	('HMGA2', 'Gene', (126, 131))	('stemness', 'Disease', 'MESH:D020295', (36, 44))	('phenformin', 'Chemical', 'MESH:D010629', (112, 122))	('let-7', 'Chemical', '-', (159, 164))
2900	27486821	As presented in Figure 3A, treatment of the HF2355 and HF2587 with phenformin decreased the expression of H19 in these cells.	('HF2355', 'CellLine', 'CVCL:L945', (44, 50))	('H19', 'Protein', (106, 109))	('HF2587', 'CellLine', 'CVCL:H185', (55, 61))	('HF2587', 'Var', (55, 61))	('HF2355', 'Var', (44, 50))	('phenformin', 'Chemical', 'MESH:D010629', (67, 77))	('decreased', 'NegReg', (78, 87))	('expression', 'MPA', (92, 102))
2901	27486821	We then examined the role of H19 in the stemness characteristics of the GSCs and found that silencing of H19 (Figure 3B) decreased both the self-renewal (Figure 3C) and stem cell markers of these cells (Figure 3D).	('stem cell markers of', 'CPA', (169, 189))	('stemness', 'Disease', 'MESH:D020295', (40, 48))	('stemness', 'Disease', (40, 48))	('GSC', 'Gene', '14836', (72, 75))	('self-renewal', 'CPA', (140, 152))	('silencing', 'Var', (92, 101))	('decreased', 'NegReg', (121, 130))	('GSC', 'Gene', (72, 75))	('H19', 'Gene', (105, 108))
2902	27486821	In addition, silencing of H19 decreased also the expression of HMGA2 (Figure 3E, 3F) and increased the inhibitory effect of let-7 on the HMGA2 as measured using the HMGA2 3'-UTR tagged to luciferase (Figure 3G).	('inhibitory effect', 'MPA', (103, 120))	('let-7', 'Chemical', '-', (124, 129))	('HMGA2', 'Gene', '15364', (137, 142))	('expression', 'MPA', (49, 59))	('HMGA2', 'Gene', (137, 142))	('HMGA2', 'Gene', (165, 170))	('decreased', 'NegReg', (30, 39))	('HMGA2', 'Gene', (63, 68))	('H19', 'Gene', (26, 29))	('increased', 'PosReg', (89, 98))	('HMGA2', 'Gene', '15364', (165, 170))	('HMGA2', 'Gene', '15364', (63, 68))	('silencing', 'Var', (13, 22))
2904	27486821	In addition to the let-7 pathway, we also found that silencing of miR-124 abrogated some of phenformin effects on the expression of differentiation, stemness and mesenchymal markers (Figure 3H, 3I).	('let-7', 'Chemical', '-', (19, 24))	('miR-124', 'Gene', (66, 73))	('differentiation', 'CPA', (132, 147))	('abrogated', 'NegReg', (74, 83))	('silencing', 'Var', (53, 62))	('phenformin effects', 'MPA', (92, 110))	('expression', 'MPA', (118, 128))	('phenformin', 'Chemical', 'MESH:D010629', (92, 102))	('stemness', 'Disease', 'MESH:D020295', (149, 157))	('stemness', 'Disease', (149, 157))
2908	27486821	Phenformin decreased tumor growth significantly as analyzed by in vivo imaging (Figure 4A) and after 4 weeks of treatment, the average tumor size of the phenformin-treated xenografts was about one third of the control untreated tumors (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('phenformin-treated', 'Var', (153, 171))	('tumor', 'Disease', (21, 26))	('Phenformin', 'Chemical', 'MESH:D010629', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('decreased', 'NegReg', (11, 20))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors', 'Disease', (228, 234))	('phenformin', 'Chemical', 'MESH:D010629', (153, 163))	('tumor', 'Disease', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
2921	27486821	The combined effects of metformin and TMZ on GSC apoptosis were less striking than that of phenformin, and metformin even at a concentration of 40 mM exerted a smaller cytotoxic effect in TMZ-treated GSCs (Figure 5A, Supplementary Figure S4).	('phenformin', 'Chemical', 'MESH:D010629', (91, 101))	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('GSC', 'Gene', (45, 48))	('GSC', 'Gene', '14836', (200, 203))	('cytotoxic effect', 'CPA', (168, 184))	('metformin', 'Chemical', 'MESH:D008687', (107, 116))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('metformin', 'Var', (107, 116))	('TMZ', 'Chemical', 'MESH:D000077204', (188, 191))	('GSC', 'Gene', (200, 203))	('GSC', 'Gene', '14836', (45, 48))	('smaller', 'NegReg', (160, 167))
2937	27486821	Our study shows that phenformin attenuates the self-renewal and stemness of GSCs and induces cell death when administered at higher concentrations.	('stemness', 'Disease', 'MESH:D020295', (64, 72))	('stemness', 'Disease', (64, 72))	('induces', 'Reg', (85, 92))	('GSC', 'Gene', '14836', (76, 79))	('self-renewal', 'CPA', (47, 59))	('phenformin', 'Var', (21, 31))	('phenformin', 'Chemical', 'MESH:D010629', (21, 31))	('GSC', 'Gene', (76, 79))	('attenuates', 'NegReg', (32, 42))	('cell death', 'CPA', (93, 103))
2938	27486821	Within a very low concentration range that is 400-fold lower than that of metformin, phenformin inhibits GSC self-renewal and stemness-related proteins.	('inhibits', 'NegReg', (96, 104))	('phenformin', 'Var', (85, 95))	('metformin', 'Chemical', 'MESH:D008687', (74, 83))	('phenformin', 'Chemical', 'MESH:D010629', (85, 95))	('GSC', 'Gene', '14836', (105, 108))	('stemness', 'Disease', 'MESH:D020295', (126, 134))	('stemness', 'Disease', (126, 134))	('GSC', 'Gene', (105, 108))
2949	27486821	In addition to the upregulation of let-7 expression, we found that phenformin also increased the bioavailability of let-7 by inhibiting the expression of H19 that acts as a let-7 sponge.	('increased', 'PosReg', (83, 92))	('expression', 'MPA', (140, 150))	('let-7', 'Chemical', '-', (173, 178))	('let-7', 'Gene', (116, 121))	('upregulation', 'PosReg', (19, 31))	('let-7', 'Chemical', '-', (116, 121))	('phenformin', 'Chemical', 'MESH:D010629', (67, 77))	('inhibiting', 'NegReg', (125, 135))	('H19', 'Gene', (154, 157))	('phenformin', 'Var', (67, 77))	('let-7', 'Chemical', '-', (35, 40))	('bioavailability', 'MPA', (97, 112))
2951	27486821	Our data demonstrate that silencing of H19 decreased the stemness of GSCs and enhanced the ability of let-7 to inhibit HMGA2 expression.	('inhibit', 'NegReg', (111, 118))	('stemness', 'Disease', 'MESH:D020295', (57, 65))	('stemness', 'Disease', (57, 65))	('GSC', 'Gene', (69, 72))	('HMGA2', 'Gene', (119, 124))	('expression', 'MPA', (125, 135))	('let-7', 'Chemical', '-', (102, 107))	('enhanced', 'PosReg', (78, 86))	('silencing', 'Var', (26, 35))	('HMGA2', 'Gene', '15364', (119, 124))	('H19', 'Gene', (39, 42))	('decreased', 'NegReg', (43, 52))	('GSC', 'Gene', '14836', (69, 72))	('ability', 'MPA', (91, 98))
2956	27486821	In addition to its inhibitory effects on GSC stemness and survival in vitro, phenformin also inhibited the growth of GSC-derived xenografts.	('phenformin', 'Chemical', 'MESH:D010629', (77, 87))	('GSC', 'Gene', (41, 44))	('GSC', 'Gene', (117, 120))	('stemness', 'Disease', 'MESH:D020295', (45, 53))	('stemness', 'Disease', (45, 53))	('GSC', 'Gene', '14836', (41, 44))	('inhibited', 'NegReg', (93, 102))	('phenformin', 'Var', (77, 87))	('GSC', 'Gene', '14836', (117, 120))
2960	27486821	In the current study, we demonstrated that phenformin inhibited GBM tumor growth and prolonged overall survival of mice bearing GSC-derived xenografts.	('tumor', 'Disease', (68, 73))	('inhibited', 'NegReg', (54, 63))	('prolonged', 'PosReg', (85, 94))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('GSC', 'Gene', (128, 131))	('overall survival', 'CPA', (95, 111))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('phenformin', 'Chemical', 'MESH:D010629', (43, 53))	('mice', 'Species', '10090', (115, 119))	('phenformin', 'Var', (43, 53))	('GSC', 'Gene', '14836', (128, 131))
2968	27486821	Analyzing the therapeutic effects of the combined treatments of phenformin with TMZ or DCA demonstrated that phenformin can synergize with other GBM treatments that increase its efficacy and safety.	('phenformin', 'Var', (109, 119))	('increase', 'PosReg', (165, 173))	('phenformin', 'Chemical', 'MESH:D010629', (64, 74))	('phenformin', 'Chemical', 'MESH:D010629', (109, 119))	('efficacy', 'MPA', (178, 186))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('GBM', 'Phenotype', 'HP:0012174', (145, 148))	('DCA', 'Chemical', 'MESH:D003999', (87, 90))
2971	27486821	The dose of metformin for diabetes treatment is approximately 10-20 times higher than that of phenformin; however, phenformin can induce glioma cell death in concentrations 80-fold and lower and attenuate GSC self-renewal in a concentration of at least 200-fold lower than metformin.	('diabetes', 'Disease', 'MESH:D003920', (26, 34))	('attenuate', 'NegReg', (195, 204))	('metformin', 'Chemical', 'MESH:D008687', (12, 21))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('metformin', 'Chemical', 'MESH:D008687', (273, 282))	('GSC', 'Gene', '14836', (205, 208))	('phenformin', 'Var', (115, 125))	('glioma cell death', 'Disease', (137, 154))	('phenformin', 'Chemical', 'MESH:D010629', (115, 125))	('phenformin', 'Chemical', 'MESH:D010629', (94, 104))	('glioma cell death', 'Disease', 'MESH:D005910', (137, 154))	('GSC', 'Gene', (205, 208))	('induce', 'Reg', (130, 136))	('diabetes', 'Disease', (26, 34))
2976	27486821	Moreover, a combined treatment of mice bearing GSC-derived xenografts with phenformin and DCA induced a more pronounced effect on the survival of the mice compared to each treatment alone, suggesting that DCA not only can minimize the most common side effects of phenformin but also increases its anti-tumor effects.	('mice', 'Species', '10090', (150, 154))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('phenformin', 'Chemical', 'MESH:D010629', (263, 273))	('tumor', 'Disease', (302, 307))	('minimize', 'NegReg', (222, 230))	('GSC', 'Gene', '14836', (47, 50))	('DCA', 'Chemical', 'MESH:D003999', (90, 93))	('increases', 'PosReg', (283, 292))	('DCA', 'Var', (205, 208))	('DCA', 'Chemical', 'MESH:D003999', (205, 208))	('phenformin', 'Chemical', 'MESH:D010629', (75, 85))	('GSC', 'Gene', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
2983	27486821	The GSCs that were used in this study are HF2414, HF2355, HF2354, HF2359, HF2927 and HF2587.	('GSC', 'Gene', (4, 7))	('HF2927', 'CellLine', 'CVCL:M656', (74, 80))	('HF2355', 'Var', (50, 56))	('HF2414', 'CellLine', 'CVCL:AR02', (42, 48))	('HF2927', 'Var', (74, 80))	('HF2414', 'Var', (42, 48))	('GSC', 'Gene', '14836', (4, 7))	('HF2587', 'CellLine', 'CVCL:H185', (85, 91))	('HF2587', 'Var', (85, 91))	('HF2359', 'CellLine', 'CVCL:7358', (66, 72))	('HF2354', 'CellLine', 'CVCL:M656', (58, 64))	('HF2354', 'Var', (58, 64))	('HF2355', 'CellLine', 'CVCL:L945', (50, 56))	('HF2359', 'Var', (66, 72))
2997	27486821	Following the guidelines of Henry Ford Hospital's Institutional Animal Care and Use Committee, dissociated GSCs (3 x 105 cells) transduced with a lentivirus vector expressing FLuc were inoculated intracranially into nude mice (Nu/Nu) as previously described.	('GSC', 'Gene', '14836', (107, 110))	('GSC', 'Gene', (107, 110))	('nude mice', 'Species', '10090', (216, 225))	('transduced', 'Var', (128, 138))	('FLuc', 'Gene', (175, 179))
3033	25741761	Furthermore, like many non-specific cytotoxic chemotherapeutics, TMZ is known to cause systemic lymphopenia, which can be leveraged as a means of host-conditioning for adoptive therapy platforms.	('systemic lymphopenia', 'Disease', (87, 107))	('lymphopenia', 'Phenotype', 'HP:0001888', (96, 107))	('systemic lymphopenia', 'Disease', 'MESH:D008231', (87, 107))	('TMZ', 'Var', (65, 68))	('TMZ', 'Chemical', 'MESH:D000077204', (65, 68))
3146	25741761	If TMZ and WBI lead to significant toxicities, then ketamine/xylazine doses can be decreased by 20-25% to reduce the risk of mortality, as animals only need to be sedated and immobilized for 10 min for delivery of small radiation doses (2-8 Gy).	('toxicities', 'Disease', (35, 45))	('TMZ', 'Var', (3, 6))	('xylazine', 'Chemical', 'MESH:D014991', (61, 69))	('ketamine', 'Chemical', 'MESH:D007649', (52, 60))	('TMZ', 'Chemical', 'MESH:D000077204', (3, 6))	('toxicities', 'Disease', 'MESH:D064420', (35, 45))	('WBI', 'Chemical', '-', (11, 14))	('ketamine/xylazine', 'MPA', (52, 69))
3157	25610711	Receptor tyrosine kinase gene amplification and mutations, PI3K catalytic and regulatory subunit genetic mutations, and PTEN gene deletion and mutation all result in constitutive PI3K pathway activation in the majority of GBMs, thus rendering the downstream effect or mechanistic target of rapamycin (mTOR) a compelling GBM drug target.	('GBM', 'Phenotype', 'HP:0012174', (222, 225))	('Receptor tyrosine kinase', 'Gene', (0, 24))	('Receptor tyrosine kinase', 'Gene', '5979', (0, 24))	('mutation', 'Var', (143, 151))	('deletion', 'Var', (130, 138))	('mTOR', 'Gene', (301, 305))	('PI3K', 'Gene', (59, 63))	('activation', 'PosReg', (192, 202))	('PTEN', 'Gene', (120, 124))	('mutations', 'Var', (105, 114))	('mTOR', 'Gene', '2475', (301, 305))	('PTEN', 'Gene', '5728', (120, 124))	('mechanistic target of rapamycin', 'Gene', (268, 299))	('GBM', 'Phenotype', 'HP:0012174', (320, 323))	('mechanistic target of rapamycin', 'Gene', '2475', (268, 299))	('mutations', 'Var', (48, 57))
3159	25610711	mTORC1, which contains mTOR kinase in complex with six known components including Raptor, links upstream growth factor receptor signaling to downstream protein translation and cell proliferation through PI3K.	('links', 'Reg', (90, 95))	('Raptor', 'Gene', (82, 88))	('PI3K', 'Var', (203, 207))	('mTORC1', 'Gene', '382056', (0, 6))	('Raptor', 'Gene', '57521', (82, 88))	('mTOR', 'Gene', '2475', (0, 4))	('upstream growth factor receptor signaling', 'MPA', (96, 137))	('mTOR', 'Gene', (23, 27))	('cell proliferation', 'CPA', (176, 194))	('mTOR', 'Gene', '2475', (23, 27))	('mTOR', 'Gene', (0, 4))	('mTORC1', 'Gene', (0, 6))	('downstream protein translation', 'MPA', (141, 171))
3180	25610711	A recent work suggests that growth factor signaling through PI3K promotes mTORC2-ribosome binding to stimulate TORC2 kinase activity.	('TORC2', 'Gene', (75, 80))	('TORC2', 'Gene', '200186', (75, 80))	('mTORC2', 'Gene', (74, 80))	('mTORC2', 'Gene', '74343', (74, 80))	('promotes', 'PosReg', (65, 73))	('TORC2', 'Gene', (111, 116))	('TORC2', 'Gene', '200186', (111, 116))	('PI3K', 'Var', (60, 64))	('stimulate', 'PosReg', (101, 110))
3181	25610711	In GBM, EGFRvIII and PTEN loss, both of which can potentially promote PI3K signaling, also stimulate mTORC2 kinase.	('mTORC2', 'Gene', (101, 107))	('PI3K', 'MPA', (70, 74))	('mTORC2', 'Gene', '74343', (101, 107))	('stimulate', 'PosReg', (91, 100))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('promote', 'PosReg', (62, 69))	('PTEN', 'Gene', (21, 25))	('loss', 'Var', (26, 30))	('PTEN', 'Gene', '5728', (21, 25))
3182	25610711	PI3K-independent mechanisms of mTORC2 activation, including WNT-LRP5 signaling through the small GTPase, RAC1, during osteoblast differentiation, miR-29 regulation of YAP and Hippo pathway activation, and Notch signaling, have recently been described.	('mTORC2', 'Gene', '74343', (31, 37))	('RAC1', 'Gene', '5879', (105, 109))	('LRP5', 'Gene', '4041', (64, 68))	('RAC1', 'Gene', (105, 109))	('Hippo pathway', 'Pathway', (175, 188))	('LRP5', 'Gene', (64, 68))	('mTORC2', 'Gene', (31, 37))	('YAP', 'Gene', '10413', (167, 170))	('activation', 'PosReg', (38, 48))	('activation', 'PosReg', (189, 199))	('osteoblast differentiation', 'CPA', (118, 144))	('YAP', 'Gene', (167, 170))	('miR-29', 'Var', (146, 152))
3212	25610711	The inactivation of FoxOs releases c-Myc from a suppressive miR-34c-dependent network, which targets the 3 -UTR of c-Myc mRNA and inhibits its translation.	('c-Myc', 'Gene', '4609', (35, 40))	('inactivation', 'Var', (4, 16))	('miR-34c', 'Gene', '407042', (60, 67))	('c-Myc', 'Gene', '4609', (115, 120))	('miR-34c', 'Gene', (60, 67))	('targets', 'NegReg', (93, 100))	('translation', 'MPA', (143, 154))	('FoxOs', 'Gene', (20, 25))	('c-Myc', 'Gene', (35, 40))	('c-Myc', 'Gene', (115, 120))	('inhibits', 'NegReg', (130, 138))
3226	25610711	In GBM, SREBP1 cleavage is activated by the mutant EGFR signaling but is insensitive to rapamycin, which suggests an emerging key function of mTORC2, or is rapamycin-resistant, despite such mTORC1-dependent mechanisms as 4E-BP1 signaling in GBM lipid metabolism reprogramming.	('mTORC2', 'Gene', (142, 148))	('mTORC1', 'Gene', (190, 196))	('rapamycin', 'Chemical', 'MESH:D020123', (156, 165))	('mTORC2', 'Gene', '74343', (142, 148))	('4E-BP1', 'Gene', (221, 227))	('rapamycin', 'Chemical', 'MESH:D020123', (88, 97))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('EGFR signaling', 'Gene', (51, 65))	('GBM', 'Phenotype', 'HP:0012174', (241, 244))	('SREBP1', 'Gene', (8, 14))	('mTORC1', 'Gene', '382056', (190, 196))	('4E-BP1', 'Gene', '1978', (221, 227))	('lipid', 'Chemical', 'MESH:D008055', (245, 250))	('mutant', 'Var', (44, 50))	('activated', 'PosReg', (27, 36))	('SREBP1', 'Gene', '6720', (8, 14))
3240	25610711	The genetic depletion of rictor in the My5 precursor cells gives rise to myocytes, brown adipose tissue, and a subset of white adipose tissue, thus significantly reducing the level of ACLY in brown fat adipose tissue and protecting against the development of obesity in mice fed with a high-fat diet under thermoneutral conditions.	('rictor', 'Gene', (25, 31))	('genetic depletion', 'Var', (4, 21))	('protecting', 'Reg', (221, 231))	('obesity', 'Disease', 'MESH:D009765', (259, 266))	('rictor', 'Gene', '78757', (25, 31))	('obesity', 'Disease', (259, 266))	('reducing', 'NegReg', (162, 170))	('mice', 'Species', '10090', (270, 274))	('obesity', 'Phenotype', 'HP:0001513', (259, 266))	('level of ACLY in brown fat adipose tissue', 'MPA', (175, 216))	('depletion', 'Var', (12, 21))
3253	25610711	As an example, LDHA, which regulates aerobic glycolysis, has been associated with taxol and trastuzumab resistance; silencing LDHA is capable of sensitizing cancer cells to these drugs.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('LDHA', 'Gene', (126, 130))	('LDHA', 'Gene', '3939', (126, 130))	('associated', 'Reg', (66, 76))	('sensitizing', 'Reg', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('LDHA', 'Gene', (15, 19))	('cancer', 'Disease', (157, 163))	('taxol', 'Chemical', 'MESH:D017239', (82, 87))	('silencing', 'Var', (116, 125))	('LDHA', 'Gene', '3939', (15, 19))	('taxol', 'MPA', (82, 87))	('trastuzumab', 'Chemical', 'MESH:D000068878', (92, 103))
3261	25610711	mTORC2 inhibition can also be required to mitigate c-Myc expression and metabolic reprogramming to achieve clinical remission.	('c-Myc', 'Gene', '4609', (51, 56))	('mitigate', 'NegReg', (42, 50))	('c-Myc', 'Gene', (51, 56))	('inhibition', 'Var', (7, 17))	('mTORC2', 'Gene', (0, 6))	('mTORC2', 'Gene', '74343', (0, 6))	('metabolic reprogramming', 'CPA', (72, 95))
3267	25610711	In GBM, the mTOR kinase inhibitors CC214-1 and CC214-2 inhibit rapamycin-resistant mTORC1 and mTORC2 signaling, thus blocking protein translation, cell proliferation, and tumor growth.	('mTOR', 'Gene', (83, 87))	('CC214-2', 'Var', (47, 54))	('cell proliferation', 'CPA', (147, 165))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mTOR', 'Gene', '2475', (94, 98))	('CC214-1', 'Var', (35, 42))	('mTOR', 'Gene', (12, 16))	('inhibit', 'NegReg', (55, 62))	('mTOR', 'Gene', '2475', (83, 87))	('mTORC1', 'Gene', (83, 89))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('mTORC1', 'Gene', '382056', (83, 89))	('mTOR', 'Gene', '2475', (12, 16))	('rapamycin', 'Chemical', 'MESH:D020123', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('mTORC2', 'Gene', (94, 100))	('blocking', 'NegReg', (117, 125))	('mTORC2', 'Gene', '74343', (94, 100))	('mTOR', 'Gene', (94, 98))	('protein translation', 'MPA', (126, 145))	('tumor', 'Disease', (171, 176))
3293	23018764	PCI resulted in a 5- to 10-fold increase in GFP protein expression compared to controls.	('PCI', 'Var', (0, 3))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('increase', 'PosReg', (32, 40))	('GFP protein', 'Protein', (44, 55))	('P', 'Chemical', 'MESH:D010758', (46, 47))
3294	23018764	PCI-bPEI/PTEN or PCI-PS/PTEN transfection of either U251 monolayers or U87 spheroids significantly inhibited their growth.	('PTEN', 'Gene', '5728', (24, 28))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('U87', 'Gene', (71, 74))	('PTEN', 'Gene', (9, 13))	('inhibited', 'NegReg', (99, 108))	('P', 'Chemical', 'MESH:D010758', (24, 25))	('PTEN', 'Gene', '5728', (9, 13))	('U251', 'CellLine', 'CVCL:0021', (52, 56))	('P', 'Chemical', 'MESH:D010758', (17, 18))	('P', 'Chemical', 'MESH:D010758', (21, 22))	('U87', 'Gene', '641648', (71, 74))	('bPEI', 'Chemical', '-', (4, 8))	('P', 'Chemical', 'MESH:D010758', (9, 10))	('growth', 'MPA', (115, 121))	('P', 'Chemical', 'MESH:D010758', (5, 6))	('PTEN', 'Gene', (24, 28))	('transfection', 'Var', (29, 41))
3296	23018764	In addition PCI-GFP transfection of gliomas cells had no effect on their growth pattern.	('transfection', 'Var', (20, 32))	('gliomas', 'Disease', (36, 43))	('gliomas', 'Disease', 'MESH:D005910', (36, 43))	('growth pattern', 'CPA', (73, 87))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('gliomas', 'Phenotype', 'HP:0009733', (36, 43))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('P', 'Chemical', 'MESH:D010758', (12, 13))
3297	23018764	Collectively, the results suggest that AlPcS2a-mediated PCI can be used to enhance cell growth inhibition via transfection of tumor suppressor genes in glioma cells containing mutant PTEN genes.	('PTEN', 'Gene', (183, 187))	('PTEN', 'Gene', '5728', (183, 187))	('mutant', 'Var', (176, 182))	('glioma', 'Disease', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('cell growth inhibition', 'CPA', (83, 105))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('P', 'Chemical', 'MESH:D010758', (56, 57))	('P', 'Chemical', 'MESH:D010758', (183, 184))	('enhance', 'PosReg', (75, 82))	('tumor', 'Disease', (126, 131))
3314	23018764	The aim of the present research was designed to evaluate the effects of PCI on protamine sulfate (PS) or PEI-mediated wild-type PTEN gene restoration in PTEN mutated U87 and U251 human glioma cells.	('U87', 'Gene', (166, 169))	('P', 'Chemical', 'MESH:D010758', (98, 99))	('human', 'Species', '9606', (179, 184))	('P', 'Chemical', 'MESH:D010758', (128, 129))	('U251', 'CellLine', 'CVCL:0021', (174, 178))	('PEI', 'Chemical', 'MESH:D011094', (105, 108))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('U87', 'Gene', '641648', (166, 169))	('PTEN', 'Gene', (153, 157))	('glioma', 'Disease', 'MESH:D005910', (185, 191))	('PTEN', 'Gene', '5728', (153, 157))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('P', 'Chemical', 'MESH:D010758', (72, 73))	('mutated', 'Var', (158, 165))	('P', 'Chemical', 'MESH:D010758', (153, 154))	('P', 'Chemical', 'MESH:D010758', (105, 106))	('glioma', 'Disease', (185, 191))
3318	23018764	Both glioma lines have been demonstrated to have a mutated PTEN gene caused by sequence insertions or deletions resulting in frameshifts.	('frameshifts', 'MPA', (125, 136))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))	('caused', 'Reg', (69, 75))	('deletions', 'Var', (102, 111))	('glioma', 'Disease', (5, 11))	('PTEN', 'Gene', (59, 63))	('glioma', 'Disease', 'MESH:D005910', (5, 11))	('PTEN', 'Gene', '5728', (59, 63))	('mutated', 'Var', (51, 58))
3356	23018764	To determine the direct toxicity of the two types of gene carriers used here, 5,000 U251 cells/well in a 96-well plate were incubated in media (200 mul/well) containing either bPEI/GFP or PS/GFP polyplexes at various concentrations for 18 hours, followed by replacement with fresh media.	('P', 'Chemical', 'MESH:D010758', (188, 189))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('toxicity', 'Disease', (24, 32))	('U251', 'CellLine', 'CVCL:0021', (84, 88))	('P', 'Chemical', 'MESH:D010758', (183, 184))	('P', 'Chemical', 'MESH:D010758', (193, 194))	('bPEI/GFP', 'Var', (176, 184))	('P', 'Chemical', 'MESH:D010758', (177, 178))	('bPEI', 'Chemical', '-', (176, 180))
3363	23018764	PCI increased the number of GFP positive cells from 15% to 27% for bPEI/GFP and from 3% to 37% for PS/GFP, respectively (Fig.	('P', 'Chemical', 'MESH:D010758', (99, 100))	('PCI', 'Var', (0, 3))	('P', 'Chemical', 'MESH:D010758', (30, 31))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('bPEI', 'Chemical', '-', (67, 71))	('GFP', 'Protein', (28, 31))	('P', 'Chemical', 'MESH:D010758', (104, 105))	('increased', 'PosReg', (4, 13))	('P', 'Chemical', 'MESH:D010758', (74, 75))
3364	23018764	Cell growth inhibition following PTEN gene transfer was investigated in U251 glioma cells transfected using bPEI/PTEN or PS/PTEN polyplexes, either alone or combined with PCI.	('P', 'Chemical', 'MESH:D010758', (109, 110))	('P', 'Chemical', 'MESH:D010758', (171, 172))	('P', 'Chemical', 'MESH:D010758', (113, 114))	('PTEN', 'Gene', (124, 128))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('PTEN', 'Gene', '5728', (124, 128))	('polyplexes', 'Var', (129, 139))	('U251', 'CellLine', 'CVCL:0021', (72, 76))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('P', 'Chemical', 'MESH:D010758', (121, 122))	('PTEN', 'Gene', (113, 117))	('glioma', 'Disease', (77, 83))	('PTEN', 'Gene', '5728', (113, 117))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('P', 'Chemical', 'MESH:D010758', (33, 34))	('bPEI', 'Chemical', '-', (108, 112))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
3370	23018764	In contrast, following light treatment significant growth inhibition (P < 0.001) was observed for PTEN gene transfection at DNA concentrations of 1 or 2 mug/ml for both PS and bPEI.	('P', 'Chemical', 'MESH:D010758', (98, 99))	('P', 'Chemical', 'MESH:D010758', (70, 71))	('PTEN', 'Gene', (98, 102))	('transfection', 'Var', (108, 120))	('P', 'Chemical', 'MESH:D010758', (169, 170))	('PTEN', 'Gene', '5728', (98, 102))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('growth', 'MPA', (51, 57))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('P', 'Chemical', 'MESH:D010758', (177, 178))	('bPEI', 'Chemical', '-', (176, 180))
3371	23018764	As can be seen from Figure 5b no significant inhibition of cell growth was observed for the PS/GFP transfection both in the absence or presence of light treatment.	('transfection', 'Var', (99, 111))	('P', 'Chemical', 'MESH:D010758', (92, 93))	('P', 'Chemical', 'MESH:D010758', (97, 98))	('PS/GFP', 'Gene', (92, 98))
3381	23018764	To ascertain the effects of PCI-PTEN transfection, on the growth and development of U87 spheroids experiments were performed consisting of four groups: (1) untreated control, (2) AlPcS2a-PDT, (3) PS/PTEN-GFP, and (4) AlPcS2a-PCI PS/PTEN-GFP.	('PTEN', 'Gene', '5728', (199, 203))	('P', 'Chemical', 'MESH:D010758', (196, 197))	('P', 'Chemical', 'MESH:D010758', (219, 220))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('P', 'Chemical', 'MESH:D010758', (225, 226))	('P', 'Chemical', 'MESH:D010758', (187, 188))	('AlPcS2a-PDT', 'Var', (179, 190))	('U87', 'Gene', '641648', (84, 87))	('P', 'Chemical', 'MESH:D010758', (232, 233))	('P', 'Chemical', 'MESH:D010758', (199, 200))	('PTEN', 'Gene', (32, 36))	('P', 'Chemical', 'MESH:D010758', (229, 230))	('PTEN', 'Gene', (232, 236))	('P', 'Chemical', 'MESH:D010758', (32, 33))	('PTEN', 'Gene', (199, 203))	('P', 'Chemical', 'MESH:D010758', (239, 240))	('P', 'Chemical', 'MESH:D010758', (181, 182))	('U87', 'Gene', (84, 87))	('P', 'Chemical', 'MESH:D010758', (206, 207))	('PTEN', 'Gene', '5728', (32, 36))	('PTEN', 'Gene', '5728', (232, 236))
3386	23018764	In contrast, the average volume of the PCI-PS/PTEN transfected spheroids were significantly reduced (P < 0.05) at both DNA concentrations.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('PTEN', 'Gene', (46, 50))	('transfected', 'Var', (51, 62))	('P', 'Chemical', 'MESH:D010758', (46, 47))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('PTEN', 'Gene', '5728', (46, 50))	('P', 'Chemical', 'MESH:D010758', (101, 102))	('reduced', 'NegReg', (92, 99))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('P', 'Chemical', 'MESH:D010758', (43, 44))
3387	23018764	The mechanisms leading to GBM development are not well understood but animal studies support the hypothesis that inactivation or mutations of tumor suppressor genes in neural stem cells (NSC), transforming them to tumor stem cells (TSC), is required and sufficient to induce glial cancers.	('N', 'Chemical', 'MESH:D009584', (187, 188))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('glial cancers', 'Disease', 'MESH:D009369', (275, 288))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (142, 147))	('glial cancers', 'Disease', (275, 288))	('mutations', 'Var', (129, 138))	('induce', 'Reg', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('tumor', 'Disease', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('inactivation', 'Var', (113, 125))
3395	23018764	More importantly PCI-enhanced transfection of PS/PTEN polyplexes, into both PTEN mutant cell lines U251 and U87 spheroids, greatly inhibited their growth potential compared to conventional bPEI transfection alone.	('PTEN', 'Gene', '5728', (49, 53))	('growth potential', 'CPA', (147, 163))	('U87', 'Gene', '641648', (108, 111))	('PTEN', 'Gene', (76, 80))	('U251', 'CellLine', 'CVCL:0021', (99, 103))	('P', 'Chemical', 'MESH:D010758', (46, 47))	('PTEN', 'Gene', '5728', (76, 80))	('P', 'Chemical', 'MESH:D010758', (17, 18))	('P', 'Chemical', 'MESH:D010758', (49, 50))	('P', 'Chemical', 'MESH:D010758', (76, 77))	('mutant', 'Var', (81, 87))	('bPEI', 'Chemical', '-', (189, 193))	('inhibited', 'NegReg', (131, 140))	('P', 'Chemical', 'MESH:D010758', (190, 191))	('U87', 'Gene', (108, 111))	('PTEN', 'Gene', (49, 53))	('transfection', 'MPA', (30, 42))
3396	23018764	PCI-PTEN transfection significantly inhibited both the growth of U251 monolayers and their transforming ability to produce secondary colonies (Table 1), as well as significantly inhibiting the growth of U87 multi cell tumor spheroids.	('PTEN', 'Gene', '5728', (4, 8))	('U87', 'Gene', '641648', (203, 206))	('inhibited', 'NegReg', (36, 45))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('U251', 'CellLine', 'CVCL:0021', (65, 69))	('inhibiting', 'NegReg', (178, 188))	('P', 'Chemical', 'MESH:D010758', (4, 5))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('growth', 'CPA', (55, 61))	('growth', 'CPA', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('transforming ability to produce secondary colonies', 'CPA', (91, 141))	('tumor', 'Disease', (218, 223))	('transfection', 'Var', (9, 21))	('U87', 'Gene', (203, 206))	('PTEN', 'Gene', (4, 8))
3404	23018764	However, as seen in Figure 5, PEI displays only moderate endosomolytic activity since gene transfection was clearly enhanced by PCI.	('PEI', 'Chemical', 'MESH:D011094', (30, 33))	('enhanced', 'PosReg', (116, 124))	('P', 'Chemical', 'MESH:D010758', (30, 31))	('gene transfection', 'CPA', (86, 103))	('PCI', 'Var', (128, 131))	('P', 'Chemical', 'MESH:D010758', (128, 129))
3410	23018764	Since PCI greatly enhances endosomal escape, the dramatic effects of PCI shown in Figure 5 for PS/DNA polyplexes support this interpretation.	('P', 'Chemical', 'MESH:D010758', (95, 96))	('PCI', 'Var', (6, 9))	('P', 'Chemical', 'MESH:D010758', (6, 7))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('endosomal escape', 'MPA', (27, 43))	('P', 'Chemical', 'MESH:D010758', (69, 70))	('enhances', 'PosReg', (18, 26))
3422	23018764	In addition these authors reported that combined gene therapy, using up regulation of wild-type PTEN reconstruct and VEGF or EGFR siRNA knock down, could demonstrate increased inhibition of tumor growth both in vitro and in vivo compared to PTEN reconstruction alone.	('inhibition', 'NegReg', (176, 186))	('PTEN', 'Gene', '5728', (96, 100))	('VEGF', 'Gene', (117, 121))	('PTEN', 'Gene', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('PTEN', 'Gene', '5728', (241, 245))	('EGFR', 'Gene', '1956', (125, 129))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('VEGF', 'Gene', '7422', (117, 121))	('EGFR', 'Gene', (125, 129))	('tumor', 'Disease', (190, 195))	('N', 'Chemical', 'MESH:D009584', (244, 245))	('knock down', 'Var', (136, 146))	('PTEN', 'Gene', (96, 100))	('up regulation', 'PosReg', (69, 82))
3425	24821384	Di-Ethylhexylphthalate (DEHP) Modulates Cell Invasion, Migration and Anchorage Independent Growth through Targeting S100P in LN-229 Glioblastoma Cells Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a median survival of 1-2 years.	('brain cancer', 'Phenotype', 'HP:0030692', (204, 216))	('Glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Modulates', 'Reg', (30, 39))	('Glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('aggressive brain cancer', 'Disease', (193, 216))	('aggressive brain cancer', 'Disease', 'MESH:D001932', (193, 216))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (151, 174))	('Glioblastoma', 'Disease', (151, 163))	('Glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('S100P', 'Gene', '6286', (116, 121))	('S100P', 'Gene', (116, 121))	('Di-Ethylhexylphthalate', 'Chemical', 'MESH:D004051', (0, 22))	('Cell', 'CPA', (40, 44))	('Glioblastoma', 'Disease', (132, 144))	('Targeting', 'Var', (106, 115))	('Glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('Glioblastoma multiforme', 'Disease', (151, 174))	('LN-229', 'CellLine', 'CVCL:0393', (125, 131))	('DEHP', 'Chemical', 'MESH:D004051', (24, 28))	('aggressive brain', 'Phenotype', 'HP:0000718', (193, 209))
3431	24821384	Silencing S100P and DEHP treatment inhibited LN-229 glioblastoma cell proliferation and induced apoptosis.	('S100P', 'Gene', (10, 15))	('induced', 'Reg', (88, 95))	('LN-229', 'CellLine', 'CVCL:0393', (45, 51))	('apoptosis', 'CPA', (96, 105))	('glioblastoma', 'Disease', (52, 64))	('inhibited', 'NegReg', (35, 44))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('DEHP', 'Chemical', 'MESH:D004051', (20, 24))	('S100P', 'Gene', '6286', (10, 15))	('Silencing', 'Var', (0, 9))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))
3432	24821384	Anchorage independent growth study revealed significantly decreased colony formation in shS100P cells.	('shS100P', 'Chemical', '-', (88, 95))	('decreased', 'NegReg', (58, 67))	('shS100P', 'Var', (88, 95))	('colony formation', 'CPA', (68, 84))
3496	24821384	To verify S100P knockdown in LN-229 cells, western blot analysis was performed (Figure 1A).	('S100P', 'Gene', '6286', (10, 15))	('S100P', 'Gene', (10, 15))	('LN-229', 'CellLine', 'CVCL:0393', (29, 35))	('knockdown', 'Var', (16, 25))
3497	24821384	The protein expression diminished to nearly non-detectable levels in the LN-229 cells infected with shS100P, compared with those infected with the control shGFP or uninfected LN-229 cells and no changes in beta-actin expression were observed.	('LN-229', 'CellLine', 'CVCL:0393', (73, 79))	('protein', 'Protein', (4, 11))	('LN-229', 'CellLine', 'CVCL:0393', (175, 181))	('diminished', 'NegReg', (23, 33))	('shS100P', 'Chemical', '-', (100, 107))	('beta-actin', 'Gene', (206, 216))	('beta-actin', 'Gene', '728378', (206, 216))	('shS100P', 'Var', (100, 107))
3498	24821384	We next asked whether shS100P knockdown is sufficient to suppress the proliferation of LN-229.	('shS100P', 'Chemical', '-', (22, 29))	('proliferation', 'CPA', (70, 83))	('suppress', 'NegReg', (57, 65))	('LN-229', 'CellLine', 'CVCL:0393', (87, 93))	('knockdown', 'Var', (30, 39))	('LN-229', 'Gene', (87, 93))	('shS100P', 'Gene', (22, 29))
3499	24821384	Viability of LN-229 cells was measured by proliferation assay upon S100P knockdown (Figure 1B).	('proliferation assay', 'CPA', (42, 61))	('LN-229', 'CellLine', 'CVCL:0393', (13, 19))	('S100P', 'Gene', '6286', (67, 72))	('S100P', 'Gene', (67, 72))	('knockdown', 'Var', (73, 82))
3500	24821384	Results showed that shS100P significantly inhibited LN-229 cells proliferation (Figure 1B).	('LN-229 cells proliferation', 'CPA', (52, 78))	('shS100P', 'Chemical', '-', (20, 27))	('inhibited', 'NegReg', (42, 51))	('LN-229', 'CellLine', 'CVCL:0393', (52, 58))	('shS100P', 'Var', (20, 27))
3503	24821384	Treatment of glioblastoma cells with DEHP significantly inhibited cell proliferation with a 47% decrease in proliferation compared to control (Figure 2, p < 0.05).	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('cell proliferation', 'CPA', (66, 84))	('DEHP', 'Chemical', 'MESH:D004051', (37, 41))	('decrease', 'NegReg', (96, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('proliferation', 'CPA', (108, 121))	('DEHP', 'Var', (37, 41))	('inhibited', 'NegReg', (56, 65))
3504	24821384	However, conjoint knockdown of S100P and DEHP treatment led to a greater inhibition (53%, p < 0.001) of LN-229 proliferation compared to either experimental group alone (Figure 2).	('knockdown', 'Var', (18, 27))	('LN-229 proliferation', 'CPA', (104, 124))	('S100P', 'Gene', '6286', (31, 36))	('inhibition', 'NegReg', (73, 83))	('S100P', 'Gene', (31, 36))	('LN-229', 'CellLine', 'CVCL:0393', (104, 110))	('DEHP', 'Chemical', 'MESH:D004051', (41, 45))
3505	24821384	We next sought to characterize the effect of S100P, DEHP and in combination on cell death.	('DEHP', 'Var', (52, 56))	('S100P', 'Gene', (45, 50))	('DEHP', 'Chemical', 'MESH:D004051', (52, 56))	('S100P', 'Gene', '6286', (45, 50))
3507	24821384	There was a significant increase in apoptosis in shS100P LN-229 cells treated with DEHP compared to the control.	('DEHP', 'Var', (83, 87))	('shS100P', 'Chemical', '-', (49, 56))	('apoptosis', 'CPA', (36, 45))	('shS100P', 'Gene', (49, 56))	('LN-229', 'CellLine', 'CVCL:0393', (57, 63))	('DEHP', 'Chemical', 'MESH:D004051', (83, 87))
3511	24821384	shS100P LN-229 cells showed significant reduction in the colony formation (Figure 4).	('shS100P', 'Chemical', '-', (0, 7))	('colony formation', 'CPA', (57, 73))	('reduction', 'NegReg', (40, 49))	('shS100P', 'Var', (0, 7))	('LN-229', 'CellLine', 'CVCL:0393', (8, 14))
3524	24821384	In this study, we hypothesized that DEHP modulates cell migration, invasion and anchorage independent growth through targeting S100P in LN-229 glioblastoma cells.	('S100P', 'Gene', (127, 132))	('glioblastoma', 'Disease', (143, 155))	('LN-229', 'CellLine', 'CVCL:0393', (136, 142))	('DEHP', 'Chemical', 'MESH:D004051', (36, 40))	('invasion', 'CPA', (67, 75))	('cell migration', 'CPA', (51, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('modulates', 'Reg', (41, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('targeting', 'Var', (117, 126))	('DEHP', 'Gene', (36, 40))	('S100P', 'Gene', '6286', (127, 132))	('anchorage independent growth', 'CPA', (80, 108))
3530	24821384	In this study, we demonstrate that knockdown of S100P expression significantly inhibited cell proliferation and anchorage independent growth in LN-229 cells.	('knockdown', 'Var', (35, 44))	('LN-229', 'CellLine', 'CVCL:0393', (144, 150))	('cell proliferation', 'CPA', (89, 107))	('S100P', 'Gene', (48, 53))	('anchorage independent growth', 'CPA', (112, 140))	('inhibited', 'NegReg', (79, 88))	('S100P', 'Gene', '6286', (48, 53))
3531	24821384	A similar study of S100P knockdown in colon cancer cells also exhibited proliferation rates lower in the knockdown cells when compared to colon cancer cells expressing S100P.	('S100P', 'Gene', (168, 173))	('colon cancer', 'Disease', (138, 150))	('proliferation rates', 'CPA', (72, 91))	('S100P', 'Gene', '6286', (19, 24))	('knockdown', 'Var', (105, 114))	('S100P', 'Gene', (19, 24))	('lower', 'NegReg', (92, 97))	('colon cancer', 'Disease', 'MESH:D015179', (38, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (38, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))	('S100P', 'Gene', '6286', (168, 173))	('colon cancer', 'Disease', 'MESH:D015179', (138, 150))	('colon cancer', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
3540	24821384	Our study revealed that blocking S100P expression inhibited glioblastoma cell migration and invasion.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('expression', 'Protein', (39, 49))	('S100P', 'Gene', '6286', (33, 38))	('invasion', 'CPA', (92, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('S100P', 'Gene', (33, 38))	('blocking', 'Var', (24, 32))	('inhibited', 'NegReg', (50, 59))
3544	24821384	Moreover, the resultant of shS100P and DEHP exposure are not additive implicating the predominant effects of DEHP on cell migration.	('shS100P', 'Chemical', '-', (27, 34))	('cell migration', 'CPA', (117, 131))	('DEHP', 'Chemical', 'MESH:D004051', (39, 43))	('DEHP', 'Chemical', 'MESH:D004051', (109, 113))	('shS100P', 'Var', (27, 34))
3552	24821384	Furthermore, our study revealed that silencing S100P using lentiviral mediated RNAi significantly inhibited glioblastoma cell growth and invasion.	('inhibited', 'NegReg', (98, 107))	('S100P', 'Gene', (47, 52))	('S100P', 'Gene', '6286', (47, 52))	('silencing', 'Var', (37, 46))	('glioblastoma', 'Disease', (108, 120))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
3555	24821384	Moreover, exposure of glioblastoma cells to DEHP revealed a significant inhibition of cell migration and invasion as well as led to a significant reduction in cell proliferation.	('invasion', 'CPA', (105, 113))	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('DEHP', 'Chemical', 'MESH:D004051', (44, 48))	('cell migration', 'CPA', (86, 100))	('DEHP', 'Var', (44, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('cell proliferation', 'CPA', (159, 177))	('reduction', 'NegReg', (146, 155))	('inhibition', 'NegReg', (72, 82))
3561	24685274	Importantly, arsenic trioxide markedly reduced clonogenic capacity of the tumor neurospheres, and the stem-like CD133-positive fraction was also diminished along with expression of the stem cell markers SOX2 and CD133.	('SOX2', 'Gene', (203, 207))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('arsenic', 'Var', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CD133', 'Gene', (112, 117))	('tumor', 'Disease', (74, 79))	('diminished', 'NegReg', (145, 155))	('reduced', 'NegReg', (39, 46))	('CD133', 'Gene', '8842', (112, 117))	('CD133', 'Gene', (212, 217))	('CD133', 'Gene', '8842', (212, 217))	('SOX2', 'Gene', '6657', (203, 207))
3584	24685274	None are mutated at the IDH1 locus, and HSR-GBM1 and 040622 lack alterations in p53, while 040821 cells have a mutation in p53 exon 7 resulting in substitution of serine for proline in amino acid 278.	('HSR', 'Gene', (40, 43))	('IDH1', 'Gene', '3417', (24, 28))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('HSR', 'Gene', '338386', (40, 43))	('p53', 'Gene', (80, 83))	('substitution', 'Var', (147, 159))	('p53', 'Gene', '7157', (80, 83))	('serine for proline in amino acid 278', 'Mutation', 'rs17849781', (163, 199))	('p53', 'Gene', (123, 126))	('IDH1', 'Gene', (24, 28))	('mutation', 'Var', (111, 119))	('p53', 'Gene', '7157', (123, 126))
3596	24685274	Proteins were extracted from HSR-GBM1, 040622 and 040821 treated with ATO for 72 hours.	('HSR', 'Gene', (29, 32))	('GBM', 'Phenotype', 'HP:0012174', (33, 36))	('HSR', 'Gene', '338386', (29, 32))	('040821', 'Var', (50, 56))	('ATO', 'Chemical', 'MESH:D000077237', (70, 73))
3629	24685274	In addition, ATO also resulted in a dose-dependent decrease of HES1 and HES5 at the protein level, further confirming the effect of ATO on Notch signaling (Figure 3C).	('HES5', 'Gene', '388585', (72, 76))	('HES1', 'Gene', '3280', (63, 67))	('ATO', 'Chemical', 'MESH:D000077237', (13, 16))	('HES5', 'Gene', (72, 76))	('HES1', 'Gene', (63, 67))	('decrease', 'NegReg', (51, 59))	('ATO', 'Var', (13, 16))	('ATO', 'Chemical', 'MESH:D000077237', (132, 135))
3634	24685274	The number of spheres over 100 muM in size was significantly reduced following ATO treatment in HSR-GBM1 and 040821 cells (Figure 4), while a modest non-significant reduction was seen in 040622 cells (data not shown).	('muM', 'Gene', '56925', (31, 34))	('HSR', 'Gene', (96, 99))	('muM', 'Gene', (31, 34))	('GBM', 'Phenotype', 'HP:0012174', (100, 103))	('ATO', 'Chemical', 'MESH:D000077237', (79, 82))	('HSR', 'Gene', '338386', (96, 99))	('ATO', 'Var', (79, 82))	('reduced', 'NegReg', (61, 68))
3645	24685274	Zhen and colleagues treated three adherent GBM lines (U87MG, U251MG and U373MG) with ATO and reported decreased protein levels of the Notch1 receptor and HES1 target, as well as reductions in growth in vitro and in vivo .	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('U373MG', 'CellLine', 'CVCL:2219', (72, 78))	('U251MG', 'CellLine', 'CVCL:0021', (61, 67))	('Notch1', 'Gene', '4851', (134, 140))	('U251MG', 'Var', (61, 67))	('ATO', 'Chemical', 'MESH:D000077237', (85, 88))	('U87MG', 'CellLine', 'CVCL:0022', (54, 59))	('protein levels', 'MPA', (112, 126))	('U87MG', 'Var', (54, 59))	('HES1', 'Gene', (154, 158))	('growth', 'MPA', (192, 198))	('U373MG', 'Var', (72, 78))	('reductions', 'NegReg', (178, 188))	('HES1', 'Gene', '3280', (154, 158))	('Notch1', 'Gene', (134, 140))	('decreased', 'NegReg', (102, 111))
3649	24685274	We found that ATO inhibits growth and clonogenicity with induction of apoptosis in all three lines.	('inhibits', 'NegReg', (18, 26))	('ATO', 'Chemical', 'MESH:D000077237', (14, 17))	('ATO', 'Var', (14, 17))
3663	23192213	Histological examination revealed the existence of highly coherent tumor organizations (circular for 9L and F98 or radial for GBM22) in the tumor rims.	('tumor rims', 'Disease', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor rims', 'Disease', 'MESH:C536816', (140, 150))	('tumor', 'Disease', (67, 72))	('F98', 'Var', (108, 111))	('tumor', 'Disease', (140, 145))
3665	23192213	There were significantly lower FA and higher lambda  in the ipsilateral white matter than in the contralateral white matter for the GBM22 tumor, whereas there were no differences for the 9L and F98 tumors.	('lambda', 'MPA', (45, 51))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('F98 tumors', 'Disease', (194, 204))	('GBM22', 'Var', (132, 137))	('lower', 'NegReg', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('higher', 'PosReg', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('F98 tumors', 'Disease', 'MESH:D009369', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
3712	23192213	There were different diffusion patterns on ADC maps within GBM22 tumors, compared to 9L and F98 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('F98 tumors', 'Disease', (92, 102))	('ADC maps', 'MPA', (43, 51))	('to 9', 'Species', '1214577', (82, 86))	('diffusion patterns', 'MPA', (21, 39))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('GBM22', 'Var', (59, 64))	('F98 tumors', 'Disease', 'MESH:D009369', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
3718	23192213	Significantly higher FA values were found in the tumor rim of F98 and GBM22 than in the tumor center (p = 0.01 and p <0.001, respectively).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('FA values', 'MPA', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('GBM22', 'Gene', (70, 75))	('tumor', 'Disease', (49, 54))	('F98', 'Var', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('higher', 'PosReg', (14, 20))
3732	23192213	These patterns were more obvious in F98 and GBM22 tumors.	('F98', 'Var', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
3786	34013207	In particular, 18F-FET PET has been recently shown to facilitate improved differentiation of TRC from TPR with high diagnostic accuracies, in the range of 80-90%.	('TPR', 'Gene', (102, 105))	('18F-FET', 'Chemical', 'MESH:C117289', (15, 22))	('TR', 'Gene', '2149', (93, 95))	('TPR', 'Gene', '7175', (102, 105))	('18F-FET PET', 'Var', (15, 26))	('facilitate improved', 'PosReg', (54, 73))
3832	34013207	Given the exploratory nature of this work and the restrictive nature of the Bonferroni correction, we additionally regarded non-corrected alpha = 0.05 and refer to the findings with 0.003 < P <= .05 for DT/KT metrics and with 0.0125 < P <= .05 as "significant prior to correction."	('KT', 'Chemical', '-', (206, 208))	('0.0125 <', 'Var', (226, 234))	('DT', 'Chemical', '-', (203, 205))	('0.003 <', 'Var', (182, 189))	('DT/KT metrics', 'MPA', (203, 216))
3854	34013207	The combination of MK C90 and TBRmax resulted in the highest diagnostic accuracy (94%) with an AUC of 0.97 (Table 2, bottom panel).	('TBRmax', 'Chemical', '-', (30, 36))	('diagnostic', 'MPA', (61, 71))	('MK C90', 'Var', (19, 25))	('TBRmax', 'Gene', (30, 36))	('MK C90', 'Chemical', '-', (19, 25))
3883	34013207	Nevertheless, 18F-FET PET has shown good diagnostic accuracy in discriminating between TRC and TPR.	('TPR', 'Gene', '7175', (95, 98))	('18F-FET', 'Var', (14, 21))	('TR', 'Gene', '2149', (87, 89))	('18F-FET', 'Chemical', 'MESH:C117289', (14, 21))	('TPR', 'Gene', (95, 98))
3902	33543833	GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter.	('CD44', 'Var', (34, 38))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('high P/C ratio', 'Var', (16, 30))	('shorter', 'NegReg', (162, 169))	('survival time', 'CPA', (125, 138))	('Bev', 'Chemical', 'MESH:D000068258', (68, 71))	('refractory', 'MPA', (54, 64))
3906	33543833	CD44 reduces the antitumor effect of Bev, resulting in much more highly invasive tumors.	('more highly', 'PosReg', (60, 71))	('invasive tumors', 'Disease', 'MESH:D009361', (72, 87))	('tumor', 'Disease', (21, 26))	('CD44', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('Bev', 'Chemical', 'MESH:D000068258', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('reduces', 'NegReg', (5, 12))	('invasive tumors', 'Disease', (72, 87))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
3917	33543833	We previously reported that GBM expressing high CD44 in the tumor periphery shows a highly invasive phenotype on MRI and is associated with worse outcomes than GBM expressing low CD44.	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('associated', 'Reg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('tumor', 'Disease', (60, 65))	('high CD44', 'Var', (43, 52))
3918	33543833	11  Among eight patients expressing high CD44, three patients who expressed CD44 at a very high level in the tumor periphery showed early tumor progression within 2 months after Bev therapy at tumor recurrence.	('Bev', 'Chemical', 'MESH:D000068258', (178, 181))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('CD44', 'Var', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
3936	33543833	Other features, including the status of methylation of the O (6)-methylguanine-DNA methyltransferase promoter, isocitrate dehydrogenase 1 (IDH1) mutation, and Ki-67 staining index were evaluated with immunohistochemical analysis and also examined for their associations to responsiveness to Bev.	('mutation', 'Var', (145, 153))	('IDH1', 'Gene', (139, 143))	('isocitrate dehydrogenase 1', 'Gene', (111, 137))	('IDH1', 'Gene', '3417', (139, 143))	('O (6)-methylguanine-DNA methyltransferase', 'Gene', '4255', (59, 100))	('Bev', 'Chemical', 'MESH:D000068258', (291, 294))	('isocitrate dehydrogenase 1', 'Gene', '3417', (111, 137))
3943	33543833	GSC-HI (previously designated SFC-2) was established from the primary cell culture of tissues surgically obtained from the tumor periphery of an invasive-type GBM expressing high CD44.	('tumor', 'Disease', (123, 128))	('high CD44', 'Var', (174, 183))	('GSC-HI', 'Chemical', '-', (0, 6))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
3948	33543833	GSC lines were treated with VEGF small interfering RNA (siRNA) or Bev to examine the relationship between intracellular and extracellular VEGF and expression of CD44.	('GSC', 'Chemical', '-', (0, 3))	('small interfering', 'Var', (33, 50))	('CD44', 'Gene', (161, 165))	('Bev', 'Chemical', 'MESH:D000068258', (66, 69))
3949	33543833	Effects of silencing VEGF on CD44-mediated invasive and migratory activities of GSC lines were also investigated.	('silencing', 'Var', (11, 20))	('VEGF', 'Gene', (21, 25))	('GSC', 'Chemical', '-', (80, 83))
3996	33543833	Silencing of VEGF using VEGF siRNA significantly up-regulated both the mRNA and protein expression of CD44 in all three GSC lines (Figure 3A,B).	('protein expression', 'MPA', (80, 98))	('CD44', 'Gene', (102, 106))	('Silencing', 'Var', (0, 9))	('GSC', 'Chemical', '-', (120, 123))	('up-regulated', 'PosReg', (49, 61))
4001	33543833	The degree of invasion and migration of GSC lines was dependent on the level of CD44 expression in these cell lines, and the activities were markedly inhibited by silencing CD44 with siRNA (Figure 4A).	('migration', 'CPA', (27, 36))	('CD44', 'Gene', (173, 177))	('inhibited', 'NegReg', (150, 159))	('silencing', 'Var', (163, 172))	('invasion', 'CPA', (14, 22))	('GSC', 'Chemical', '-', (40, 43))	('CD44', 'Protein', (80, 84))
4004	33543833	These activities of invasion and migration of the GSC lines were significantly enhanced by VEGF knockdown with siRNA (Figure 4B).	('knockdown', 'Var', (96, 105))	('enhanced', 'PosReg', (79, 87))	('GSC', 'Chemical', '-', (50, 53))	('activities', 'CPA', (6, 16))	('VEGF', 'Protein', (91, 95))
4010	33543833	Immunohistochemistry revealed that the tumor generated from the transplant of GDC40(GFP)CD44 expressed CD44 in almost all tumor cells, whereas CD34-positive neovascularization was very low compared with the tumor from the transplant of GDC40(GFP) (Figure 5D, middle and right panels).	('GDC40', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CD34', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('CD34', 'Gene', '947', (143, 147))	('CD44', 'Var', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (122, 127))	('CD44', 'Var', (88, 92))
4011	33543833	The median OS times of mice with tumors generated by transplants of GDC40(GFP) and GDC40(GFP)CD44 were 67.0 and 73.0 days, respectively, showing no significant difference in OS times between the two groups (p = 0.1915).	('GDC40', 'Var', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('mice', 'Species', '10090', (23, 27))
4013	33543833	In the mice transplanted with GDC40 expressing low CD44, treatment with Bev significantly prolonged the survival time compared to no Bev treatment, but the mice transplanted with GDC40 overexpressing CD44 did not obtain a survival benefit when treated with Bev (p = 0.0013) (Figure 5E).	('Bev', 'Chemical', 'MESH:D000068258', (257, 260))	('low CD44', 'Var', (47, 55))	('CD44', 'Var', (51, 55))	('mice', 'Species', '10090', (7, 11))	('Bev', 'Chemical', 'MESH:D000068258', (72, 75))	('prolonged', 'PosReg', (90, 99))	('survival time', 'CPA', (104, 117))	('mice', 'Species', '10090', (156, 160))	('Bev', 'Chemical', 'MESH:D000068258', (133, 136))
4019	33543833	Here, we demonstrated that the P/C ratio of CD44 expression in GBM was significantly correlated with responsiveness to Bev for the treatment of recurrent GBM.	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('CD44', 'Gene', (44, 48))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('correlated', 'Reg', (85, 95))	('P/C ratio', 'Var', (31, 40))	('responsiveness to Bev for', 'MPA', (101, 126))	('Bev', 'Chemical', 'MESH:D000068258', (119, 122))
4026	33543833	We previously reported that GBMs expressing high CD44 in the tumor periphery show a highly invasive phenotype on MRI and are associated with early tumor progression and worse prognosis compared with GBMs expressing low CD44, which represent a less invasive and highly proliferative phenotype on MRI.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('high CD44', 'Var', (44, 53))	('invasive phenotype', 'MPA', (91, 109))	('associated', 'Reg', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MRI', 'Disease', (113, 116))	('tumor', 'Disease', (61, 66))
4027	33543833	11  In the present study, patients with R-type tumors expressing high CD44 in the tumor periphery of GBM showed the shortest survival time after Bev therapy, and the primary tumor showed a much more invasive type on MRI compared with patients with S-type tumors (Figure S3).	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('shortest', 'NegReg', (116, 124))	('tumors', 'Disease', (255, 261))	('Bev', 'Chemical', 'MESH:D000068258', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (82, 87))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('S-type tumors', 'Disease', (248, 261))	('tumors', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('high CD44', 'Var', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('patients', 'Species', '9606', (234, 242))	('survival', 'CPA', (125, 133))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (174, 179))	('S-type tumors', 'Disease', 'MESH:D018455', (248, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('invasive type', 'CPA', (199, 212))	('CD44', 'Var', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
4038	33543833	Inhibition of VEGF significantly enhanced invasion and migration of GSC lines whose activities were inhibited by knockdown of CD44.	('Inhibition', 'Var', (0, 10))	('CD44', 'Gene', (126, 130))	('GSC', 'Chemical', '-', (68, 71))	('VEGF', 'Gene', (14, 18))	('enhanced', 'PosReg', (33, 41))
4040	33543833	Several studies have shown that inhibition of angiogenesis may promote tumor cell invasiveness and formation of metastasis.	('inhibition', 'Var', (32, 42))	('formation of metastasis', 'CPA', (99, 122))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promote', 'PosReg', (63, 70))	('tumor', 'Disease', (71, 76))	('angiogenesis', 'CPA', (46, 58))
4044	33543833	When c-Met is upregulated by inhibition of VEGF with Bev, c-Met forms homodimers to which HGF/SF binds and promotes tumor cell invasion.	('c-Met', 'Gene', (58, 63))	('c-Met', 'Gene', '4233', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('binds', 'Interaction', (97, 102))	('c-Met', 'Gene', (5, 10))	('HGF/SF', 'Gene', (90, 96))	('promotes', 'PosReg', (107, 115))	('c-Met', 'Gene', '4233', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('HGF/SF', 'Gene', '3082', (90, 96))	('upregulated', 'PosReg', (14, 25))	('Bev', 'Chemical', 'MESH:D000068258', (53, 56))	('tumor', 'Disease', (116, 121))	('inhibition', 'Var', (29, 39))
4045	33543833	32  Also, the CD44 variant isoform, CD44v6, acts as a co-receptor for the receptor tyrosine kinase, c-Met, and promotes tumor cell invasion.	('c-Met', 'Gene', (100, 105))	('CD44v6', 'Var', (36, 42))	('c-Met', 'Gene', '4233', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('promotes', 'PosReg', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
4059	33543833	Among M-type patients, those who show a high P/C ratio of CD44 expression may develop resistance to Bev relatively early after Bev therapy, resulting in a much more highly invasive tumor.	('invasive tumor', 'Disease', (172, 186))	('Bev', 'Chemical', 'MESH:D000068258', (127, 130))	('Bev', 'Chemical', 'MESH:D000068258', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('patients', 'Species', '9606', (13, 21))	('invasive tumor', 'Disease', 'MESH:D009361', (172, 186))	('P/C ratio', 'Var', (45, 54))	('CD44', 'Gene', (58, 62))	('resistance to Bev', 'MPA', (86, 103))	('develop', 'PosReg', (78, 85))
4065	33543833	GBMs expressing CD44 at a much higher level in the tumor periphery than in the tumor core (high P/C ratio of CD44) were refractory to Bev therapy, and patients showed much shorter survival than when their tumors expressed a low P/C ratio of CD44.	('CD44', 'Var', (16, 20))	('Bev', 'Chemical', 'MESH:D000068258', (134, 137))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('shorter', 'NegReg', (172, 179))	('tumor', 'Disease', (51, 56))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('patients', 'Species', '9606', (151, 159))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Disease', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
4067	33543833	Bev treatment of mice transplanted with GSCs with low expression of CD44 induced significantly longer survival time than no Bev treatment.	('low expression', 'Var', (50, 64))	('mice', 'Species', '10090', (17, 21))	('longer', 'PosReg', (95, 101))	('survival time', 'CPA', (102, 115))	('Bev', 'Chemical', 'MESH:D000068258', (0, 3))	('CD44', 'Gene', (68, 72))	('Bev', 'Chemical', 'MESH:D000068258', (124, 127))	('GSC', 'Chemical', '-', (40, 43))
4070	33543833	In addition, GBMs expressing high CD44 in the tumor periphery show enhanced expression of CD44 by inhibition of VEGF with Bev, leading to more invasive and aggressive tumors, and resulting in earlier progression and worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))	('VEGF', 'Protein', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('CD44', 'Gene', (90, 94))	('Bev', 'Chemical', 'MESH:D000068258', (122, 125))	('CD44', 'Var', (34, 38))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (46, 51))	('inhibition', 'NegReg', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('Bev', 'Protein', (122, 125))	('expression', 'MPA', (76, 86))	('more', 'PosReg', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('progression', 'CPA', (200, 211))	('tumors', 'Disease', (167, 173))	('enhanced', 'PosReg', (67, 75))
4072	33628829	miR-193a-3p was highly expressed in glioma tissues and significantly correlated with poor survival in patients with glioma.	('correlated', 'Reg', (69, 79))	('patients', 'Species', '9606', (102, 110))	('poor', 'NegReg', (85, 89))	('miR-193a-3p', 'Var', (0, 11))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
4073	33628829	The target genes for miR-193a-3p were involved in many cancer-related signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('involved', 'Reg', (38, 46))	('miR-193a-3p', 'Var', (21, 32))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
4077	33628829	It has been confirmed that the miR-193a-3p in exosomes promotes lung cancer cell invasion by activating STAT3 signaling-induced epithelial-mesenchymal transition (EMT) and suppresses the progression of non-small-cell lung cancer via the p53/Slug/L1CAM pathway.	('lung cancer', 'Disease', (64, 75))	('STAT3', 'Gene', '6774', (104, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('lung cancer', 'Disease', (217, 228))	('STAT3', 'Gene', (104, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('promotes', 'PosReg', (55, 63))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (202, 228))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (206, 228))	('p53/Slug/L1CAM pathway', 'Pathway', (237, 259))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('activating', 'PosReg', (93, 103))	('miR-193a-3p', 'Var', (31, 42))	('suppresses', 'NegReg', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('progression', 'CPA', (187, 198))
4105	33628829	So far, a number of miRNAs with prognostic value, such as miR-196a, miR-503, and miR-26b, have been proposed.	('miR-26b', 'Gene', (81, 88))	('miR-503', 'Gene', (68, 75))	('miR-26b', 'Gene', '407017', (81, 88))	('miR-196a', 'Var', (58, 66))	('miR-503', 'Gene', '574506', (68, 75))
4107	33628829	The roles of miR-193a-3p in cancer progression have been reported that it inhibits the proliferation and migration of lung cancer and colorectal adenocarcinoma cells by targeting kirsten rat sarcoma viral oncogene (KRAS).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal adenocarcinoma', 'Disease', (134, 159))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('proliferation', 'CPA', (87, 100))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (134, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('miR-193a-3p', 'Var', (13, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('inhibits', 'NegReg', (74, 82))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('targeting', 'Reg', (169, 178))
4108	33628829	miR-193a-3p acts as a suppressor of metastatic disease progression in non-small-cell lung cancer (NSCLC) via the modulation of p53/Slug/L1CAM pathway.	('metastatic disease progression', 'CPA', (36, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('non-small-cell lung cancer', 'Disease', (70, 96))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('modulation', 'Reg', (113, 123))	('p53/Slug/L1CAM pathway', 'Pathway', (127, 149))	('miR-193a-3p', 'Var', (0, 11))	('NSCLC', 'Disease', (98, 103))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
4109	33628829	reported that miR-193a-3p is specifically downregulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer.	('BRAF', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BRAF', 'Gene', '673', (90, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('downregulated', 'NegReg', (42, 55))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-193a-3p', 'Var', (14, 25))
4110	33628829	miR-193a-3p could suppress proliferation and promote apoptosis by targeting cyclin D1 in hepatocellular carcinoma cells.	('hepatocellular carcinoma', 'Disease', (89, 113))	('cyclin D1', 'Gene', '595', (76, 85))	('suppress', 'NegReg', (18, 26))	('apoptosis', 'CPA', (53, 62))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cyclin D1', 'Gene', (76, 85))	('proliferation', 'CPA', (27, 40))	('miR-193a-3p', 'Var', (0, 11))	('promote', 'PosReg', (45, 52))	('targeting', 'Reg', (66, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))
4112	33628829	In addition, miR-193a-3p was involved in the tumorigenicity of renal cell carcinoma (RCC) tissues and cell lines and can increase the proliferation and migration by targeting ST3GalIV via PI3K/Akt pathway in RCC cells.	('ST3GalIV', 'Gene', '6484', (175, 183))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('proliferation', 'CPA', (134, 147))	('tumorigenicity', 'CPA', (45, 59))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 83))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('Akt', 'Gene', (193, 196))	('RCC', 'Disease', (208, 211))	('ST3GalIV', 'Gene', (175, 183))	('renal cell carcinoma', 'Disease', (63, 83))	('involved', 'Reg', (29, 37))	('Akt', 'Gene', '207', (193, 196))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('increase', 'PosReg', (121, 129))	('targeting', 'Reg', (165, 174))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('miR-193a-3p', 'Var', (13, 24))	('RCC', 'Disease', (85, 88))
4113	33628829	It was identified that silencing of miR-193a-3p through hypermethylation can promote HER2 positive breast cancer progress by targeting growth factor receptor bound protein 7 (GRB7), extracellular signal-regulated kinase 1/2 (ERK1/2), and forkhead box M1 (FOXM1) signaling.	('forkhead box M1', 'Gene', (238, 253))	('FOXM1', 'Gene', (255, 260))	('promote', 'PosReg', (77, 84))	('miR-193a-3p', 'Gene', (36, 47))	('GRB7', 'Gene', '2886', (175, 179))	('hypermethylation', 'Var', (56, 72))	('forkhead box M1', 'Gene', '2305', (238, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('growth factor receptor bound protein 7', 'Gene', '2886', (135, 173))	('silencing', 'Var', (23, 32))	('HER2', 'Gene', (85, 89))	('targeting', 'Reg', (125, 134))	('HER2', 'Gene', '2064', (85, 89))	('growth factor receptor bound protein 7', 'Gene', (135, 173))	('GRB7', 'Gene', (175, 179))	('FOXM1', 'Gene', '2305', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
4117	33628829	For example, miR-204-5p suppresses EMT and snail family transcriptional repressor 2 (STAT3) signaling pathways by targeting SNAI2, (SUZ12) polycomb repressive complex 2 subunit HDAC1, and Janus kinase 2 (JAK2).	('HDAC1', 'Gene', (177, 182))	('EMT', 'CPA', (35, 38))	('Janus kinase 2', 'Gene', '3717', (188, 202))	('JAK2', 'Gene', (204, 208))	('HDAC1', 'Gene', '3065', (177, 182))	('miR-204-5p', 'Chemical', '-', (13, 23))	('DA', 'Chemical', 'MESH:C025953', (178, 180))	('SNAI2', 'Gene', (124, 129))	('snail family transcriptional repressor 2', 'Gene', (43, 83))	('SUZ12', 'Gene', '23512', (132, 137))	('miR-204-5p', 'Var', (13, 23))	('suppresses', 'NegReg', (24, 34))	('JAK2', 'Gene', '3717', (204, 208))	('SNAI2', 'Gene', '6591', (124, 129))	('snail family transcriptional repressor 2', 'Gene', '6591', (43, 83))	('SUZ12', 'Gene', (132, 137))	('targeting', 'Reg', (114, 123))	('Janus kinase 2', 'Gene', (188, 202))
4131	33009892	For example, additional gene mutations induced by the low expression of DNA mismatch repair genes in a low oxygen environment could promote a more aggressive tumour phenotype.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('low', 'NegReg', (54, 57))	('mutations', 'Var', (29, 38))	('aggressive tumour', 'Disease', 'MESH:D009369', (147, 164))	('oxygen', 'Chemical', 'MESH:D010100', (107, 113))	('promote', 'PosReg', (132, 139))	('DNA mismatch repair genes', 'Gene', (72, 97))	('aggressive tumour', 'Disease', (147, 164))
4159	33009892	The ESTIMATE algorithm revealed the immune (-1448 to 3210.47) and stromal scores (-3055.72 to 2016.62) of the 416 GBM patients.	('-3055.72', 'Var', (82, 90))	('stromal scores', 'CPA', (66, 80))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('-1448', 'Var', (44, 49))	('patients', 'Species', '9606', (118, 126))
4161	33009892	Immune/stromal scores in the non-G-CIMP cluster were remarkably higher than those in the G-CIMP cluster (Figure 1B).	('higher', 'PosReg', (64, 70))	('G-CIMP', 'Chemical', '-', (33, 39))	('Immune/stromal scores', 'CPA', (0, 21))	('G-CIMP', 'Chemical', '-', (89, 95))	('non-G-CIMP', 'Var', (29, 39))
4174	33009892	Each module was tagged with a random colour for reference: black, blue, brown, cyan, dark red, green, green yellow, grey60, light cyan, light green, light yellow, magenta, midnight blue, pink, purple, red, royal blue, salmon, tan, turquoise and yellow.	('pink', 'Var', (187, 191))	('light cyan', 'Var', (124, 134))	('cyan', 'Disease', (79, 83))	('red', 'Var', (201, 204))	('green yellow', 'Var', (102, 114))	('light green', 'Var', (136, 147))	('light yellow', 'Var', (149, 161))	('grey60', 'Var', (116, 122))	('blue, salmon', 'Species', '210139', (212, 224))	('dark red', 'Var', (85, 93))
4182	33009892	Likewise, the high-risk group patients harbouring non-G-CIMP had the shortest median survival.	('non-G-CIMP', 'Var', (50, 60))	('median survival', 'MPA', (78, 93))	('patients', 'Species', '9606', (30, 38))	('G-CIMP', 'Chemical', '-', (54, 60))	('shortest', 'NegReg', (69, 77))
4213	33009892	Recently, several genetic biomarkers, such as O(6)-methylguanine-DNA methyltransferase (MGMT) methylation, epidermal growth factor receptor variant III (EGFRvIII), vascular endothelial growth factor (VEGF) and isocitrate dehydrogenase (IDH), have been well-established in GBM.	('isocitrate dehydrogenase', 'Gene', '3417', (210, 234))	('O(6)-methylguanine-DNA methyltransferase', 'Gene', '4255', (46, 86))	('VEGF', 'Gene', (200, 204))	('vascular endothelial growth factor', 'Gene', (164, 198))	('IDH', 'Gene', (236, 239))	('MGMT', 'Gene', (88, 92))	('GBM', 'Phenotype', 'HP:0012174', (272, 275))	('vascular endothelial growth factor', 'Gene', '7422', (164, 198))	('VEGF', 'Gene', '7422', (200, 204))	('IDH', 'Gene', '3417', (236, 239))	('MGMT', 'Gene', '4255', (88, 92))	('methylation', 'Var', (94, 105))	('isocitrate dehydrogenase', 'Gene', (210, 234))
4235	32983080	This can be accomplished by gene transfer of T-cell receptors (TCRs) or chimeric antigen receptors (CARs) into autologous T cells before reinfusing them into the patient.	('patient', 'Species', '9606', (162, 169))	('gene', 'Var', (28, 32))	('TCR', 'Gene', '6962', (63, 66))	('TCR', 'Gene', (63, 66))
4237	32983080	Here, we review data on cancer/testis (CT) antigens as targets for CAR T-cell therapy and present a strategy to upregulate CT antigen expression on tumor cells via epigenetic treatment to sensitize cancer cells to CAR T-cell therapy (Figure 1).	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (198, 204))	('upregulate', 'PosReg', (112, 122))	('tumor', 'Disease', (148, 153))	('epigenetic treatment', 'Var', (164, 184))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
4265	32983080	Malignant transformation is often associated with global DNA hypomethylation, which leads to the induction of CT antigen gene expression in some tumors.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('global DNA', 'Var', (50, 60))	('CT antigen gene', 'Gene', (110, 125))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('induction', 'PosReg', (97, 106))	('Malignant transformation', 'CPA', (0, 24))	('tumors', 'Disease', 'MESH:D009369', (145, 151))
4267	32983080	This may give rise to immune-escape variants in the form of tumor cells not expressing the antigen, creating an obstacle when targeting CT antigens with immunotherapy.	('immune-escape', 'MPA', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('variants', 'Var', (36, 44))	('tumor', 'Disease', (60, 65))
4269	32983080	Therefore, epigenetic treatment can be used to sensitize cancer cells for immunotherapy, such as CAR T-cell therapy, and lead to increased elimination of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('epigenetic treatment', 'Var', (11, 31))	('cancer', 'Disease', (57, 63))	('increased', 'PosReg', (129, 138))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('elimination', 'CPA', (139, 150))
4270	32983080	For instance, in an immunocompetent murine breast cancer model, epigenetic priming of tumors combined with adoptive transfer was demonstrated to control metastatic spread.	('breast cancer', 'Disease', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('murine', 'Species', '10090', (36, 42))	('metastatic spread', 'CPA', (153, 170))	('epigenetic priming', 'Var', (64, 82))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('control', 'PosReg', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))
4283	32983080	SP17 is overexpressed in multiple cancer types, and expression is upregulated by DNMTis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('SP17', 'Gene', (0, 4))	('upregulated', 'PosReg', (66, 77))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('expression', 'MPA', (52, 62))	('cancer', 'Disease', (34, 40))	('DNMTis', 'Var', (81, 87))
4292	32983080	CARs with antigen-binding domains composed of IL13 mutants, with increased affinity for IL13RA2 and lowered affinity for IL13RA1, have been developed.	('increased', 'PosReg', (65, 74))	('mutants', 'Var', (51, 58))	('IL13', 'Gene', (121, 125))	('IL13', 'Gene', '3596', (46, 50))	('IL13', 'Gene', (46, 50))	('IL13', 'Gene', '3596', (121, 125))	('affinity', 'Interaction', (75, 83))	('IL13', 'Gene', '3596', (88, 92))	('IL13RA1', 'Gene', (121, 128))	('IL13', 'Gene', (88, 92))	('affinity', 'MPA', (108, 116))	('IL13RA1', 'Gene', '3597', (121, 128))
4297	32983080	The clinical response to immune checkpoint blockade is generally most significant in patients with tumors that carry a high mutational burden, such as melanoma and non-small-cell lung cancer, but even in these cancer types, the response varies among patients.	('cancer', 'Disease', (184, 190))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (168, 190))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (164, 190))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('lung cancer', 'Disease', (179, 190))	('patients', 'Species', '9606', (250, 258))	('mutational burden', 'Var', (124, 141))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('cancer', 'Disease', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
4300	32983080	One might speculate that epigenetic modulators also induce CT antigen expression in healthy tissue to cause serious side effects, but the induction by DNMTis seems to be tumor-specific.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('induce', 'Reg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('epigenetic modulators', 'Var', (25, 46))	('tumor', 'Disease', (170, 175))	('CT antigen', 'Protein', (59, 69))
4301	32983080	This may be due to differences in chromatin organization and epigenetic control of gene expression, leaving cancer cells more susceptible to epigenetic enhancement of CT antigen expression than normal cells, but the subject needs further clarification.	('epigenetic', 'Var', (141, 151))	('enhancement', 'PosReg', (152, 163))	('expression', 'MPA', (178, 188))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
4302	32983080	The safety of combining epigenetic enhancement of antigen presentation with adoptive transfer was further validated in a murine model, where no adverse effects were reported.	('epigenetic enhancement', 'Var', (24, 46))	('antigen', 'MPA', (50, 57))	('murine', 'Species', '10090', (121, 127))
4303	32983080	Even after upregulation of antigen expression by epigenetic modulators, antigen-escape variants, in the form of antigen-negative cells, may be present in tumors.	('epigenetic modulators', 'Var', (49, 70))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('upregulation', 'PosReg', (11, 23))
4306	32983080	It is now clear that, apart from upregulating CT antigens, DNMTis upregulate a series of immune pathways that augment tumor recognition and elimination by T cells, such as interferon signaling pathways, cytokine and chemokine signaling, inflammation, and genes in the antigen presentation and processing machinery.	('elimination', 'CPA', (140, 151))	('inflammation', 'Disease', (237, 249))	('DNMTis', 'Var', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('immune pathways', 'Pathway', (89, 104))	('augment', 'PosReg', (110, 117))	('interferon signaling pathways', 'Pathway', (172, 201))	('tumor', 'Disease', (118, 123))	('inflammation', 'Disease', 'MESH:D007249', (237, 249))	('upregulate', 'PosReg', (66, 76))
4335	32443610	X-ray diffraction data for monocrystals were collected on an Xcalibur Ruby diffractometer with MoKalpha radiation at 80(2) K. The Cambridge Crystallographic Data Centre (CCDC) reference numbers for 12a and 12d: CCDC 1992131 (12a) and 1992390 (12d) (Supplementary data available from CCDC, 12 Union Road, Cambridge CB2, 1EZ, UK on request).	('C', 'Chemical', 'MESH:D002244', (212, 213))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('C', 'Chemical', 'MESH:D002244', (162, 163))	('C', 'Chemical', 'MESH:D002244', (314, 315))	('C', 'Chemical', 'MESH:D002244', (304, 305))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('C', 'Chemical', 'MESH:D002244', (211, 212))	('1992131', 'Var', (216, 223))	('CB2', 'Gene', '1269', (314, 317))	('MoKalpha', 'Chemical', '-', (95, 103))	('C', 'Chemical', 'MESH:D002244', (286, 287))	('1992390', 'Var', (234, 241))	('C', 'Chemical', 'MESH:D002244', (214, 215))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('CB2', 'Gene', (314, 317))	('C', 'Chemical', 'MESH:D002244', (283, 284))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('C', 'Chemical', 'MESH:D002244', (284, 285))	('C', 'Chemical', 'MESH:D002244', (140, 141))
4390	32443610	Here, 50 microM of compounds 10a, 10c, 10e, 10f, 10g, 11a, 11e, 11f, 11g, 12i, and 13a reduced cell viability in all 4 cell lines (Supplementary Figures S5A, S7A, S9A and S11A:data available in Supplementary Materials).	('S9A', 'Mutation', 'p.S9A', (163, 166))	('S7A', 'Mutation', 'p.S7A', (158, 161))	('S11A', 'Var', (171, 175))	('S11A', 'SUBSTITUTION', 'None', (171, 175))	('reduced', 'NegReg', (87, 94))	('10c', 'Gene', '64333', (34, 37))	('11f', 'Chemical', '-', (64, 67))	('10c', 'Gene', (34, 37))	('cell viability', 'CPA', (95, 109))
4392	32443610	LDH release indicative for loss of membrane integrity is shown in Supplementary Figures S5B, S7B, S9B, and S11B.	('S5B', 'Gene', (88, 91))	('LDH release', 'MPA', (0, 11))	('S11B', 'SUBSTITUTION', 'None', (107, 111))	('S11B', 'Var', (107, 111))	('S9B', 'Var', (98, 101))	('S5B', 'Gene', '5711', (88, 91))
4393	32443610	Among the compounds tested, 10b, 10c, 10e, 10g, and 11e significantly reduced D425 cell viability as compared to HUVEC cells (* p <=0.05, and ** p <=0.01; Supplementary Figure S10:data available in Supplementary Materials).	('10c', 'Gene', '64333', (33, 36))	('reduced', 'NegReg', (70, 77))	('D425 cell viability', 'CPA', (78, 97))	('10e', 'Var', (38, 41))	('10c', 'Gene', (33, 36))	('HUVEC', 'CellLine', 'CVCL:2959', (113, 118))
4395	32443610	LD50 values for compounds 10c (5.38 microM) and 10g (6.61 microM) in D425 cells (Table 2) were slightly below the LD50 values of the above known chemotherapeutics, etoposide, and cisplatin (8 and 10 microM, respectively) reported in the study by von Bueren et al..	('10c', 'Gene', '64333', (26, 29))	('10c', 'Gene', (26, 29))	('10g', 'Var', (48, 51))	('etoposide', 'Chemical', 'MESH:D005047', (164, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))
4398	32443610	Compounds 10a, 10b, 10c, 10e, 10f, 10g, 11a, 11e, 11f, 11g, 12i, and 13a decreased cell viability by more than 50% (Supplementary Figure S13A:data available in Supplementary Materials).	('decreased', 'NegReg', (73, 82))	('S13A', 'Var', (137, 141))	('cell viability', 'CPA', (83, 97))	('10c', 'Gene', '64333', (20, 23))	('11f', 'Chemical', '-', (50, 53))	('10c', 'Gene', (20, 23))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('S13A', 'SUBSTITUTION', 'None', (137, 141))
4399	32443610	The LDH (lactate dehydrogenase) cytotoxicity assay was performed to assess necrotic cell death (Supplementary Figure S13B:data available in Supplementary Materials).	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('S13B', 'Var', (117, 121))	('S13B', 'SUBSTITUTION', 'None', (117, 121))	('necrotic cell death', 'Disease', 'MESH:D003643', (75, 94))	('cytotoxicity', 'Disease', (32, 44))	('necrotic cell death', 'Disease', (75, 94))
4400	32443610	There were no statistically significant differences in cytotoxicity between U251 cells as compared to HUVEC cells (Supplementary Figure S14:data available in Supplementary Materials).	('U251', 'Var', (76, 80))	('U251', 'CellLine', 'CVCL:0021', (76, 80))	('cytotoxicity', 'Disease', (55, 67))	('HUVEC', 'CellLine', 'CVCL:2959', (102, 107))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
4414	32443610	Among substituents present in the sulfonamide, biphenyl-containing methoxy group (10e, 11e) or fluorine (10c) were found to be most active.	('10c', 'Gene', '64333', (105, 108))	('biphenyl-containing', 'Var', (47, 66))	('10c', 'Gene', (105, 108))	('fluorine', 'Chemical', 'MESH:D005461', (95, 103))	('active', 'MPA', (132, 138))	('sulfonamide', 'Chemical', 'MESH:D013449', (34, 45))
4418	32443610	Our results indicate that compounds 10b, 10c, 10e, 10g, and 11e notably reduce cell viability on the D425 cell line (* p <= 0.05, and ** p <= 0.01) as compared to HUVEC cells.	('10c', 'Gene', '64333', (41, 44))	('HUVEC', 'CellLine', 'CVCL:2959', (163, 168))	('10e', 'Var', (46, 49))	('10c', 'Gene', (41, 44))	('reduce', 'NegReg', (72, 78))	('cell viability on the D425 cell line', 'CPA', (79, 115))
4430	32373211	Results: We show that marizomib inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy.	('marizomib', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('better', 'PosReg', (96, 102))	('tumor', 'Disease', (108, 113))	('marizomib', 'Chemical', 'MESH:C475865', (22, 31))	('inhibits', 'NegReg', (32, 40))	('patient', 'Species', '9606', (146, 153))	('BC', 'Phenotype', 'HP:0003002', (128, 130))
4444	32373211	While Btz, Cfz, and Ixz selectively inhibit the chymotrypsin-like proteasome activity (CT-L), they fail to inhibit the trypsin-like (T-L) and caspase-like (CP-L) proteasome activity, which are known to degrade proteins.	('Btz', 'Chemical', 'MESH:D000069286', (6, 9))	('chymotrypsin-like proteasome activity', 'MPA', (48, 85))	('inhibit', 'NegReg', (36, 43))	('trypsin-like', 'MPA', (119, 131))	('Btz', 'Var', (6, 9))	('Cfz', 'Chemical', 'MESH:C524865', (11, 14))	('Ixz', 'Chemical', 'MESH:C548400', (20, 23))
4453	32373211	Based on this information, we hypothesized that Mzb can simultaneously inhibit multiple proteasome catalytic sites, which may enhance its anti-tumor activity in TNBCs compared to the previous generation compounds.	('enhance', 'PosReg', (126, 133))	('Mzb', 'Var', (48, 51))	('tumor', 'Disease', (143, 148))	('inhibit', 'NegReg', (71, 78))	('BC', 'Phenotype', 'HP:0003002', (163, 165))	('TNBCs', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Mzb', 'Chemical', 'MESH:C475865', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
4455	32373211	We show that Mzb strongly inhibits proteasome functions by blocking CT-L, T-L, and CP-L proteasome activity, induces caspase-3 dependent apoptosis, and inhibits tumor cell proliferation in vitro in 2D and 3D cultures.	('tumor', 'Disease', (161, 166))	('inhibits', 'NegReg', (26, 34))	('CT-L', 'MPA', (68, 72))	('T-L', 'MPA', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('caspase-3', 'Gene', '836', (117, 126))	('inhibits', 'NegReg', (152, 160))	('Mzb', 'Chemical', 'MESH:C475865', (13, 16))	('activity', 'MPA', (99, 107))	('proteasome functions', 'MPA', (35, 55))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CP-L', 'Var', (83, 87))	('blocking', 'NegReg', (59, 67))	('Mzb', 'Var', (13, 16))	('caspase-3', 'Gene', (117, 126))	('induces', 'Reg', (109, 116))
4456	32373211	Here, we describe an additional, novel mechanism for the anti-cancer activity of Mzb and demonstrate that Mzb inhibits complex II-dependent mitochondrial respiration leading to a reduced oxidative phosphorylation (OXPHOS).	('oxidative phosphorylation', 'MPA', (187, 212))	('complex II-dependent mitochondrial respiration', 'MPA', (119, 165))	('Mzb', 'Chemical', 'MESH:C475865', (81, 84))	('inhibits', 'NegReg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mzb', 'Chemical', 'MESH:C475865', (106, 109))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('reduced', 'NegReg', (179, 186))	('Mzb', 'Var', (106, 109))
4457	32373211	We further show that Mzb significantly reduces primary tumor growth and induces apoptosis in human TNBC cell line xenografts, a murine syngeneic TNBC model, and patient-derived tumor xenograft (PDX) models in vivo.	('murine', 'Species', '10090', (128, 134))	('tumor', 'Disease', (177, 182))	('TNBC', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('BC', 'Phenotype', 'HP:0003002', (101, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('patient', 'Species', '9606', (161, 168))	('induces', 'Reg', (72, 79))	('human', 'Species', '9606', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (55, 60))	('BC', 'Phenotype', 'HP:0003002', (147, 149))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Mzb', 'Chemical', 'MESH:C475865', (21, 24))	('Mzb', 'Var', (21, 24))	('apoptosis', 'CPA', (80, 89))	('reduces', 'NegReg', (39, 46))
4459	32373211	Our results document that Mzb inhibits TNBC metastasis by inhibiting OXPHOS and reducing the number of circulating tumor cells (CTCs) in vivo.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Mzb', 'Chemical', 'MESH:C475865', (26, 29))	('tumor', 'Disease', (115, 120))	('OXPHOS', 'MPA', (69, 75))	('inhibiting', 'NegReg', (58, 68))	('Mzb', 'Var', (26, 29))	('BC', 'Phenotype', 'HP:0003002', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('reducing', 'NegReg', (80, 88))	('inhibits', 'NegReg', (30, 38))	('TNBC', 'Gene', (39, 43))
4460	32373211	Finally, we show that Mzb significantly reduces lung and brain metastatic burden in vivo after resecting the primary TNBC tumors.	('Mzb', 'Chemical', 'MESH:C475865', (22, 25))	('TNBC tumors', 'Disease', (117, 128))	('BC', 'Phenotype', 'HP:0003002', (119, 121))	('Mzb', 'Var', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('reduces', 'NegReg', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('TNBC tumors', 'Disease', 'MESH:D009369', (117, 128))
4467	32373211	SUM159PT or MDA-MB-231 were grown to 50-70% confluence, treated with either Mzb or Btz (100 nM) for 9 h and 24 h, respectively.	('Mzb', 'Chemical', 'MESH:C475865', (76, 79))	('Btz', 'Chemical', 'MESH:D000069286', (83, 86))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (12, 22))	('SUM159PT', 'Var', (0, 8))	('MDA-MB-231', 'Gene', (12, 22))	('SUM159PT', 'Chemical', '-', (0, 8))
4470	32373211	SUM159PT or MDA-MB-231 were grown to 50-70% confluence, treated with Mzb (100 nM) for 9 h and 24 h, respectively.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (12, 22))	('Mzb', 'Chemical', 'MESH:C475865', (69, 72))	('SUM159PT', 'Var', (0, 8))	('MDA-MB-231', 'Gene', (12, 22))	('SUM159PT', 'Chemical', '-', (0, 8))
4498	32373211	Additionally, Mzb also increased the expression of p27, a known proteasome substrate, in SUM159PT and MDA-MB-231 cells, indicating proteasome activity inhibition (Figure S1C).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (102, 112))	('Mzb', 'Var', (14, 17))	('p27', 'Gene', '10671', (51, 54))	('Mzb', 'Chemical', 'MESH:C475865', (14, 17))	('p27', 'Gene', (51, 54))	('increased', 'PosReg', (23, 32))	('proteasome', 'MPA', (131, 141))	('expression', 'MPA', (37, 47))	('SUM159PT', 'Var', (89, 97))	('SUM159PT', 'Chemical', '-', (89, 97))
4499	32373211	Thus, Mzb inhibits all three proteasome active sites in TNBC cells, exerting an overall stronger proteasome inhibitory effect in TNBCs.	('inhibits', 'NegReg', (10, 18))	('proteasome inhibitory effect', 'MPA', (97, 125))	('BC', 'Phenotype', 'HP:0003002', (58, 60))	('stronger', 'PosReg', (88, 96))	('Mzb', 'Chemical', 'MESH:C475865', (6, 9))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('Mzb', 'Var', (6, 9))
4505	32373211	Mzb significantly reduced the number of colonies for TNBC lines (SUM159PT and MDA-MB-231) but not for non-TNBC lines (MCF7 and ZR-75-1) (Figure 1C, D), suggesting that Mzb selectively inhibits TNBC cell growth.	('SUM159PT', 'Chemical', '-', (65, 73))	('TNBC cell growth', 'CPA', (193, 209))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (78, 88))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('reduced', 'NegReg', (18, 25))	('Mzb', 'Chemical', 'MESH:C475865', (168, 171))	('MCF7', 'CellLine', 'CVCL:0031', (118, 122))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('inhibits', 'NegReg', (184, 192))	('BC', 'Phenotype', 'HP:0003002', (108, 110))	('Mzb', 'Var', (168, 171))	('BC', 'Phenotype', 'HP:0003002', (55, 57))
4506	32373211	We next examined whether Mzb can inhibit tumor growth in a 3D culture setting, which simulates the in vivo physiological environment of tumor cells and is used for enriching tumor-initiating cells.	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('inhibit', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Mzb', 'Chemical', 'MESH:C475865', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (136, 141))	('Mzb', 'Var', (25, 28))
4509	32373211	Interestingly, Mzb completely eliminated SUM159PT spheroid formation (Figure 1E).	('SUM159PT', 'Var', (41, 49))	('SUM159PT', 'Chemical', '-', (41, 49))	('Mzb', 'Chemical', 'MESH:C475865', (15, 18))	('eliminated', 'NegReg', (30, 40))
4510	32373211	Thus, Mzb effectively reduces tumor cell growth in both 2D and 3D cultures.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Mzb', 'Chemical', 'MESH:C475865', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduces', 'NegReg', (22, 29))	('tumor', 'Disease', (30, 35))	('Mzb', 'Var', (6, 9))
4512	32373211	We therefore examined whether Mzb induces caspase-dependent apoptosis in TNBC cells.	('BC', 'Phenotype', 'HP:0003002', (75, 77))	('Mzb', 'Chemical', 'MESH:C475865', (30, 33))	('induces', 'Reg', (34, 41))	('caspase-dependent', 'CPA', (42, 59))	('Mzb', 'Var', (30, 33))
4513	32373211	Mzb increased caspase-3 activity, as measured by the cleavage of caspase-3-specific substrate Ac-DEVD-AMC in TNBC cells but not in non-malignant breast cells (Figure S2A).	('activity', 'MPA', (24, 32))	('caspase-3', 'Gene', '836', (14, 23))	('caspase-3', 'Gene', '836', (65, 74))	('BC', 'Phenotype', 'HP:0003002', (111, 113))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('caspase-3', 'Gene', (14, 23))	('caspase-3', 'Gene', (65, 74))	('Ac-DEVD-AMC', 'Chemical', 'MESH:C112287', (94, 105))	('increased', 'PosReg', (4, 13))	('Mzb', 'Var', (0, 3))
4515	32373211	Furthermore, Mzb treatment resulted in a considerable cleavage of PARP1, a classical marker of apoptosis, in TNBCs cells (SUM159PT, MDA-MB-231, and BT-549) (Figure S2C).	('PARP1', 'Gene', '142', (66, 71))	('PARP1', 'Gene', (66, 71))	('BT-549', 'CellLine', 'CVCL:1092', (148, 154))	('Mzb', 'Chemical', 'MESH:C475865', (13, 16))	('SUM159PT', 'Chemical', '-', (122, 130))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (132, 142))	('SUM159PT', 'Var', (122, 130))	('BC', 'Phenotype', 'HP:0003002', (111, 113))	('cleavage', 'MPA', (54, 62))
4517	32373211	Our results showed that Mzb reduced the expression of anti-apoptotic proteins Mcl-1 and Bcl-2, and of the survival protein survivin.	('expression', 'MPA', (40, 50))	('Mcl-1', 'Gene', (78, 83))	('Mzb', 'Var', (24, 27))	('reduced', 'NegReg', (28, 35))	('anti-apoptotic', 'CPA', (54, 68))	('Bcl-2', 'Gene', (88, 93))	('Bcl-2', 'Gene', '596', (88, 93))	('survivin', 'Protein', (123, 131))	('Mcl-1', 'Gene', '4170', (78, 83))	('Mzb', 'Chemical', 'MESH:C475865', (24, 27))
4519	32373211	Hence, our data reveal that Mzb induces caspase-3-dependent apoptosis in TNBC cells.	('BC', 'Phenotype', 'HP:0003002', (75, 77))	('Mzb', 'Var', (28, 31))	('caspase-3', 'Gene', (40, 49))	('Mzb', 'Chemical', 'MESH:C475865', (28, 31))	('caspase-3', 'Gene', '836', (40, 49))
4532	32373211	We found that Mzb significantly reduced routine respiration of the cells by ~50% after 9- and 24- h treatments, however the maximum respiratory capacity of the cells was unaffected (Figure 2E).	('Mzb', 'Chemical', 'MESH:C475865', (14, 17))	('reduced', 'NegReg', (32, 39))	('Mzb', 'Var', (14, 17))	('routine respiration', 'MPA', (40, 59))
4533	32373211	In order to better understand the respiration inhibition capability of Mzb, we next examined if Mzb inhibits complex I-dependent or complex II-dependent respiration in SUM159PT cells.	('SUM159PT', 'Chemical', '-', (168, 176))	('Mzb', 'Var', (96, 99))	('inhibits', 'NegReg', (100, 108))	('complex II-dependent respiration', 'MPA', (132, 164))	('Mzb', 'Chemical', 'MESH:C475865', (71, 74))	('complex I-dependent', 'MPA', (109, 128))	('Mzb', 'Chemical', 'MESH:C475865', (96, 99))
4536	32373211	Furthermore, Mzb reduced ATP generation (Figure 2G) and increased reactive oxygen species (ROS) formation (Figure 2H) in SUM159PT cells in a dose-dependent manner.	('ATP generation', 'MPA', (25, 39))	('increased', 'PosReg', (56, 65))	('SUM159PT', 'Chemical', '-', (121, 129))	('ATP', 'Chemical', 'MESH:D000255', (25, 28))	('Mzb', 'Chemical', 'MESH:C475865', (13, 16))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (56, 89))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (66, 89))	('ROS', 'Chemical', 'MESH:D017382', (91, 94))	('Mzb', 'Var', (13, 16))	('reduced', 'NegReg', (17, 24))
4537	32373211	Similar to the effects on SUM159PT cells, Mzb reduced routine and complex II-dependent respiration (Figure S3A, B), decreased ATP generation (Figure S3C), and increased ROS levels (Figure S3D) in MDA-MB-231 cells.	('increased ROS levels', 'Phenotype', 'HP:0025464', (159, 179))	('Mzb', 'Var', (42, 45))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (196, 206))	('increased', 'PosReg', (159, 168))	('ROS levels', 'MPA', (169, 179))	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('ROS', 'Chemical', 'MESH:D017382', (169, 172))	('reduced', 'NegReg', (46, 53))	('ATP generation', 'MPA', (126, 140))	('Mzb', 'Chemical', 'MESH:C475865', (42, 45))	('SUM159PT', 'Chemical', '-', (26, 34))	('decreased', 'NegReg', (116, 125))
4538	32373211	Hence, Mzb inhibits mitochondrial respiration in TNBC cells in addition to the proteasome complex inhibition.	('Mzb', 'Var', (7, 10))	('mitochondrial respiration', 'MPA', (20, 45))	('inhibits', 'NegReg', (11, 19))	('BC', 'Phenotype', 'HP:0003002', (51, 53))	('Mzb', 'Chemical', 'MESH:C475865', (7, 10))
4542	32373211	We next delineated the mechanism by which Mzb inhibits OXPHOS in TNBC cells.	('BC', 'Phenotype', 'HP:0003002', (67, 69))	('Mzb', 'Var', (42, 45))	('OXPHOS', 'MPA', (55, 61))	('inhibits', 'NegReg', (46, 54))	('Mzb', 'Chemical', 'MESH:C475865', (42, 45))
4550	32373211	Interestingly, PGC-1alpha overexpression partially rescued SUM159PT cells from undergoing Mzb-induced cell death (Figure S4E) and it also rescued Mzb-induced OXPHOS gene downregulation (Figure S4F).	('Mzb', 'Chemical', 'MESH:C475865', (146, 149))	('downregulation', 'NegReg', (170, 184))	('SUM159PT', 'Var', (59, 67))	('Mzb', 'Chemical', 'MESH:C475865', (90, 93))	('PGC-1alpha', 'Gene', (15, 25))	('SUM159PT', 'Chemical', '-', (59, 67))
4560	32373211	Mzb treatment significantly reduced the percentage of ALDH1+ BCSCs from approximately 23% in control tumors to 4-5% (Figure 3E), suggesting that Mzb does not only impact the bulk-tumor population but also impacts BCSCs, and therefore regressed patient-derived tumors in vivo.	('tumor', 'Disease', (260, 265))	('BCSCs', 'CPA', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('Mzb', 'Chemical', 'MESH:C475865', (145, 148))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('Mzb', 'Var', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('ALDH1', 'Gene', '216', (54, 59))	('tumors', 'Disease', (260, 266))	('BC', 'Phenotype', 'HP:0003002', (213, 215))	('patient', 'Species', '9606', (244, 251))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('tumors', 'Disease', (101, 107))	('impacts', 'Reg', (205, 212))	('BC', 'Phenotype', 'HP:0003002', (61, 63))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumor', 'Disease', (101, 106))	('ALDH1', 'Gene', (54, 59))	('impact', 'Reg', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (179, 184))
4563	32373211	Our results show that Mzb significantly reduced 4T1.2 tumor growth (Figure 4A) and tumor weight (Figure 4B) compared to the vehicle-treated group.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Mzb', 'Chemical', 'MESH:C475865', (22, 25))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Mzb', 'Var', (22, 25))	('reduced', 'NegReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('4T1.2', 'Gene', (48, 53))
4568	32373211	Mzb treatment (100 nM) reduced mRNA levels of multiple EMT markers including ZEB1, Vimentin, and Slug in 4T1.2, SUM159PT, and MDA-MB-231 cells (Figure S5A-C).	('mRNA levels of multiple', 'MPA', (31, 54))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (126, 136))	('Slug', 'MPA', (97, 101))	('Vimentin', 'Protein', (83, 91))	('SUM159PT', 'Chemical', '-', (112, 120))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('SUM159PT', 'Var', (112, 120))	('reduced', 'NegReg', (23, 30))
4569	32373211	Mzb also reduced SUM159PT and MDA-MB-231 cell migration in vitro (Figure S5D).	('MDA-MB-231 cell migration', 'CPA', (30, 55))	('reduced', 'NegReg', (9, 16))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('SUM159PT', 'Chemical', '-', (17, 25))	('SUM159PT', 'Var', (17, 25))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (30, 40))
4570	32373211	Thus, our data indicate that Mzb reduces TNBC tumor growth and inhibits metastases.	('BC', 'Phenotype', 'HP:0003002', (43, 45))	('metastases', 'Disease', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('Mzb', 'Chemical', 'MESH:C475865', (29, 32))	('TNBC tumor', 'Disease', 'MESH:D009369', (41, 51))	('inhibits', 'NegReg', (63, 71))	('Mzb', 'Var', (29, 32))	('TNBC tumor', 'Disease', (41, 51))	('reduces', 'NegReg', (33, 40))
4572	32373211	Mice were treated with half-maximum tolerated dose (MTD) of Mzb (0.075 mg/kg) or doxorubicin (5 mg/kg) alone or in combination.	('Mzb', 'Chemical', 'MESH:C475865', (60, 63))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('0.075', 'Var', (65, 70))	('Mzb', 'Gene', (60, 63))	('Mice', 'Species', '10090', (0, 4))
4581	32373211	Our data revealed that Mzb dramatically reduced the number of micro and macro lung metastatic nodules in 4T1BR4 tumor model (Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('macro lung', 'Phenotype', 'HP:0002088', (72, 82))	('Mzb', 'Chemical', 'MESH:C475865', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('reduced', 'NegReg', (40, 47))	('Mzb', 'Var', (23, 26))	('tumor', 'Disease', (112, 117))
4582	32373211	Similarly, Mzb reduced the number of micro brain metastatic nodules (Figure 5B).	('reduced', 'NegReg', (15, 22))	('Mzb', 'Chemical', 'MESH:C475865', (11, 14))	('Mzb', 'Var', (11, 14))	('micro brain metastatic nodules', 'CPA', (37, 67))
4584	32373211	Our data convincingly show that Mzb exerts potent cytotoxicity on metastatic TNBCs by reducing the overall lung metastasis burden and micro metastasis in the brain.	('Mzb', 'Chemical', 'MESH:C475865', (32, 35))	('cytotoxicity', 'Disease', 'MESH:D064420', (50, 62))	('Mzb', 'Var', (32, 35))	('micro metastasis in the brain', 'CPA', (134, 163))	('lung metastasis burden', 'CPA', (107, 129))	('reducing', 'NegReg', (86, 94))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('cytotoxicity', 'Disease', (50, 62))
4586	32373211	In our study we also found that Mzb-induced a significant downregulation of the key regulator of cell metabolism PGC-1alpha, which has been shown to be upregulated in metastatic breast cancer cells and to promote breast cancer metastasis by stimulating OXPHOS, increasing cell motility and invasive properties without impacting the expression of EMT-related genes, suggesting that Mzb catalyzed suppression of PGC-1alpha levels is not mutually exclusive to suppression of EMT markers.	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('PGC-1alpha', 'Gene', (113, 123))	('increasing', 'PosReg', (261, 271))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', (213, 226))	('promote', 'PosReg', (205, 212))	('Mzb', 'Chemical', 'MESH:C475865', (32, 35))	('invasive properties', 'CPA', (290, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('downregulation', 'NegReg', (58, 72))	('cell motility', 'CPA', (272, 285))	('Mzb', 'Chemical', 'MESH:C475865', (381, 384))	('Mzb-induced', 'Var', (32, 43))	('upregulated', 'PosReg', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))	('OXPHOS', 'MPA', (253, 259))
4588	32373211	Notably, Mzb significantly reduced the mRNA levels of PGC-1alpha and EMT genes including ZEB1, vimentin, and slug (Figure 5D) in primary tumors.	('reduced', 'NegReg', (27, 34))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('Mzb', 'Chemical', 'MESH:C475865', (9, 12))	('slug', 'Gene', (109, 113))	('primary tumors', 'Disease', 'MESH:D001932', (129, 143))	('PGC-1alpha', 'Protein', (54, 64))	('vimentin', 'Gene', '7431', (95, 103))	('slug', 'Gene', '6591', (109, 113))	('mRNA levels', 'MPA', (39, 50))	('Mzb', 'Var', (9, 12))	('vimentin', 'Gene', (95, 103))	('ZEB1', 'Gene', (89, 93))	('EMT genes', 'Gene', (69, 78))	('primary tumors', 'Disease', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
4592	32373211	Interestingly, Mzb dramatically reduced CTCs in the 4T1BR model in vivo (Figure 5E).	('Mzb', 'Var', (15, 18))	('CTCs', 'MPA', (40, 44))	('Mzb', 'Chemical', 'MESH:C475865', (15, 18))	('reduced', 'NegReg', (32, 39))
4593	32373211	Hence, our data suggested that Mzb may inhibit TNBC lung metastasis via repressing PGC-1alpha and consequent OXPHOS inhibition in addition to suppressing expression of EMT markers.	('repressing', 'NegReg', (72, 82))	('TNBC lung metastasis', 'Disease', 'MESH:D009362', (47, 67))	('TNBC lung metastasis', 'Disease', (47, 67))	('Mzb', 'Var', (31, 34))	('inhibit', 'NegReg', (39, 46))	('Mzb', 'Chemical', 'MESH:C475865', (31, 34))	('EMT markers', 'CPA', (168, 179))	('suppressing', 'NegReg', (142, 153))	('PGC-1alpha', 'Gene', (83, 93))	('BC', 'Phenotype', 'HP:0003002', (49, 51))	('OXPHOS inhibition', 'MPA', (109, 126))	('expression', 'MPA', (154, 164))
4599	32373211	We therefore examined if Mzb upregulates glycolysis in TNBC cells when OXPHOS is inhibited.	('BC', 'Phenotype', 'HP:0003002', (57, 59))	('upregulates', 'PosReg', (29, 40))	('Mzb', 'Chemical', 'MESH:C475865', (25, 28))	('glycolysis', 'MPA', (41, 51))	('Mzb', 'Var', (25, 28))
4613	32373211	Collectively, our data indicate that upon OXPHOS inhibition TNBC cells switch to glycolysis, and co-inhibition of glycolysis with Mzb may provide better efficacy.	('OXPHOS inhibition', 'MPA', (42, 59))	('glycolysis', 'MPA', (81, 91))	('Mzb', 'Chemical', 'MESH:C475865', (130, 133))	('BC', 'Phenotype', 'HP:0003002', (62, 64))	('switch', 'Reg', (71, 77))	('co-inhibition', 'Var', (97, 110))
4614	32373211	In this study, we show for the first time that Mzb strongly inhibits TNBC primary tumor growth and inhibits its metastasis to the lungs and micro-metastasis to the brain in vivo.	('BC', 'Phenotype', 'HP:0003002', (71, 73))	('inhibits', 'NegReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('TNBC', 'Gene', (69, 73))	('micro-metastasis to the brain', 'CPA', (140, 169))	('Mzb', 'Chemical', 'MESH:C475865', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibits', 'NegReg', (60, 68))	('tumor', 'Disease', (82, 87))	('Mzb', 'Var', (47, 50))
4622	32373211	In line with these studies, we show that while Btz only inhibited the CT-L1 activity in TNBC cells, Mzb at much lower concentration inhibited all three proteasome activities and exerted a greater apoptosis in TNBC cells.	('inhibited', 'NegReg', (132, 141))	('BC', 'Phenotype', 'HP:0003002', (211, 213))	('Mzb', 'Var', (100, 103))	('CT-L1 activity', 'MPA', (70, 84))	('apoptosis', 'CPA', (196, 205))	('Mzb', 'Chemical', 'MESH:C475865', (100, 103))	('inhibited', 'NegReg', (56, 65))	('BC', 'Phenotype', 'HP:0003002', (90, 92))	('Btz', 'Chemical', 'MESH:D000069286', (47, 50))
4625	32373211	In line with this notion, our data indicates that Mzb, by simultaneously inhibiting proteasome activity and OXPHOS, may provide an effective therapy option for TNBC patients.	('Mzb', 'Chemical', 'MESH:C475865', (50, 53))	('proteasome activity', 'MPA', (84, 103))	('OXPHOS', 'MPA', (108, 114))	('TNBC', 'Disease', (160, 164))	('Mzb', 'Var', (50, 53))	('patients', 'Species', '9606', (165, 173))	('inhibiting', 'NegReg', (73, 83))	('BC', 'Phenotype', 'HP:0003002', (162, 164))
4628	32373211	Mzb also inhibited in vivo tumor growth in pancreatic cancer models.	('inhibited', 'NegReg', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('Mzb', 'Chemical', 'MESH:C475865', (0, 3))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Mzb', 'Var', (0, 3))
4630	32373211	In line with these studies, our results showed that Mzb significantly reduced the tumor growth and induced apoptosis in multiple TNBC xenograft models.	('reduced', 'NegReg', (70, 77))	('induced', 'Reg', (99, 106))	('Mzb', 'Var', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('apoptosis', 'CPA', (107, 116))	('tumor', 'Disease', (82, 87))	('Mzb', 'Chemical', 'MESH:C475865', (52, 55))
4633	32373211	Thus, our data convincingly demonstrates that Mzb exerts a superior anti-cancer activity in TNBC preclinical models both as monotherapy and in combination with chemotherapy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Mzb', 'Chemical', 'MESH:C475865', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Mzb', 'Var', (46, 49))	('BC', 'Phenotype', 'HP:0003002', (94, 96))	('TNBC', 'Gene', (92, 96))
4645	32373211	These data also imply that similar to glioblastoma, Mzb can cross the blood-brain barrier, reach brain metastatic TNBC, and exert cytotoxic effect.	('cytotoxic effect', 'CPA', (130, 146))	('brain metastatic TNBC', 'CPA', (97, 118))	('BC', 'Phenotype', 'HP:0003002', (116, 118))	('Mzb', 'Var', (52, 55))	('glioblastoma', 'Disease', (38, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (38, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('reach', 'PosReg', (91, 96))	('Mzb', 'Chemical', 'MESH:C475865', (52, 55))
4646	32373211	Our findings also show that Mzb significantly reduces lung metastasis in the aggressive and highly metastatic 4T1BR4 syngeneic TNBC model in vivo (Figure 5).	('BC', 'Phenotype', 'HP:0003002', (129, 131))	('Mzb', 'Var', (28, 31))	('Mzb', 'Chemical', 'MESH:C475865', (28, 31))	('lung metastasis', 'CPA', (54, 69))	('reduces', 'NegReg', (46, 53))
4655	32373211	Notably, our data also show that Mzb has potential to reduce lung and brain metastatic burden in TNBC patients and hence can be translated into a clinical trial for TNBC patients in metastatic settings.	('patients', 'Species', '9606', (170, 178))	('BC', 'Phenotype', 'HP:0003002', (167, 169))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('reduce', 'NegReg', (54, 60))	('patients', 'Species', '9606', (102, 110))	('Mzb', 'Chemical', 'MESH:C475865', (33, 36))	('TNBC', 'Disease', (97, 101))	('Mzb', 'Var', (33, 36))
4734	31096609	Namely, cancer cells in that stage have a decreased possibility to already possess mutations that account for development of drug resistance.	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (8, 14))	('drug resistance', 'Phenotype', 'HP:0020174', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
4774	31096609	Cell destruction is usually caused by protein denaturation, nucleic acids breakage, membrane perforation and ROS generation.	('nucleic acids', 'Var', (60, 73))	('protein', 'Protein', (38, 45))	('nucleic acids breakage', 'Phenotype', 'HP:0040012', (60, 82))	('Cell destruction', 'CPA', (0, 16))	('membrane perforation', 'CPA', (84, 104))	('caused by', 'Reg', (28, 37))	('ROS generation', 'CPA', (109, 123))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))
4776	31096609	Impaired regulation of vascularization in tumors leads to the appearance of "enhanced permeability and retention" effect (EPR), which is aided by the increased pore size between endothelial cells (50-800 nm) in contrast to normal endothelium where pore size varies between 5-10 nm.	('enhanced', 'PosReg', (77, 85))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('pore', 'MPA', (160, 164))	('retention" effect', 'MPA', (103, 120))	('permeability', 'MPA', (86, 98))	('50-800 nm', 'Var', (197, 206))	('increased', 'PosReg', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
4779	31096609	Usually, Fe3O4 or gamma-Fe2O3 form a core of particles that are additionally coated by polyvinylalcohol (PVA), dextran, PEG, polyvinylpyrrolidon (PVP) or chitosan.	('PVP', 'Chemical', 'MESH:D011205', (146, 149))	('dextran', 'Chemical', 'MESH:D003911', (111, 118))	('chitosan', 'Chemical', 'MESH:D048271', (154, 162))	('Fe3O4', 'Var', (9, 14))	('PVA', 'Chemical', 'MESH:D011142', (105, 108))	('polyvinylalcohol', 'Chemical', 'MESH:D011142', (87, 103))	('gamma-Fe2O3', 'Var', (18, 29))	('Fe3O4', 'Chemical', '-', (9, 14))	('polyvinylpyrrolidon', 'Chemical', '-', (125, 144))	('PEG', 'Chemical', 'MESH:D011092', (120, 123))	('gamma-Fe2O3', 'Chemical', '-', (18, 29))
4781	31096609	Both Fe3O4 and gamma-Fe2O3 nanoparticles are supermagnetic, which means that they have magnetic properties only when an external magnetic field is applied.	('gamma-Fe2O3', 'Chemical', '-', (15, 26))	('Fe3O4', 'Var', (5, 10))	('Fe3O4', 'Chemical', '-', (5, 10))	('supermagnetic', 'MPA', (45, 58))	('gamma-Fe2O3', 'Var', (15, 26))
4787	31096609	The main risk poses free Fe2+ that, in reaction with hydrogen peroxide or oxygen, can form hydroxyl radicals and Fe3+ which in turn damage DNA and other molecules.	('DNA', 'MPA', (139, 142))	('oxygen', 'Chemical', 'MESH:D010100', (74, 80))	('Fe3+', 'Var', (113, 117))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (91, 108))	('hydroxyl radicals', 'MPA', (91, 108))	('damage', 'Reg', (132, 138))	('Fe2+', 'Chemical', 'MESH:C038178', (25, 29))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (53, 70))	('Fe3+', 'Chemical', '-', (113, 117))
4826	31096609	In addition, two of the other most common dendrimers, poly(propylene imine) (PPI) and poly-L-lysine dendrimeres, show toxicity due to their cationic nature and, if they are negatively charged, the toxicity is lowered.	('poly-L-lysine', 'Var', (86, 99))	('lowered', 'NegReg', (209, 216))	('PPI', 'Chemical', 'MESH:C443641', (77, 80))	('cationic', 'MPA', (140, 148))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('poly-L-lysine dendrimeres', 'Chemical', '-', (86, 111))	('toxicity', 'Disease', (118, 126))	('poly(propylene imine)', 'Chemical', 'MESH:C443641', (54, 75))	('toxicity', 'Disease', 'MESH:D064420', (197, 205))	('toxicity', 'Disease', (197, 205))
4856	31096609	In vivo, nanobodies are able to reach tumors from vessels by diffusion and help of fluid transport.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('nanobodies', 'Var', (9, 19))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
4889	31096609	Besides being an effective drug transport system for treating glioblastoma as they can carry chemotherapeutic doxorubicin, it has been shown that, after modification with transactivator of transcription (TAT) peptide, they can deliver both therapeutic (doxorubicin) and diagnostic (gadolinium chelates that are the most widely used contrast in clinical setting) agents across the BBB and into the tumor.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('modification', 'Var', (153, 165))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('doxorubicin', 'Chemical', 'MESH:D004317', (253, 264))	('TAT', 'Disease', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('gadolinium', 'Chemical', 'MESH:D005682', (282, 292))	('deliver', 'MPA', (227, 234))	('glioblastoma', 'Disease', (62, 74))	('tumor', 'Disease', (397, 402))	('doxorubicin', 'Chemical', 'MESH:D004317', (110, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('TAT', 'Disease', 'None', (204, 207))
4892	31096609	Further in vivo experiments on animals showed that modification of liposomes with short cell-penetrating peptides of eight arginines (R8) conjugated with oleic acid leads to assembly of effective carriers for doxorubicin, which currently represents an alternative treatment option to temozolomide.	('carriers', 'MPA', (196, 204))	('doxorubicin', 'Chemical', 'MESH:D004317', (209, 220))	('arginines', 'Chemical', 'MESH:D001120', (123, 132))	('oleic acid', 'Chemical', 'MESH:D019301', (154, 164))	('modification', 'Var', (51, 63))	('temozolomide', 'Chemical', 'MESH:D000077204', (284, 296))	('doxorubicin', 'MPA', (209, 220))
4902	31096609	IRI inhibits DNA topoisomerase I and causes DNA breaks that result in apoptosis, while MET activates AMP-activated protein kinase (AMPK) and therefore inhibits the mechanistic target of rapamycin (mTOR) pathway.	('inhibits', 'NegReg', (151, 159))	('inhibits', 'NegReg', (4, 12))	('DNA topoisomerase I', 'Enzyme', (13, 32))	('DNA breaks', 'Disease', (44, 54))	('MET', 'Var', (87, 90))	('mechanistic target of rapamycin', 'Gene', (164, 195))	('mechanistic target of rapamycin', 'Gene', '2475', (164, 195))	('mTOR', 'Gene', (197, 201))	('mTOR', 'Gene', '2475', (197, 201))	('activates', 'PosReg', (91, 100))	('result in', 'Reg', (60, 69))	('AMP-activated', 'MPA', (101, 114))	('apoptosis', 'CPA', (70, 79))	('causes', 'Reg', (37, 43))
4944	31096609	Nanodiagnostic-based platforms are currently developed for the detection of biomarkers for genetic diseases, single nucleotide polymorphism (SNPs) and pathogen nucleic acids.	('genetic diseases', 'Disease', (91, 107))	('single nucleotide polymorphism', 'Var', (109, 139))	('genetic diseases', 'Disease', 'MESH:D030342', (91, 107))	('poly', 'Chemical', '-', (127, 131))
4948	31096609	Additionally, biocompatible dendrimers are being developed and surface modification with PEGylation, acetylation and glycosylation are proposed to reduce toxicity.	('acetylation', 'MPA', (101, 112))	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('toxicity', 'Disease', (154, 162))	('PEG', 'Chemical', 'MESH:D011092', (89, 92))	('glycosylation', 'MPA', (117, 130))	('PEGylation', 'Var', (89, 99))
5146	28860608	All patients had [18F]-FMISO and multiparametric MRI (anatomic, PWI, MRS) scans.	('patients', 'Species', '9606', (4, 12))	('MRS', 'Disease', 'MESH:D008556', (69, 72))	('[18F]-FMISO', 'Var', (17, 28))	('MRS', 'Disease', (69, 72))
5151	28860608	Lactate (and lipid) concentration increased in GBM (27.8 +- 13.8%) relative to nGBM (p < 0.01).	('lipid', 'Chemical', 'MESH:D008055', (13, 18))	('GBM', 'Var', (47, 50))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('nGBM', 'Chemical', '-', (79, 83))	('increased', 'PosReg', (34, 43))
5199	28860608	Additionally, in the nGBM group, the calculated ptO2 was 33.3 +- 11.3 mmHg in the tumoral tissue.	('nGBM', 'Chemical', '-', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('nGBM', 'Var', (21, 25))	('ptO2', 'Chemical', 'MESH:C514637', (48, 52))
5217	28860608	Another limitation of this study is that [18F]-FMISO is trapped into hypoxic cells when ptO2 is less than 10 mmHg rendering the calculation of ptO2 less adapted for low grade gliomas.	('[18F]-FMISO', 'Var', (41, 52))	('ptO2', 'Chemical', 'MESH:C514637', (88, 92))	('ptO2', 'Chemical', 'MESH:C514637', (143, 147))	('gliomas', 'Disease', (175, 182))	('gliomas', 'Disease', 'MESH:D005910', (175, 182))	('gliomas', 'Phenotype', 'HP:0009733', (175, 182))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))
5272	27566556	Due to postoperative changes, formation of scarred tissue, altered vascular supply, and post radiogenic changes, the risk of infarction is increased in patients with recurrent surgery.	('altered', 'Reg', (59, 66))	('infarction', 'Disease', 'MESH:D007238', (125, 135))	('vascular supply', 'CPA', (67, 82))	('changes', 'Var', (21, 28))	('infarction', 'Disease', (125, 135))	('scar', 'Phenotype', 'HP:0100699', (43, 47))	('patients', 'Species', '9606', (152, 160))
5385	26257061	Most importantly, in an intracranial tumour model with BP wafer in situ treatment, we demonstrated that the BP wafer not only significantly increased the survival rate but also decreased Axl expression, and inhibited tumour invasion.	('BP wafer', 'Var', (108, 116))	('intracranial tumour', 'Disease', (24, 43))	('inhibited', 'NegReg', (207, 216))	('Axl expression', 'MPA', (187, 201))	('survival rate', 'CPA', (154, 167))	('BP', 'Chemical', 'MESH:C026105', (108, 110))	('rat', 'Species', '10116', (163, 166))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('intracranial tumour', 'Disease', 'MESH:D001932', (24, 43))	('tumour invasion', 'Disease', (217, 232))	('tumour invasion', 'Disease', 'MESH:D009361', (217, 232))	('decreased', 'NegReg', (177, 186))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('increased', 'PosReg', (140, 149))	('BP', 'Chemical', 'MESH:C026105', (55, 57))	('rat', 'Species', '10116', (93, 96))
5416	26257061	BP targeting of Axl may represent a promising new method for intervening in GBM progression and invasion.	('BP targeting', 'Var', (0, 12))	('BP', 'Chemical', 'MESH:C026105', (0, 2))	('Axl', 'Protein', (16, 19))	('GBM', 'Disease', (76, 79))
5418	26257061	A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that BP exerted an antiproliferative effect on GBM cells; the IC50 concentration of DBTRG-05MG was 100+-3 mug/ml.	('DBTRG', 'Chemical', '-', (168, 173))	('rat', 'Species', '10116', (114, 117))	('antiproliferative effect', 'CPA', (103, 127))	('DBTRG-05MG', 'Var', (168, 178))	('MTT', 'Chemical', 'MESH:C070243', (64, 67))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (2, 62))	('BP', 'Chemical', 'MESH:C026105', (89, 91))	('rat', 'Species', '10116', (158, 161))
5422	26257061	In addition, the protein expression of Axl was downregulated in DBTRG-05MG in a dose-dependent manner after BP treatment (Figure 1b).	('DBTRG', 'Chemical', '-', (64, 69))	('downregulated', 'NegReg', (47, 60))	('protein expression', 'MPA', (17, 35))	('BP', 'Chemical', 'MESH:C026105', (108, 110))	('Axl', 'Protein', (39, 42))	('DBTRG-05MG', 'Var', (64, 74))
5445	26257061	The inhibition of ERK kinase by PD98059 effectively blocked the BP-mediated inhibition of Axl.	('blocked', 'NegReg', (52, 59))	('ERK', 'Gene', (18, 21))	('ERK', 'Gene', '5594', (18, 21))	('BP', 'Chemical', 'MESH:C026105', (64, 66))	('Axl', 'MPA', (90, 93))	('PD98059', 'Var', (32, 39))	('inhibition', 'NegReg', (4, 14))	('PD98059', 'Chemical', 'MESH:C093973', (32, 39))
5587	25722938	Personalized Medicine for Gliomas Personalized medicine for cancer entails tailoring therapy for each patient based on unique features of the patient's tumor; physiologic, molecular, genetic and epigenetic.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('Gliomas', 'Disease', 'MESH:D005910', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('patient', 'Species', '9606', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Disease', (152, 157))	('Gliomas', 'Disease', (26, 33))	('cancer', 'Disease', (60, 66))	('patient', 'Species', '9606', (142, 149))	('epigenetic', 'Var', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
5594	25722938	Personalized medicine for cancer entails tailoring therapy for each patient based on genomic or epigenomic mutations unique to the tumor.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('patient', 'Species', '9606', (68, 75))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('epigenomic mutations', 'Var', (96, 116))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
5595	25722938	High throughput analysis of hundreds of glioblastoma multiforme (GBM) patient samples show that gliomas may contain many types of mutations, including mutations to TP53, INK4A/ARF, PTEN or NF-1.	('TP53', 'Gene', '7157', (164, 168))	('PTEN', 'Gene', '5728', (181, 185))	('TP53', 'Gene', (164, 168))	('INK4A/ARF', 'Gene', (170, 179))	('PTEN', 'Gene', (181, 185))	('glioblastoma multiforme', 'Disease', (40, 63))	('NF-1', 'Gene', '4763', (189, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('contain', 'Reg', (108, 115))	('patient', 'Species', '9606', (70, 77))	('NF-1', 'Gene', (189, 193))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (40, 63))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('INK4A/ARF', 'Gene', '1029', (170, 179))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('mutations', 'Var', (151, 160))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
5596	25722938	Some of these mutations are thought to contribute to the progression of the tumor.	('contribute', 'Reg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
5603	25722938	Although these combinations induced remission and showed for the first time that inducing remission in cancer was a possibility, the cancer invariably recurred and the side effects during treatment were devastating.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('induced', 'Reg', (28, 35))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('combinations', 'Var', (15, 27))
5623	25722938	Furthermore, GBMs with hypermethylation and suppression of O-6-Methylguanine DNA methyltransferase (MGMT) are more sensitive to the TMZ.	('O-6-Methylguanine DNA methyltransferase', 'Gene', (59, 98))	('MGMT', 'Gene', '4255', (100, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('hypermethylation', 'Var', (23, 39))	('suppression', 'NegReg', (44, 55))	('sensitive', 'MPA', (115, 124))	('O-6-Methylguanine DNA methyltransferase', 'Gene', '4255', (59, 98))	('MGMT', 'Gene', (100, 104))
5624	25722938	MGMT hypermethylation, however, represents a small minority of patients with GBM.	('MGMT', 'Gene', (0, 4))	('GBM', 'Disease', (77, 80))	('hypermethylation', 'Var', (5, 21))	('patients', 'Species', '9606', (63, 71))	('MGMT', 'Gene', '4255', (0, 4))
5630	25722938	Interestingly GBMs have arisen from inducing recombination in mouse neural stem cells, oligodenrocyte precursor cells or astrocytes.	('mouse', 'Species', '10090', (62, 67))	('recombination', 'Var', (45, 58))	('inducing', 'Reg', (36, 44))
5635	25722938	Therefore, there are ongoing pre-clinical studies evaluating the susceptibility of this sub-type to various chemotherapeutic agents including PDGFR-A inhibitors and anti-Vascular endothelial growth factor (VEGF) therapy.	('PDGFR', 'Gene', (142, 147))	('PDGFR', 'Gene', '5159', (142, 147))	('inhibitors', 'Var', (150, 160))	('clinical', 'Species', '191496', (33, 41))
5637	25722938	Recent studies in mice show that forced expression of a constitutively active variant Egfr version III (vIII) alone, in some cases, results in GBMs that are similar to classic human GBMs.	('GBMs', 'Disease', (143, 147))	('results in', 'Reg', (132, 142))	('Egfr', 'Gene', '13649', (86, 90))	('Egfr', 'Gene', (86, 90))	('mice', 'Species', '10090', (18, 22))	('human', 'Species', '9606', (176, 181))	('variant', 'Var', (78, 85))
5638	25722938	The mesenchymal subtype of GBM is driven by NF-1 and TP53 mutations.	('NF-1', 'Gene', (44, 48))	('mutations', 'Var', (58, 67))	('driven by', 'Reg', (34, 43))	('mesenchymal subtype', 'CPA', (4, 23))	('NF-1', 'Gene', '4763', (44, 48))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
5649	25722938	Several studies have shown that MRI combined with NMR spectroscopy could be usefull for detecting specific glioma subtypes such as the mesenchymal sub-type or Isocitrate dehydrogenase 1 (IDH1) mutant tumors without invasive tests.	('Isocitrate dehydrogenase 1', 'Gene', (159, 185))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('IDH1', 'Gene', '3417', (187, 191))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('mutant', 'Var', (193, 199))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('mesenchymal sub-type', 'Disease', (135, 155))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (159, 185))	('glioma', 'Disease', (107, 113))	('IDH1', 'Gene', (187, 191))
5651	25722938	The discovery of cells with different driver mutations existing side by side within tumors suggests that targeting a single mutation may be an ineffective strategy in GBMs.	('GBMs', 'Disease', (167, 171))	('mutations', 'Var', (45, 54))	('side within tumors', 'Disease', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('side within tumors', 'Disease', 'MESH:D001929', (72, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
5652	25722938	Recent evidence suggests that cells with mutations to Epidermal growth factor receptor (EGFR), Platelet derived growth factor receptor (PDGFR) and Receptor tyrosine kinase (RTK) co-exist within the same GBM.	('mutations', 'Var', (41, 50))	('Epidermal growth factor receptor', 'Gene', (54, 86))	('Epidermal growth factor receptor', 'Gene', '1956', (54, 86))	('RTK', 'Gene', (173, 176))	('PDGFR', 'Gene', (136, 141))	('EGFR', 'Gene', '1956', (88, 92))	('PDGFR', 'Gene', '5159', (136, 141))	('RTK', 'Gene', '5979', (173, 176))	('Receptor tyrosine kinase', 'Gene', (147, 171))	('Platelet derived growth factor receptor', 'Gene', '5159', (95, 134))	('Receptor tyrosine kinase', 'Gene', '5979', (147, 171))	('EGFR', 'Gene', (88, 92))	('Platelet derived growth factor receptor', 'Gene', (95, 134))
5653	25722938	Therefore, a single agent targeting the EGFR mutation may not show efficacy in these tumor types.	('tumor', 'Disease', (85, 90))	('EGFR', 'Gene', '1956', (40, 44))	('mutation', 'Var', (45, 53))	('EGFR', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
5680	25722938	A recent study using an RCAS-hPDGFB driven GEMM showed that inhibition of macrophage colony stimulating factor 1R (CSF-1R) and hence GBM associated macrophages did not kill the macrophages but coerced them to eliminate glioblastoma cells.	('CSF-1R', 'Gene', '1436', (115, 121))	('inhibition', 'Var', (60, 70))	('glioblastoma', 'Disease', (219, 231))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('eliminate', 'NegReg', (209, 218))	('CSF-1R', 'Gene', (115, 121))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))
5702	25722938	Some of these mutations including NF-1 or PI3K were not previously recognized to be involved in gliomagenesis.	('NF-1', 'Gene', '4763', (34, 38))	('NF-1', 'Gene', (34, 38))	('PI3K', 'Var', (42, 46))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('involved', 'Reg', (84, 92))	('glioma', 'Disease', (96, 102))
5703	25722938	For instance, it is reported that hypermethylation phenotypes may be associated with better prognosis in patients with GBM.	('GBM', 'Disease', (119, 122))	('patients', 'Species', '9606', (105, 113))	('hypermethylation', 'Var', (34, 50))
5716	33842887	However, no single biomarker or subclinical signature failed to predict GBM LTS perfectly, including classic genetic prognostic factors such as O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase (IDH) mutation.	('IDH', 'Gene', (241, 244))	('isocitrate dehydrogenase', 'Gene', (215, 239))	('mutation', 'Var', (246, 254))	('IDH', 'Gene', '3417', (241, 244))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (144, 182))	('MGMT', 'Gene', '4255', (184, 188))	('isocitrate dehydrogenase', 'Gene', '3417', (215, 239))	('MGMT', 'Gene', (184, 188))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('O6-methylguanine-DNA methyltransferase', 'Gene', (144, 182))
5732	32856125	Co-stimulatory and co-inhibitory receptors provide T cells with activating or suppressing signals, respectively, and a disruption of this balance can lead to autoimmunity or prevent specific immune responses.	('lead to', 'Reg', (150, 157))	('activating', 'MPA', (64, 74))	('prevent', 'NegReg', (174, 181))	('autoimmunity', 'Disease', 'MESH:D001327', (158, 170))	('suppressing', 'NegReg', (78, 89))	('disruption', 'Var', (119, 129))	('autoimmunity', 'Phenotype', 'HP:0002960', (158, 170))	('autoimmunity', 'Disease', (158, 170))
5738	32856125	Inhibition of NCR has proven to mount an anti-tumour response in certain types of CNS-associated human tumours.	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('tumours', 'Disease', (103, 110))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('NCR', 'Gene', (14, 17))	('human', 'Species', '9606', (97, 102))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('Inhibition', 'Var', (0, 10))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('tumour', 'Disease', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
5740	32856125	Detailed clinical studies assessing the effectiveness of modulating NCR in CNS inflammation, ageing and neurodegeneration are lacking.	('neurodegeneration', 'Disease', (104, 121))	('CNS', 'Disease', (75, 78))	('neurodegeneration', 'Disease', 'MESH:D019636', (104, 121))	('modulating', 'Var', (57, 67))	('inflammation', 'Disease', 'MESH:D007249', (79, 91))	('inflammation', 'Disease', (79, 91))	('neurodegeneration', 'Phenotype', 'HP:0002180', (104, 121))
5741	32856125	Deletion of VISTA exacerbates autoimmunity in mice including EAE.	('EAE', 'Disease', (61, 64))	('autoimmunity', 'Disease', 'MESH:D001327', (30, 42))	('exacerbates', 'PosReg', (18, 29))	('VISTA', 'Gene', (12, 17))	('autoimmunity', 'Phenotype', 'HP:0002960', (30, 42))	('autoimmunity', 'Disease', (30, 42))	('mice', 'Species', '10090', (46, 50))	('Deletion', 'Var', (0, 8))
5751	32856125	Although the counterreceptor of VISTA remains elusive, multiple candidate binding partners have been proposed: VSIG3/IGSF11, VISTA itself through homophilic interaction and PSGL1.	('IGSF11', 'Gene', '207683', (117, 123))	('PSGL1', 'Gene', '20345', (173, 178))	('VISTA', 'Gene', (125, 130))	('PSGL1', 'Gene', (173, 178))	('homophilic', 'Var', (146, 156))	('IGSF11', 'Gene', (117, 123))
5753	32856125	In this study, PSGL1 was proposed as a binding partner via histidine residues within the extracellular domain of VISTA.	('PSGL1', 'Gene', '20345', (15, 20))	('PSGL1', 'Gene', (15, 20))	('histidine residues', 'Var', (59, 77))	('histidine', 'Chemical', 'MESH:D006639', (59, 68))
5764	32856125	VISTA is also involved in differentiation as reducing VISTA expression using siRNA or miRNA-125b inhibits the differentiation of mouse embryonic stem cells and preadipocytes.	('expression', 'MPA', (60, 70))	('VISTA', 'Gene', (54, 59))	('differentiation', 'CPA', (110, 125))	('inhibits', 'NegReg', (97, 105))	('reducing', 'NegReg', (45, 53))	('miRNA-125b', 'Var', (86, 96))	('mouse', 'Species', '10090', (129, 134))
5776	32856125	Underscoring this non-redundant role of VISTA, double KO of VISTA and PD1 significantly increases T cell responses to foreign antigens and exacerbates EAE compared with VISTA or PD1 single KO mice.	('increases T cell', 'Phenotype', 'HP:0100828', (88, 104))	('mice', 'Species', '10090', (192, 196))	('double KO', 'Var', (47, 56))	('T cell responses to foreign antigens', 'MPA', (98, 134))	('PD1', 'Gene', (70, 73))	('EAE', 'CPA', (151, 154))	('exacerbates', 'PosReg', (139, 150))	('increases', 'PosReg', (88, 97))
5778	32856125	In multiple mouse models of inflammation, VISTA KO is associated with an increase in pro-inflammatory cytokines.	('inflammation', 'Disease', (28, 40))	('VISTA KO', 'Var', (42, 50))	('increase', 'PosReg', (73, 81))	('pro-inflammatory cytokines', 'MPA', (85, 111))	('mouse', 'Species', '10090', (12, 17))	('inflammation', 'Disease', 'MESH:D007249', (28, 40))
5779	32856125	In a psoriasis mouse model, for example, VISTA KO enhances the production of Il23 by DCs.	('VISTA KO', 'Var', (41, 49))	('production of Il23', 'MPA', (63, 81))	('enhances', 'PosReg', (50, 58))	('psoriasis', 'Disease', (5, 14))	('DC', 'Gene', '13179', (85, 87))	('psoriasis', 'Phenotype', 'HP:0003765', (5, 14))	('mouse', 'Species', '10090', (15, 20))	('psoriasis', 'Disease', 'MESH:D011565', (5, 14))
5800	32856125	Upregulation or induction of PDL1 in microglia and astrocytes during inflammation may limit CNS inflammation and pathology by inhibition of T cell activation.	('Upregulation', 'PosReg', (0, 12))	('PDL1', 'Gene', (29, 33))	('induction', 'Var', (16, 25))	('inflammation', 'Disease', (69, 81))	('limit', 'NegReg', (86, 91))	('inhibition', 'NegReg', (126, 136))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('T cell activation', 'CPA', (140, 157))	('inflammation', 'Disease', (96, 108))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))
5801	32856125	Conversely, deletion of PDL1 or PDL2 in mice reduces the infarct volume after middle cerebral artery occlusion, due to reduction of immune-activated microglia and infiltrating peripheral immune cells.	('deletion', 'Var', (12, 20))	('artery occlusion', 'Phenotype', 'HP:0025324', (94, 110))	('infarct', 'Disease', (57, 64))	('infarct', 'Disease', 'MESH:D007238', (57, 64))	('reduces', 'NegReg', (45, 52))	('PDL1', 'Gene', (24, 28))	('immune-activated microglia', 'CPA', (132, 158))	('mice', 'Species', '10090', (40, 44))	('reduction', 'NegReg', (119, 128))	('middle cerebral artery occlusion', 'Disease', 'MESH:D020244', (78, 110))	('middle cerebral artery occlusion', 'Disease', (78, 110))	('PDL2', 'Gene', (32, 36))
5816	32856125	Since overexpression of VISTA in vitro leads to spontaneous cytokine secretion (TNF, IL1beta) in human monocytes, and knockout of VISTA is associated with an altered cytokine/chemokine profile (Ccl2, Il23), VISTA may also be involved in microglia cytokine/chemokine production.	('cytokine/chemokine profile', 'MPA', (166, 192))	('VISTA', 'Gene', (130, 135))	('human', 'Species', '9606', (97, 102))	('TNF', 'Gene', (80, 83))	('spontaneous cytokine secretion', 'MPA', (48, 78))	('overexpression', 'PosReg', (6, 20))	('IL1beta', 'Gene', (85, 92))	('altered', 'Reg', (158, 165))	('TNF', 'Gene', '7124', (80, 83))	('involved', 'Reg', (225, 233))	('knockout', 'Var', (118, 126))	('IL1beta', 'Gene', '3552', (85, 92))
5829	32856125	In the transgenic APP/PS1 (APPswe/PS1dE9) mouse model for Alzheimer's disease, depletion of microglia using a Csf1r inhibitor (PLX5622) results in an increase in parenchymal T cell numbers and a reduction of anti-inflammatory cytokines.	('PS1', 'Gene', (34, 37))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (58, 77))	('mouse', 'Species', '10090', (42, 47))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (58, 77))	("Alzheimer's disease", 'Disease', (58, 77))	('PS1', 'Gene', (22, 25))	('Csf1r', 'Gene', '12978', (110, 115))	('PS1', 'Gene', '19164', (34, 37))	('depletion', 'Var', (79, 88))	('reduction', 'NegReg', (195, 204))	('Csf1r', 'Gene', (110, 115))	('increase', 'PosReg', (150, 158))	('parenchymal T cell numbers', 'CPA', (162, 188))	('anti-inflammatory cytokines', 'MPA', (208, 235))	('PS1', 'Gene', '19164', (22, 25))	('transgenic', 'Species', '10090', (7, 17))
5837	32856125	In the AD mouse model 5XFAD and ALS model SOD1G93A, microglia downregulate expression of homeostatic genes, while upregulating genes involved in immune activation and phagocytosis.	('mouse', 'Species', '10090', (10, 15))	('genes', 'MPA', (127, 132))	('SOD1G93A', 'Var', (42, 50))	('expression of homeostatic genes', 'MPA', (75, 106))	('microglia', 'CPA', (52, 61))	('ALS', 'Disease', 'MESH:D008113', (32, 35))	('ALS', 'Phenotype', 'HP:0007354', (32, 35))	('upregulating', 'PosReg', (114, 126))	('AD', 'Chemical', '-', (7, 9))	('AD', 'Chemical', '-', (25, 27))	('downregulate', 'NegReg', (62, 74))	('ALS', 'Disease', (32, 35))
5840	32856125	The decrease in microglia VISTA expression is consistent across multiple AD mouse models including 5XFAD, APP/PS1 and PS2APP (Fig.	('PS1', 'Gene', (110, 113))	('mouse', 'Species', '10090', (76, 81))	('PS2APP', 'Var', (118, 124))	('decrease', 'NegReg', (4, 12))	('PS1', 'Gene', '19164', (110, 113))	('AD', 'Chemical', '-', (102, 104))	('microglia VISTA', 'Gene', (16, 31))	('expression', 'MPA', (32, 42))	('AD', 'Chemical', '-', (73, 75))
5842	32856125	In tau mouse models that carry P301L or P301S mutations associated with FTD and PD, VISTA expression in microglia is also reduced (Fig.	('P301S', 'Var', (40, 45))	('P301L', 'Mutation', 'rs749067022', (31, 36))	('mouse', 'Species', '10090', (7, 12))	('FTD', 'Disease', 'MESH:C563003', (72, 75))	('P301L', 'Var', (31, 36))	('FTD', 'Phenotype', 'HP:0002145', (72, 75))	('VISTA expression', 'MPA', (84, 100))	('P301S', 'Mutation', 'rs770888554', (40, 45))	('FTD', 'Disease', (72, 75))	('reduced', 'NegReg', (122, 129))
5849	32856125	Microglia VISTA expression is reduced during all stages of actively induced disease by MOG35-55 in CFA, and VISTA knockout exacerbates EAE in a spontaneous TCR-transgenic.	('CFA', 'Gene', (99, 102))	('TCR', 'Gene', (156, 159))	('Microglia VISTA', 'Protein', (0, 15))	('TCR', 'Gene', '328483', (156, 159))	('transgenic', 'Species', '10090', (160, 170))	('EAE', 'Disease', (135, 138))	('CFA', 'Gene', '21371', (99, 102))	('VISTA', 'Gene', (108, 113))	('reduced', 'NegReg', (30, 37))	('exacerbates', 'PosReg', (123, 134))	('expression', 'MPA', (16, 26))	('knockout', 'Var', (114, 122))	('MOG35-55', 'Var', (87, 95))
5855	32856125	Upon response towards microbial compounds such as LPS (TLR4), polyI:C (TLR3), beta-glucan (Dectin-1, TLR2/6), Pam3CSK4 (TLR1/2), VISTA expression decreases in mouse and rhesus macaque microglia in vitro by 50-70%.	('Pam3CSK4', 'Var', (110, 118))	('beta-glucan', 'Chemical', 'MESH:D047071', (78, 89))	('mouse', 'Species', '10090', (159, 164))	('Dectin-1', 'Gene', (91, 99))	('TLR1/2', 'Gene', (120, 126))	('VISTA', 'Gene', (129, 134))	('TLR4', 'Gene', (55, 59))	('decreases', 'NegReg', (146, 155))	('LPS', 'Disease', (50, 53))	('TLR3', 'Gene', '142980', (71, 75))	('expression', 'MPA', (135, 145))	('TLR1/2', 'Gene', '384059;21897;24088', (120, 126))	('TLR2/6', 'Gene', '24088;21899', (101, 107))	('TLR2/6', 'Gene', (101, 107))	('TLR4', 'Gene', '21898', (55, 59))	('LPS', 'Disease', 'MESH:C536528', (50, 53))	('Dectin-1', 'Gene', '56644', (91, 99))	('rhesus macaque', 'Species', '9544', (169, 183))	('TLR3', 'Gene', (71, 75))	('polyI:C', 'Chemical', 'MESH:D011070', (62, 69))
5861	32856125	MFP2 defects in humans usually lead to severe developmental pathologies including neonatal hypotonia, seizures, psychomotor retardation and brain malformations.	('neonatal hypotonia', 'Phenotype', 'HP:0001319', (82, 100))	('brain malformations', 'Disease', 'MESH:D000014', (140, 159))	('neonatal hypotonia', 'Disease', 'MESH:D009123', (82, 100))	('MFP2', 'Gene', (0, 4))	('psychomotor retardation', 'Phenotype', 'HP:0025356', (112, 135))	('seizures', 'Disease', (102, 110))	('brain malformations', 'Disease', (140, 159))	('humans', 'Species', '9606', (16, 22))	('seizures', 'Phenotype', 'HP:0001250', (102, 110))	('lead to', 'Reg', (31, 38))	('psychomotor retardation', 'Disease', (112, 135))	('defects', 'Var', (5, 12))	('psychomotor retardation', 'Disease', 'MESH:D011596', (112, 135))	('neonatal hypotonia', 'Disease', (82, 100))	('hypotonia', 'Phenotype', 'HP:0001290', (91, 100))	('brain malformations', 'Phenotype', 'HP:0012443', (140, 159))	('seizures', 'Disease', 'MESH:D012640', (102, 110))
5862	32856125	In mice, MFP2 knockout leads to Purkinje cell degeneration and neuroinflammation.	('degeneration', 'NegReg', (46, 58))	('mice', 'Species', '10090', (3, 7))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('MFP2', 'Gene', (9, 13))	('Purkinje cell', 'CPA', (32, 45))	('inflammation', 'Disease', (68, 80))	('knockout', 'Var', (14, 22))
5867	32856125	A decrease in VISTA expression may be beneficial for GBM, since knockout of VISTA renders mice high resistance against glioma tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('decrease', 'NegReg', (2, 10))	('expression', 'MPA', (20, 30))	('glioma tumours', 'Disease', (119, 133))	('glioma tumours', 'Disease', 'MESH:D005910', (119, 133))	('knockout', 'Var', (64, 72))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('VISTA', 'Gene', (14, 19))	('mice', 'Species', '10090', (90, 94))	('VISTA', 'Gene', (76, 81))
5874	32856125	VISTA is a more recently identified target for immunotherapy and blocking or activating VISTA has been proven effective in mouse models of cancer, inflammation and autoimmunity.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('VISTA', 'Gene', (88, 93))	('mouse', 'Species', '10090', (123, 128))	('autoimmunity', 'Disease', 'MESH:D001327', (164, 176))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('blocking', 'Var', (65, 73))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('autoimmunity', 'Phenotype', 'HP:0002960', (164, 176))	('autoimmunity', 'Disease', (164, 176))	('inflammation', 'Disease', (147, 159))	('activating', 'PosReg', (77, 87))	('cancer', 'Disease', (139, 145))
5875	32856125	The understanding of VISTA biology in the CNS is limited, and VISTA manipulation to enhance or mute its activity may offer novel therapeutic approaches for CNS diseases including GBM, NDD and MS.	('mute', 'NegReg', (95, 99))	('GBM', 'Disease', (179, 182))	('CNS diseases', 'Disease', (156, 168))	('CNS diseases', 'Disease', 'MESH:D002493', (156, 168))	('activity', 'MPA', (104, 112))	('manipulation', 'Var', (68, 80))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('NDD', 'Phenotype', 'HP:0002180', (184, 187))	('NDD', 'Disease', (184, 187))	('enhance', 'PosReg', (84, 91))
5880	32856125	Immunosuppressive anti-VISTA antibodies reduce the severity of inflammatory disease in mice including autoimmunity.	('autoimmunity', 'Disease', 'MESH:D001327', (102, 114))	('antibodies', 'Var', (29, 39))	('reduce', 'NegReg', (40, 46))	('mice', 'Species', '10090', (87, 91))	('severity', 'MPA', (51, 59))	('autoimmunity', 'Phenotype', 'HP:0002960', (102, 114))	('anti-VISTA', 'Protein', (18, 28))	('inflammatory disease', 'Disease', (63, 83))	('autoimmunity', 'Disease', (102, 114))
5902	32856125	In mice, VISTA knockout enhances anti-glioma responses in mice.	('knockout', 'Var', (15, 23))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('mice', 'Species', '10090', (3, 7))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('mice', 'Species', '10090', (58, 62))	('VISTA', 'Gene', (9, 14))	('glioma', 'Disease', (38, 44))	('enhances', 'PosReg', (24, 32))
5949	32393192	Immunohistochemical studies demonstrated positivity for GFAP, a high Ki-67 proliferation index (approximately 40%), negativity for vimentin, negativity for silver staining, and positivity for phosphatase and tensin homolog (PTEN).	('PTEN', 'Gene', '5728', (224, 228))	('phosphatase and tensin homolog', 'Gene', '5728', (192, 222))	('Ki-67', 'Gene', (69, 74))	('vimentin', 'Gene', '7431', (131, 139))	('GFAP', 'Gene', (56, 60))	('vimentin', 'Gene', (131, 139))	('GFAP', 'Gene', '2670', (56, 60))	('silver', 'Chemical', 'MESH:D012834', (156, 162))	('negativity', 'NegReg', (116, 126))	('positivity', 'Var', (177, 187))	('PTEN', 'Gene', (224, 228))
5953	32393192	Immunohistochemical examination revealed negativity for GFAP and IDH-1(wild-type), a high Ki-67 index (> 50%), positivity for vimentin, positivity for silver staining, and negativity for PTEN.	('positivity', 'Var', (136, 146))	('vimentin', 'Gene', (126, 134))	('IDH-1', 'Gene', '3417', (65, 70))	('IDH-1', 'Gene', (65, 70))	('PTEN', 'Gene', (187, 191))	('PTEN', 'Gene', '5728', (187, 191))	('GFAP', 'Gene', (56, 60))	('GFAP', 'Gene', '2670', (56, 60))	('positivity', 'Var', (111, 121))	('Ki-67', 'Gene', (90, 95))	('negativity', 'Var', (41, 51))	('vimentin', 'Gene', '7431', (126, 134))	('silver', 'Chemical', 'MESH:D012834', (151, 157))	('silver staining', 'Protein', (151, 166))
6013	31206012	The tests include O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation analysis, epidermal growth factor receptor (EGFR) variant III (EGFRvIII) analysis, and interrogation of a wider array of recurrently mutated genes in solid tumors by next-generation sequencing (NGS).	('O6-methylguanine-DNA-methyltransferase', 'Gene', (18, 56))	('MGMT', 'Gene', '4255', (58, 62))	('MGMT', 'Gene', (58, 62))	('variant', 'Var', (135, 142))	('epidermal growth factor receptor', 'Gene', '1956', (95, 127))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('solid tumors', 'Disease', 'MESH:D009369', (235, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (18, 56))	('EGFR', 'Gene', '1956', (129, 133))	('epidermal growth factor receptor', 'Gene', (95, 127))	('EGFR', 'Gene', (129, 133))	('solid tumors', 'Disease', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
6014	31206012	O6-methylguanine-DNA-methyltransferase promoter methylation is present in 40% to 50% of isocitrate dehydrogenase (IDH)-wild-type GBMs and is predictive of improved progression-free survival and overall survival in response to the alkylating chemotherapeutic agent, temozolomide.	('progression-free survival', 'CPA', (164, 189))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('IDH', 'Gene', (114, 117))	('improved', 'PosReg', (155, 163))	('isocitrate dehydrogenase', 'Gene', (88, 112))	('overall survival', 'CPA', (194, 210))	('isocitrate dehydrogenase', 'Gene', '3417', (88, 112))	('IDH', 'Gene', '3417', (114, 117))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (0, 38))	('temozolomide', 'Chemical', 'MESH:D000077204', (265, 277))	('O6-methylguanine-DNA-methyltransferase', 'Gene', (0, 38))	('methylation', 'Var', (48, 59))
6018	31206012	EGFR variant III results in the creation of a novel glycine residue at the junction of exons 1 and 8 and leads to ligand-independent constitutive activation of intracellular signaling cascades.	('activation', 'PosReg', (146, 156))	('EGFR', 'Gene', (0, 4))	('glycine residue', 'MPA', (52, 67))	('intracellular signaling', 'MPA', (160, 183))	('variant', 'Var', (5, 12))	('glycine', 'Chemical', 'MESH:D005998', (52, 59))	('EGFR', 'Gene', '1956', (0, 4))
6020	31206012	This article describes the assays and coordinated detection of gene variants by NGS, the EGFRvIII RNA transcriptional variant by NGS, and MGMT promotor methylation, as well as use of immunohistochemistry (IHC).	('variants', 'Var', (68, 76))	('MGMT', 'Gene', (138, 142))	('EGFR', 'Gene', (89, 93))	('MGMT', 'Gene', '4255', (138, 142))	('EGFR', 'Gene', '1956', (89, 93))
6025	31206012	Immunohistochemistry was performed on all tumors with GFAP, IDH1-R132 H, p53, EGFR, and Ki-67, with a subset of specimens also stained for ATRX.	('GFAP', 'Gene', (54, 58))	('IDH1-R132 H', 'Disease', 'MESH:D000848', (60, 71))	('ATRX', 'Gene', '546', (139, 143))	('p53', 'Gene', (73, 76))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('p53', 'Gene', '7157', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('GFAP', 'Gene', '2670', (54, 58))	('EGFR', 'Gene', '1956', (78, 82))	('IDH1-R132 H', 'Disease', (60, 71))	('EGFR', 'Gene', (78, 82))	('Ki-67', 'Var', (88, 93))	('ATRX', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
6031	31206012	The initial panel (Penn-47) used for detection of variants in brain tumor specimens included 47 genes, ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CSF1 R, CTNNB1, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53, VHL.	('FGFR3', 'Gene', '2261', (199, 204))	('SMO', 'Gene', '6608', (370, 373))	('PTEN', 'Gene', '5728', (330, 334))	('CSF1 R', 'Gene', '1436', (142, 148))	('SMARCB1', 'Gene', '6598', (361, 368))	('FBXW7', 'Gene', '55294', (178, 183))	('FGFR1', 'Gene', '2260', (185, 190))	('CTNNB1', 'Gene', '1499', (150, 156))	('VHL', 'Disease', 'MESH:D006623', (393, 396))	('GNAQ', 'Gene', (219, 223))	('SMO', 'Gene', (370, 373))	('FGFR2', 'Gene', (192, 197))	('ALK', 'Gene', (115, 118))	('PIK3CA', 'Gene', '5290', (322, 328))	('CSF1 R', 'Gene', (142, 148))	('NRAS', 'Gene', (308, 312))	('SRC', 'Gene', '6714', (375, 378))	('JAK2', 'Gene', '3717', (250, 254))	('FLT3', 'Gene', (206, 210))	('FBXW7', 'Gene', (178, 183))	('FGFR3', 'Gene', (199, 204))	('ERBB2', 'Gene', '2064', (164, 169))	('SMAD4', 'Gene', '4089', (354, 359))	('FLT3', 'Gene', '2322', (206, 210))	('PTEN', 'Gene', (330, 334))	('PTPN11', 'Gene', '5781', (336, 342))	('TP53', 'Gene', (387, 391))	('APC', 'Disease', 'MESH:D011125', (120, 123))	('JAK3', 'Gene', (256, 260))	('KDR', 'Gene', '3791', (262, 265))	('MPL', 'Gene', (289, 292))	('NPM1', 'Gene', (302, 306))	('KRAS', 'Gene', '3845', (272, 276))	('NOTCH1', 'Gene', '4851', (294, 300))	('HNF1A', 'Gene', '6927', (231, 236))	('JAK3', 'Gene', '3718', (256, 260))	('TP53', 'Gene', '7157', (387, 391))	('ERBB4', 'Gene', '2066', (171, 176))	('SMAD4', 'Gene', (354, 359))	('RB1', 'Gene', (344, 347))	('HNF1A', 'Gene', (231, 236))	('FGFR2', 'Gene', '2263', (192, 197))	('CDH1', 'Gene', '999', (136, 140))	('IDH1', 'Gene', '3417', (244, 248))	('BRAF', 'Gene', '673', (130, 134))	('KDR', 'Gene', (262, 265))	('PTPN11', 'Gene', (336, 342))	('RB1', 'Gene', '5925', (344, 347))	('AKT1', 'Gene', '207', (109, 113))	('SRC', 'Gene', (375, 378))	('HRAS', 'Gene', (238, 242))	('CDH1', 'Gene', (136, 140))	('PIK3CA', 'Gene', (322, 328))	('JAK2', 'Gene', (250, 254))	('NOTCH1', 'Gene', (294, 300))	('variants', 'Var', (50, 58))	('RET', 'Gene', '5979', (349, 352))	('AKT1', 'Gene', (109, 113))	('GNAQ', 'Gene', '2776', (219, 223))	('SMARCB1', 'Gene', (361, 368))	('ABL1', 'Gene', (103, 107))	('MLH1', 'Gene', (283, 287))	('ATM', 'Gene', '472', (125, 128))	('brain tumor', 'Phenotype', 'HP:0030692', (62, 73))	('ABL1', 'Gene', '25', (103, 107))	('RET', 'Gene', (349, 352))	('MLH1', 'Gene', '4292', (283, 287))	('ERBB4', 'Gene', (171, 176))	('brain tumor', 'Disease', (62, 73))	('NPM1', 'Gene', '4869', (302, 306))	('BRAF', 'Gene', (130, 134))	('FGFR1', 'Gene', (185, 190))	('HRAS', 'Gene', '3265', (238, 242))	('MPL', 'Gene', '4352', (289, 292))	('GNAS', 'Gene', '2778', (225, 229))	('GNA11', 'Gene', (212, 217))	('APC', 'Disease', (120, 123))	('STK11', 'Gene', '6794', (380, 385))	('NRAS', 'Gene', '4893', (308, 312))	('EGFR', 'Gene', '1956', (158, 162))	('PDGFRA', 'Gene', '5156', (314, 320))	('ALK', 'Gene', '238', (115, 118))	('PDGFRA', 'Gene', (314, 320))	('IDH1', 'Gene', (244, 248))	('KRAS', 'Gene', (272, 276))	('brain tumor', 'Disease', 'MESH:D001932', (62, 73))	('ERBB2', 'Gene', (164, 169))	('GNA11', 'Gene', '2767', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('GNAS', 'Gene', (225, 229))	('STK11', 'Gene', (380, 385))	('EGFR', 'Gene', (158, 162))	('ATM', 'Gene', (125, 128))	('CTNNB1', 'Gene', (150, 156))	('VHL', 'Disease', (393, 396))
6036	31206012	All variants were identified using an in-house data processing bioinformatics pipeline capable of detecting SNVs, insertions and/or deletions (indels), and copy number events which include aneuploidy and amplification, referred to in this manuscript as copy number gains.	('aneuploidy', 'Disease', (189, 199))	('aneuploidy', 'Disease', 'MESH:D000782', (189, 199))	('insertions', 'Var', (114, 124))	('SNVs', 'Disease', (108, 112))	('deletions', 'Var', (132, 141))	('amplification', 'MPA', (204, 217))
6037	31206012	Next-generation sequencing often cannot distinguish between aneuploidy in a high number of cells and true amplification occurring in a smaller number of cells; copy number gains refer to both scenarios.	('copy number', 'Var', (160, 171))	('aneuploidy', 'Disease', (60, 70))	('aneuploidy', 'Disease', 'MESH:D000782', (60, 70))
6039	31206012	Variants identified by sequencing were classified internally as one of the following: disease-associated variants, probably disease-associated variants, variants of uncertain significance (VUS), likely benign, or benign polymorphisms.	('VUS', 'Chemical', '-', (189, 192))	('disease-associated', 'Reg', (86, 104))	('variants', 'Var', (105, 113))
6040	31206012	The category of disease-associated variants included variants associated with disease in any tumor type and was determined using an in-house curated database incorporating data available from the current literature as well as public databases such as COSMIC.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('variants', 'Var', (35, 43))	('tumor', 'Disease', (93, 98))	('disease-associated', 'Reg', (16, 34))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
6041	31206012	Probably disease-associated variants, VUS, and likely benign variants are reported together under the category VUS.	('VUS', 'Chemical', '-', (111, 114))	('VUS', 'Chemical', '-', (38, 41))	('variants', 'Var', (28, 36))	('disease-associated', 'Reg', (9, 27))
6051	31206012	These patients were further subdivided into 2 overlapping cohorts: 164 unique patients with sequencing on the Penn-47 solid tumor panel and 32 unique patients with sequencing on the Penn-153 solid tumor panel.	('solid tumor', 'Disease', (191, 202))	('solid tumor', 'Disease', 'MESH:D009369', (118, 129))	('solid tumor', 'Disease', 'MESH:D009369', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('patients', 'Species', '9606', (78, 86))	('sequencing', 'Var', (92, 102))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('solid tumor', 'Disease', (118, 129))
6056	31206012	In the cohort of 164 patients who have results for Penn-47, the EGFRvIII assay, and MGMT methylation testing, the NGS assay detected copy number gains in EGFR, KIT, PDGFRA, MET, and PIK3CA and point mutations in TP53, PTEN, EGFR, PIK3CA, IDH1, PTPN11, APC, RB1, KRAS, and RET (Figure 2A).	('RET', 'Gene', '5979', (272, 275))	('patients', 'Species', '9606', (21, 29))	('MGMT', 'Gene', (84, 88))	('APC', 'Disease', 'MESH:D011125', (252, 255))	('EGFR', 'Gene', (154, 158))	('APC', 'Disease', (252, 255))	('PDGFRA', 'Gene', '5156', (165, 171))	('PDGFRA', 'Gene', (165, 171))	('IDH1', 'Gene', (238, 242))	('EGFR', 'Gene', (224, 228))	('PTEN', 'Gene', (218, 222))	('PIK3CA', 'Gene', '5290', (182, 188))	('MET', 'Gene', (173, 176))	('RET', 'Gene', (272, 275))	('PIK3CA', 'Gene', '5290', (230, 236))	('PTPN11', 'Gene', (244, 250))	('EGFR', 'Gene', (64, 68))	('RB1', 'Gene', (257, 260))	('TP53', 'Gene', '7157', (212, 216))	('point mutations', 'Var', (193, 208))	('KRAS', 'Gene', '3845', (262, 266))	('PTPN11', 'Gene', '5781', (244, 250))	('IDH1', 'Gene', '3417', (238, 242))	('MGMT', 'Gene', '4255', (84, 88))	('KIT', 'Gene', (160, 163))	('PTEN', 'Gene', '5728', (218, 222))	('EGFR', 'Gene', '1956', (154, 158))	('EGFR', 'Gene', '1956', (224, 228))	('KRAS', 'Gene', (262, 266))	('gains', 'PosReg', (145, 150))	('RB1', 'Gene', '5925', (257, 260))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', (230, 236))	('EGFR', 'Gene', '1956', (64, 68))	('TP53', 'Gene', (212, 216))
6057	31206012	Among gliomas, EGFR copy number gain, which often reflects amplification, but in some instances reflects aneuploidy, is found essentially only in GBMs.	('aneuploidy', 'Disease', 'MESH:D000782', (105, 115))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('aneuploidy', 'Disease', (105, 115))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('gliomas', 'Disease', (6, 13))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))	('copy number gain', 'Var', (20, 36))	('gliomas', 'Disease', 'MESH:D005910', (6, 13))	('gliomas', 'Phenotype', 'HP:0009733', (6, 13))
6058	31206012	EGFR copy number gain is the most common alteration found in the cohort (63 patients, 38%), followed by MGMT promoter methylation (60 patients, 37%), TP53 variants (45 patients, 27%), PTEN variants (35 patients, 21%), EGFRvIII (26 patients, 16%), and EGFR point mutations exclusive of EGFRvIII (26 patients, 16%).	('TP53', 'Gene', (150, 154))	('EGFR', 'Gene', '1956', (285, 289))	('patients', 'Species', '9606', (134, 142))	('EGFR', 'Gene', (218, 222))	('EGFR', 'Gene', '1956', (251, 255))	('gain', 'PosReg', (17, 21))	('patients', 'Species', '9606', (298, 306))	('patients', 'Species', '9606', (202, 210))	('TP53', 'Gene', '7157', (150, 154))	('point mutations', 'Var', (256, 271))	('MGMT', 'Gene', (104, 108))	('patients', 'Species', '9606', (76, 84))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (285, 289))	('PTEN', 'Gene', (184, 188))	('EGFR', 'Gene', '1956', (218, 222))	('copy number', 'Var', (5, 16))	('EGFR', 'Gene', (251, 255))	('variants', 'Var', (155, 163))	('patients', 'Species', '9606', (231, 239))	('PTEN', 'Gene', '5728', (184, 188))	('patients', 'Species', '9606', (168, 176))	('EGFR', 'Gene', '1956', (0, 4))	('MGMT', 'Gene', '4255', (104, 108))
6060	31206012	Across these 7 patients, 8 mutations were detected on the Penn-47 panel, of which 5 (62.5%) mutations were also detected on the Penn-153 panel.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (15, 23))	('detected', 'Reg', (42, 50))
6062	31206012	The NGS assay detected disease-associated variations in 71 different genes on the 153-gene panel, including copy number gains of EGFR, KIT, and PDGFRA.	('PDGFRA', 'Gene', '5156', (144, 150))	('variations', 'Var', (42, 52))	('KIT', 'Gene', (135, 138))	('EGFR', 'Gene', '1956', (129, 133))	('disease-associated', 'Reg', (23, 41))	('copy number gains', 'Var', (108, 125))	('EGFR', 'Gene', (129, 133))	('PDGFRA', 'Gene', (144, 150))
6063	31206012	Again, the most common alteration is EGFR copy number gain (17 patients, 53%), followed by MGMT methylation (13 patients, 41%), EGFRvIII mutations (10 patients, 31%), EGFR point mutations exclusive of EGFRvIII (10 patients, 31%), PTEN variants (9 patients, 28%), and TP53 (8 patients, 25%; Figure 2B and Supplementary Figure 3).	('PTEN', 'Gene', '5728', (230, 234))	('patients', 'Species', '9606', (214, 222))	('point mutations', 'Var', (172, 187))	('EGFR', 'Gene', (201, 205))	('copy number', 'Var', (42, 53))	('patients', 'Species', '9606', (275, 283))	('TP53', 'Gene', (267, 271))	('EGFR', 'Gene', (128, 132))	('EGFR', 'Gene', '1956', (37, 41))	('MGMT', 'Gene', (91, 95))	('EGFR', 'Gene', (167, 171))	('EGFR', 'Gene', '1956', (201, 205))	('patients', 'Species', '9606', (247, 255))	('gain', 'PosReg', (54, 58))	('TP53', 'Gene', '7157', (267, 271))	('PTEN', 'Gene', (230, 234))	('EGFR', 'Gene', '1956', (128, 132))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (151, 159))	('mutations', 'Var', (137, 146))	('EGFR', 'Gene', '1956', (167, 171))	('patients', 'Species', '9606', (63, 71))	('EGFR', 'Gene', (37, 41))	('MGMT', 'Gene', '4255', (91, 95))
6065	31206012	Variants were found in CIC, FUBP1, MDM2, and ATRX, among other genes, which would not have been detected by the Penn-47 panel.	('Variants', 'Var', (0, 8))	('FUBP1', 'Gene', '8880', (28, 33))	('ATRX', 'Gene', (45, 49))	('CIC', 'Gene', '23152', (23, 26))	('FUBP1', 'Gene', (28, 33))	('CIC', 'Gene', (23, 26))	('ATRX', 'Gene', '546', (45, 49))	('MDM2', 'Gene', '4193', (35, 39))	('MDM2', 'Gene', (35, 39))
6066	31206012	Analysis of 189 cases of GBM with MGMT promoter methylation and genomic testing showed a correlation between tumors containing IDH1 mutations with hypermethylated MGMT (odds ratio [OR] = 8.88, 95% confidence interval [CI] = 1.80-59.18, Fisher exact P = .002, False Discovery Rate = 0.028), as expected from the hypermethylated profile seen in IDH-mutated tumors.	('IDH1', 'Gene', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (355, 361))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('IDH', 'Gene', '3417', (343, 346))	('IDH', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('MGMT', 'Gene', (163, 167))	('tumors', 'Disease', (355, 361))	('IDH1', 'Gene', '3417', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MGMT', 'Gene', (34, 38))	('tumors', 'Disease', (109, 115))	('IDH', 'Gene', '3417', (127, 130))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('tumors', 'Disease', 'MESH:D009369', (355, 361))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('correlation', 'Interaction', (89, 100))	('mutations', 'Var', (132, 141))	('MGMT', 'Gene', '4255', (163, 167))	('IDH', 'Gene', (343, 346))	('MGMT', 'Gene', '4255', (34, 38))
6067	31206012	The mutation rate was not significantly different between initial GBM occurrences and recurrent tumors when comparing MGMT methylated versus MGMT unmethylated tumors in either cohort sequenced (Figure 2C, Supplementary Figure 4).	('methylated', 'Var', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MGMT', 'Gene', '4255', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('MGMT', 'Gene', (141, 145))	('tumors', 'Disease', (96, 102))	('MGMT', 'Gene', '4255', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('MGMT', 'Gene', (118, 122))	('tumors', 'Disease', (159, 165))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
6068	31206012	Among the subcohort of recurrent/residual GBMs that are negative for IDH1 mutations, a trend toward increased TP53 variants when MGMT is methylated (4 tumors had TP53 variants out of 8 MGMT methylated recurrent/residual GBMs) compared to unmethylated (6 tumors had TP53 variants out of 33 MGMT unmethylated recurrent/residual GBMs) was observed.	('MGMT', 'Gene', '4255', (185, 189))	('tumors', 'Disease', (254, 260))	('TP53', 'Gene', '7157', (265, 269))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('GBM', 'Phenotype', 'HP:0012174', (220, 223))	('variants', 'Var', (115, 123))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('MGMT', 'Gene', (289, 293))	('increased', 'PosReg', (100, 109))	('TP53', 'Gene', '7157', (110, 114))	('tumors', 'Disease', (151, 157))	('TP53', 'Gene', (162, 166))	('MGMT', 'Gene', (129, 133))	('IDH1', 'Gene', (69, 73))	('MGMT', 'Gene', (185, 189))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('TP53', 'Gene', (265, 269))	('GBM', 'Phenotype', 'HP:0012174', (42, 45))	('MGMT', 'Gene', '4255', (289, 293))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('IDH1', 'Gene', '3417', (69, 73))	('GBM', 'Phenotype', 'HP:0012174', (326, 329))	('TP53', 'Gene', (110, 114))	('TP53', 'Gene', '7157', (162, 166))	('MGMT', 'Gene', '4255', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
6070	31206012	Disease-associated variants co-occurring with EGFR changes include additional variants in EGFR and/or variants in other genes.	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (90, 94))	('EGFR', 'Gene', (46, 50))	('changes', 'Var', (51, 58))	('variants', 'Var', (19, 27))	('variants', 'Var', (78, 86))
6071	31206012	Copy number gains of EGFR were found in 39.7% of the GBMs studied (data not shown).	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('Copy number gains', 'Var', (0, 17))
6072	31206012	EGFR disease-associated variants other than EGFRvIII are seen in 28 (37.3%) out of the 75 cases with EGFR copy number gains.	('copy number gains', 'Var', (106, 123))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (0, 4))
6073	31206012	In agreement with previous studies, IDH1 mutations and EGFR copy number gain are mutually exclusive events in our cohort, demonstrating statistically significant anticorrelation (OR = 0.00, 95% CI = 0.00-0.51, Fisher exact test P = .004).	('mutations', 'Var', (41, 50))	('EGFR', 'Gene', '1956', (55, 59))	('IDH1', 'Gene', (36, 40))	('EGFR', 'Gene', (55, 59))	('gain', 'PosReg', (72, 76))	('IDH1', 'Gene', '3417', (36, 40))
6076	31206012	Within our combined cohort of 189 total patients with GBM, 29 out of 34 EGFRvIII-mutated tumors have EGFR copy number gains (85.3%; Figure 4A and C), demonstrating a high degree of association between EGFRvIII and EGFR copy number gains (OR = 13.5, 95% CI = 4.8-47.6, Fisher exact test P = 2.23 x 10-9).	('tumors', 'Disease', (89, 95))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('copy number gains', 'Var', (106, 123))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('EGFR', 'Gene', '1956', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('EGFR', 'Gene', '1956', (201, 205))	('EGFR', 'Gene', '1956', (101, 105))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (214, 218))	('EGFR', 'Gene', (72, 76))	('EGFR', 'Gene', (201, 205))	('EGFR', 'Gene', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
6077	31206012	Similarly, 28 out of 33 patients with EGFR variants excluding EGFRvIII are also likely EGFR amplified (84.8%; Fisher exact test P = 6.34 x 10-9).	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', (62, 66))	('EGFR', 'Gene', (87, 91))	('patients', 'Species', '9606', (24, 32))	('variants', 'Var', (43, 51))
6078	31206012	The combination of EGFR copy number gain, EGFRvIII splice variant, and EGFR SNVs was identified in 8 (4.2%) cases.	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('EGFR', 'Gene', '1956', (19, 23))	('gain', 'PosReg', (36, 40))	('EGFR', 'Gene', '1956', (71, 75))	('copy number', 'Var', (24, 35))	('EGFR', 'Gene', (19, 23))	('EGFR', 'Gene', (71, 75))
6079	31206012	In GBM, EGFR point mutations are more often found in the extracellular domain, as opposed to the cytoplasmic kinase domain (Figure 4A and 4B), as has been seen in previous studies, and may partially underlie the resistance of GBMs to kinase domain inhibition.	('point mutations', 'Var', (13, 28))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('EGFR', 'Gene', '1956', (8, 12))	('GBM', 'Phenotype', 'HP:0012174', (226, 229))	('EGFR', 'Gene', (8, 12))
6080	31206012	Notably, interpretation EGFR mutation variant allele frequency is complicated by the presence of concurrent copy number alterations, including EGFRvIII (deletion of exons 2-7) and EGFR copy number gain (Figure 4D).	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (143, 147))	('deletion', 'Var', (153, 161))	('EGFR', 'Gene', (24, 28))	('copy', 'MPA', (108, 112))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('copy number', 'Var', (185, 196))	('gain', 'PosReg', (197, 201))	('EGFR', 'Gene', '1956', (143, 147))	('variant', 'Var', (38, 45))
6086	31206012	The prognostic value of IDH mutational status is reflected in the 2016 update of the WHO classification of tumors, in which a diagnosis of any grade astrocytoma requires the mutational status of IDH.	('mutational status', 'Var', (174, 191))	('IDH', 'Gene', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('IDH', 'Gene', (24, 27))	('astrocytoma', 'Disease', 'MESH:D001254', (149, 160))	('IDH', 'Gene', '3417', (195, 198))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('astrocytoma', 'Disease', (149, 160))	('IDH', 'Gene', '3417', (24, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (149, 160))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
6088	31206012	Our cohort includes 13 cases of lower grade tumors that progressed to GBM ("secondary GBMs"): 5 tumors with IDH1 mutations and 8 IDH1-wild-type tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('mutations', 'Var', (113, 122))	('IDH1', 'Gene', '3417', (129, 133))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('IDH1', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', (44, 50))	('IDH1', 'Gene', '3417', (108, 112))	('IDH1', 'Gene', (129, 133))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('GBM', 'Disease', (70, 73))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
6089	31206012	Of the 8 IDH1-wild-type tumors, 5 cases had EGFR abnormalities (ie, copy number gain, EGFR point mutation, and/or EGFRvIII), findings that would be inconsistent with co-occurrence of an IDH variant, including those not covered by the panel.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('IDH1', 'Gene', (9, 13))	('IDH', 'Gene', (9, 12))	('IDH', 'Gene', '3417', (186, 189))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('EGFR', 'Gene', '1956', (86, 90))	('IDH1', 'Gene', '3417', (9, 13))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (114, 118))	('IDH', 'Gene', '3417', (9, 12))	('gain', 'PosReg', (80, 84))	('point mutation', 'Var', (91, 105))	('abnormalities', 'Var', (49, 62))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('copy number', 'Var', (68, 79))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'Gene', (86, 90))	('IDH', 'Gene', (186, 189))	('EGFR', 'Gene', (44, 48))
6092	31206012	These findings illustrate the importance of testing IDH mutational status, given that IDH mutation does not consistently correlate with "secondary GBM," and not all "primary GBM" are IDH-wild type.	('IDH', 'Gene', (86, 89))	('IDH', 'Gene', '3417', (86, 89))	('GBM', 'Phenotype', 'HP:0012174', (174, 177))	('GBM', 'Phenotype', 'HP:0012174', (147, 150))	('IDH', 'Gene', (183, 186))	('IDH', 'Gene', (52, 55))	('IDH', 'Gene', '3417', (52, 55))	('IDH', 'Gene', '3417', (183, 186))	('mutation', 'Var', (90, 98))
6093	31206012	Additionally, of the remaining 3 IDH1-wild-type cases that lacked EGFR changes, one case showed PTPN11 and TP53 mutations, another showed an MLH1 mutation, and the last case showing no changes on Penn-47.	('EGFR', 'Gene', '1956', (66, 70))	('PTPN11', 'Gene', '5781', (96, 102))	('EGFR', 'Gene', (66, 70))	('IDH1', 'Gene', (33, 37))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('PTPN11', 'Gene', (96, 102))	('mutations', 'Var', (112, 121))	('IDH1', 'Gene', '3417', (33, 37))	('MLH1', 'Gene', '4292', (141, 145))	('MLH1', 'Gene', (141, 145))	('mutation', 'Var', (146, 154))
6098	31206012	Similarly, the presence or absence of the EGFR p.R108 K and p.G589 V variants and their allele frequencies varies among tumor blocks, despite no significant difference in the tumor percentage of each block.	('tumor', 'Disease', (175, 180))	('EGFR', 'Gene', '1956', (42, 46))	('p.R108 K', 'Mutation', 'rs1057519828', (47, 55))	('EGFR', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('p.G589 V', 'Mutation', 'p.G589V', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('p.R108 K', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (120, 125))	('p.G589 V', 'Var', (60, 68))
6099	31206012	EGFR copy number gain was detected in all 3 blocks.	('EGFR', 'Gene', '1956', (0, 4))	('copy number gain', 'Var', (5, 21))	('EGFR', 'Gene', (0, 4))
6100	31206012	These results exemplify the known molecular heterogeneity present in primary GBM and the complexity of EGFR alterations in GBM.	('EGFR', 'Gene', '1956', (103, 107))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('alterations', 'Var', (108, 119))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('EGFR', 'Gene', (103, 107))	('primary GBM', 'Disease', (69, 80))
6109	31206012	Testing for 1p/19q codeletion might be performed on specimens demonstrating IDH mutation, detected either by IHC for IDH1-R132 H or by sequencing, depending on the patient's age and the immunohistochemical profile of the tumor.	('IDH1-R132 H', 'Disease', (117, 128))	('IDH', 'Gene', (117, 120))	('patient', 'Species', '9606', (164, 171))	('IDH', 'Gene', (76, 79))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('IDH', 'Gene', '3417', (117, 120))	('IDH', 'Gene', '3417', (76, 79))	('IDH1-R132 H', 'Disease', 'MESH:D000848', (117, 128))	('mutation', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
6116	31206012	The benefits of this approach are illustrated by a case of a minute biopsy of a spinal cord tumor with an histological differential that included pilocytic astrocytoma (grade I) and H3 K27M-mutant diffuse midline glioma (DMG, grade IV).	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (146, 167))	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('midline glioma', 'Disease', 'MESH:D005910', (205, 219))	('DMG', 'Chemical', '-', (221, 224))	('spinal cord tumor', 'Disease', 'MESH:D013120', (80, 97))	('K27M', 'Mutation', 'p.K27M', (185, 189))	('spinal cord tumor', 'Disease', (80, 97))	('midline glioma', 'Disease', (205, 219))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('spinal cord tumor', 'Phenotype', 'HP:0010302', (80, 97))	('pilocytic astrocytoma', 'Disease', (146, 167))	('astrocytoma', 'Phenotype', 'HP:0009592', (156, 167))	('H3 K27M-mutant', 'Var', (182, 196))
6118	31206012	An initial limited panel of immunohistochemical stains for H3 K27M, IDH1-R132H, and Ki-67 was performed for tumor classification and histological grading, and the order to cut for molecular testing was placed simultaneously with the order for these immunohistochemical stains to avoid resurfacing the block.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('IDH1', 'Gene', (68, 72))	('tumor', 'Disease', (108, 113))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('K27M', 'Mutation', 'p.K27M', (62, 66))	('IDH1', 'Gene', '3417', (68, 72))	('H3 K27M', 'Var', (59, 66))
6128	31206012	Co-occurrence is clinically relevant because the constellation of variants found in a tumor can be helpful in clarifying the grade of the tumor, and on occasion the diagnosis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (86, 91))	('variants', 'Var', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
6130	31206012	Although the histology may not warrant the diagnosis of a grade IV tumor, the molecular changes are the prognostically relevant finding and may make the patient eligible for clinical trials to treat GBM.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('changes', 'Var', (88, 95))	('GBM', 'Phenotype', 'HP:0012174', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patient', 'Species', '9606', (153, 160))
6135	31206012	Clinical trials evaluating immunotherapy in GBM with a hypermutated genotype, particularly seen after temozolomide therapy, may indicate greater efficacy of checkpoint blockade therapy.	('GBM', 'Disease', (44, 47))	('hypermutated', 'Var', (55, 67))	('temozolomide', 'Chemical', 'MESH:D000077204', (102, 114))	('GBM', 'Phenotype', 'HP:0012174', (44, 47))
6138	31206012	Although we do not measure tumor mutational burden or hypermutated genotypes in our clinical assay, the modest increase in the number of pathogenic variants observed and even more dramatically numerous VUS changes present most often in MGMT promoter-methylated recurrent GBMs on sequencing on Penn-153 are consistent with the known hypermutated genotype observed in many temozolomide-treated tumors.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('temozolomide', 'Chemical', 'MESH:D000077204', (371, 383))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('VUS', 'Chemical', '-', (202, 205))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('tumors', 'Disease', 'MESH:D009369', (392, 398))	('GBM', 'Phenotype', 'HP:0012174', (271, 274))	('tumor', 'Disease', (392, 397))	('variants', 'Var', (148, 156))	('tumors', 'Phenotype', 'HP:0002664', (392, 398))	('MGMT', 'Gene', '4255', (236, 240))	('MGMT', 'Gene', (236, 240))	('tumors', 'Disease', (392, 398))
6140	31206012	Detection of many low-level variants may be indicative of tumor complexity and demonstrates the real-world detection of variants in these complex tumors and clinical settings.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('variants', 'Var', (28, 36))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumors', 'Disease', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
6145	31206012	In our cohort, some tumors had multiple point mutations in EGFR, others showed EGFRvIII co-occurring with point mutations, and some had copy number gain of EGFR but also EGFRvIII and EGFR point mutations.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('point mutations', 'Var', (40, 55))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (183, 187))	('copy number', 'Var', (136, 147))	('EGFR', 'Gene', '1956', (183, 187))	('gain', 'PosReg', (148, 152))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', '1956', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('EGFR', 'Gene', (170, 174))	('EGFR', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('EGFR', 'Gene', '1956', (59, 63))
6148	31206012	A recent case highlights the value of EGFR mutation identification.	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (38, 42))
6150	31206012	Given the identification through the pathway of an activating EGFR mutation in the tumor, the patient was treated off-label with a third generation tyrosine kinase inhibitor, osimertinib, to which the tumor initially responded.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('EGFR', 'Gene', '1956', (62, 66))	('mutation', 'Var', (67, 75))	('osimertinib', 'Chemical', 'MESH:C000603933', (175, 186))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('EGFR', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('activating', 'PosReg', (51, 61))	('patient', 'Species', '9606', (94, 101))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
6151	31206012	Although the tumor did eventually progress, the patient derived benefit from the mutation profile-based treatment decision.	('tumor', 'Disease', (13, 18))	('mutation', 'Var', (81, 89))	('patient', 'Species', '9606', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
6154	31206012	Interrogation of IDH2 for mutations in gliomas of younger patients allows the definitive call of an astrocytoma as "IDH-wild type" or "IDH-mutant" and, in the case of an IDH2 mutation, allows the diagnosis of "oligodendroglioma, IDH-mutant, and 1p/19q-codeleted."	('IDH', 'Gene', '3417', (116, 119))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('mutations', 'Var', (26, 35))	('oligodendroglioma', 'Disease', 'MESH:D009837', (210, 227))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('IDH', 'Gene', '3417', (170, 173))	('IDH', 'Gene', '3417', (17, 20))	('astrocytoma', 'Disease', 'MESH:D001254', (100, 111))	('oligodendroglioma', 'Disease', (210, 227))	('astrocytoma', 'Disease', (100, 111))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('IDH', 'Gene', (229, 232))	('IDH', 'Gene', (135, 138))	('IDH2', 'Gene', (170, 174))	('mutation', 'Var', (175, 183))	('IDH2', 'Gene', '3418', (170, 174))	('IDH2', 'Gene', (17, 21))	('IDH', 'Gene', '3417', (135, 138))	('patients', 'Species', '9606', (58, 66))	('IDH', 'Gene', '3417', (229, 232))	('IDH2', 'Gene', '3418', (17, 21))	('IDH', 'Gene', (116, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('IDH', 'Gene', (170, 173))	('gliomas', 'Disease', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('IDH', 'Gene', (17, 20))
6157	31206012	Similarly, gliomas with midline location must be tested for the change in histone 3 at amino acid residue 27 from lysine to methionine (K27M), which is most commonly seen in histone variant 3.3, to make a diagnosis of "DMG, H3 K27M-mutant, WHO grade IV."	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('H3 K27M-mutant', 'Var', (224, 238))	('K27M', 'Mutation', 'p.K27M', (136, 140))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('27 from lysine to methionine', 'Mutation', 'p.K27M', (106, 134))	('K27M', 'Mutation', 'p.K27M', (227, 231))	('midline', 'Chemical', '-', (24, 31))	('DMG', 'Chemical', '-', (219, 222))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
6159	31206012	Patients with diffuse gliomas harboring this variant have been shown to have a poor prognosis, regardless of the tumors' histological features, whose assessment is the classic method of grading gliomas.	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('gliomas', 'Disease', (22, 29))	('gliomas', 'Disease', 'MESH:D005910', (22, 29))	('gliomas', 'Disease', (194, 201))	('gliomas', 'Phenotype', 'HP:0009733', (194, 201))	('Patients', 'Species', '9606', (0, 8))	('gliomas', 'Phenotype', 'HP:0009733', (22, 29))	('gliomas', 'Disease', 'MESH:D005910', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('variant', 'Var', (45, 52))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
6160	31206012	Therefore, the DMG is a WHO grade IV glioma based simply on the presence of the variant, making the inclusion of H3F3A on the sequencing panel critical for diagnosis and patient care.	('H3F3A', 'Gene', '3020', (113, 118))	('DMG', 'Chemical', '-', (15, 18))	('variant', 'Var', (80, 87))	('glioma', 'Disease', (37, 43))	('H3F3A', 'Gene', (113, 118))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('patient', 'Species', '9606', (170, 177))
6162	31206012	In cases of tumors with unique biology, such as rarer IDH mutations, BRAF variants, FGFR variants, and the EGFRvIII variant, having the molecular results raises the possibility of response to targeted therapies and/or allows screening for eligibility to enroll in clinical trials for treatments targeting specific mutations.	('mutations', 'Var', (58, 67))	('variants', 'Var', (89, 97))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('IDH', 'Gene', (54, 57))	('BRAF', 'Gene', '673', (69, 73))	('tumors', 'Disease', (12, 18))	('IDH', 'Gene', '3417', (54, 57))	('variants', 'Var', (74, 82))	('FGFR', 'Gene', (84, 88))	('BRAF', 'Gene', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
6163	31206012	H3 K27M-mutant DMGs and GBM with extracellular domain variants in EGFR, such as A289 V, R108 K, and changes at residue 598, may be added to this list in the future, given ongoing studies.	('A289 V', 'Mutation', 'rs149840192', (80, 86))	('DMG', 'Chemical', '-', (15, 18))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('R108 K', 'Var', (88, 94))	('A289 V', 'Var', (80, 86))	('K27M', 'Mutation', 'p.K27M', (3, 7))	('GBM', 'Phenotype', 'HP:0012174', (24, 27))	('R108 K', 'Mutation', 'rs1057519828', (88, 94))	('changes at residue 598', 'Var', (100, 122))
6165	31206012	In our cohort, 135 (82%) of 164 brain tumors sequenced on Penn-47 and 31 (97%) of 32 tumors sequenced on Penn-153 demonstrate pathogenic variants.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('brain tumors', 'Disease', (32, 44))	('brain tumors', 'Disease', 'MESH:D001932', (32, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('brain tumor', 'Phenotype', 'HP:0030692', (32, 43))	('brain tumors', 'Phenotype', 'HP:0030692', (32, 44))	('pathogenic', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('variants', 'Var', (137, 145))	('tumors', 'Disease', (85, 91))
6171	30926639	We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in TCGA, a pattern that can be partially explained by the different patient composition and sequencing depth.	('LGGs', 'Disease', (49, 53))	('EGFR', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('patient', 'Species', '9606', (167, 174))	('higher', 'PosReg', (79, 85))	('EGFR', 'Gene', '1956', (25, 29))	('detected', 'Reg', (3, 11))
6172	30926639	IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%).	('GBM', 'Phenotype', 'HP:0012174', (84, 87))	('IDH', 'Gene', (0, 3))	('mutations', 'Var', (12, 21))	('IDH', 'Gene', '3417', (0, 3))	('secondary GBM', 'Disease', (74, 87))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))	('LGG', 'Disease', (60, 63))
6173	30926639	Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation.	('IDH', 'Gene', '3417', (102, 105))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutation', 'Var', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('IDH', 'Gene', (102, 105))
6174	30926639	We predicted 1p/19q status using the panel sequencing data, and received only modest performance by benchmarking the prediction to Fluorescent In Situ Hybridization (FISH) results of 50 tumors.	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('1p/19q status', 'Var', (13, 26))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))
6182	30926639	Integrated DNA sequencing and copy number analysis pinpointed potential driver genes including not only known players such as EGFR, TP53, IDH1, CDKN2A, etc., but also novel genes such as LZTR1 and FGFR-TACC fusions.	('FGFR-TACC', 'Gene', (197, 206))	('EGFR', 'Gene', (126, 130))	('fusions', 'Var', (207, 214))	('LZTR1', 'Gene', '8216', (187, 192))	('TP53', 'Gene', '7157', (132, 136))	('IDH1', 'Gene', '3417', (138, 142))	('TP53', 'Gene', (132, 136))	('CDKN2A', 'Gene', (144, 150))	('LZTR1', 'Gene', (187, 192))	('CDKN2A', 'Gene', '1029', (144, 150))	('IDH1', 'Gene', (138, 142))	('EGFR', 'Gene', '1956', (126, 130))
6183	30926639	Unsupervised clustering of gene expression and DNA methylation profiles led to the discoveries of three robust transcriptome based GBM subtypes and a hypermethylation phenotype (G-CIMP) featuring recurrent mutations in IDH genes.	('IDH', 'Gene', (219, 222))	('mutations', 'Var', (206, 215))	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('IDH', 'Gene', '3417', (219, 222))
6186	30926639	In this classification, IDH mutations are the top tier marker that separates LGGs into mutant and wildtype, followed by 1p/19q codeletion as the second marker that further divides mutant tumors.	('IDH', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('IDH', 'Gene', '3417', (24, 27))	('tumors', 'Disease', (187, 193))	('LGGs', 'Disease', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('mutations', 'Var', (28, 37))
6211	30926639	Mutations in IDH1 and IDH2 (collectively referred to as IDH hereafter) were found with high prevalence in lower grand gliomas (83%) and secondary glioblastomas (77%) but much less commonly in primary (9%) and recurrent glioblastomas (9%).	('found', 'Reg', (76, 81))	('glioblastomas', 'Phenotype', 'HP:0012174', (219, 232))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('glioblastomas', 'Phenotype', 'HP:0012174', (146, 159))	('lower grand gliomas', 'Disease', (106, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('IDH', 'Gene', (56, 59))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('IDH', 'Gene', (22, 25))	('Mutations', 'Var', (0, 9))	('IDH2', 'Gene', '3418', (22, 26))	('IDH', 'Gene', (13, 16))	('glioblastomas', 'Disease', (219, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('glioblastomas', 'Disease', (146, 159))	('lower grand gliomas', 'Disease', 'MESH:D005910', (106, 125))	('IDH', 'Gene', '3417', (56, 59))	('glioblastomas', 'Disease', 'MESH:D005909', (219, 232))	('IDH', 'Gene', '3417', (22, 25))	('IDH1', 'Gene', '3417', (13, 17))	('glioblastomas', 'Disease', 'MESH:D005909', (146, 159))	('IDH', 'Gene', '3417', (13, 16))
6212	30926639	The similar frequencies of IDH mutation in primary and recurrent glioblastomas corroborate the contention that these mutations are acquired early in gliomagenesis.	('IDH', 'Gene', (27, 30))	('glioma', 'Disease', (149, 155))	('IDH', 'Gene', '3417', (27, 30))	('mutation', 'Var', (31, 39))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
6221	30926639	Eighty-five per cent of mutations found by T200 were also detected on T200.1.	('detected', 'Reg', (58, 66))	('T200', 'Gene', '5788', (43, 47))	('T200', 'Gene', (70, 74))	('mutations', 'Var', (24, 33))	('T200', 'Gene', (43, 47))	('T200', 'Gene', '5788', (70, 74))
6222	30926639	T200.1 panel generally identified more mutations due to its larger targeted territories, but this difference was not statistically different (P=0.4, Wilcox rank sum test).	('T200', 'Gene', '5788', (0, 4))	('T200', 'Gene', (0, 4))	('mutations', 'Var', (39, 48))
6224	30926639	These two cases included an IDH mutant, 1p/19q non-codeletion grade II glioma and an IDH wild type primary glioblastoma.	('IDH', 'Gene', '3417', (85, 88))	('IDH', 'Gene', (28, 31))	('IDH', 'Gene', '3417', (28, 31))	('glioma', 'Disease', (71, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('glioblastoma', 'Disease', (107, 119))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('1p/19q', 'Var', (40, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('IDH', 'Gene', (85, 88))
6226	30926639	Interestingly for this case, we detected five mutations in the first specimen and four mutations in the second specimen, and BRAF V600E mutation was the only mutation shared between the two specimens (Supplementary Fig.	('V600E', 'Mutation', 'rs113488022', (130, 135))	('BRAF', 'Gene', '673', (125, 129))	('V600E', 'Var', (130, 135))	('BRAF', 'Gene', (125, 129))
6227	30926639	Both specimens harbored mutations in PTEN, but the mutations occurred at different loci in distinct forms (missense point mutation vs a two-nucleotide deletion), suggesting a remarkable selective pressure driven evolutionary convergence on this important tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('mutations', 'Var', (24, 33))	('harbored', 'Reg', (15, 23))
6228	30926639	Only 35 mutations (1.4%) were synonymous, compared to 24% observed in TCGA (P<0.05, t test), suggesting a strong selection for nonsynonymous mutations in the cancer genes sequenced on T200.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('T200', 'Gene', (184, 188))	('nonsynonymous mutations', 'Var', (127, 150))	('T200', 'Gene', '5788', (184, 188))
6229	30926639	Tumor suppressors, including PTEN, RB1, and ATRX, were enriched for deactivating mutations such as frame-shift indels and gain of stop codons, illustrated by a panel of manually curated driver genes (Fig.	('ATRX', 'Gene', (44, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RB1', 'Gene', (35, 38))	('ATRX', 'Gene', '546', (44, 48))	('PTEN', 'Gene', (29, 33))	('RB1', 'Gene', '5925', (35, 38))	('PTEN', 'Gene', '5728', (29, 33))	('stop', 'MPA', (130, 134))	('gain', 'PosReg', (122, 126))	('frame-shift indels', 'Var', (99, 117))
6231	30926639	PI3K pathway genes, including PIK3CA, PIK3CG, and PIK3R1, were collectively mutated in 37 patients (16%), suggesting that targeting this pathway could have important potential in treating glioma.	('PIK3CG', 'Gene', (38, 44))	('PIK3CA', 'Gene', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('PIK3CG', 'Gene', '5294', (38, 44))	('mutated', 'Var', (76, 83))	('PIK3CA', 'Gene', '5290', (30, 36))	('PI3K', 'Gene', (0, 4))	('PIK3R1', 'Gene', '5295', (50, 56))	('glioma', 'Disease', (188, 194))	('PIK3R1', 'Gene', (50, 56))	('patients', 'Species', '9606', (90, 98))
6232	30926639	Surprisingly, we found 10 patients harboring BRAF mutations, nine of which were V600E.	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (26, 34))	('V600E', 'Var', (80, 85))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('V600E', 'Mutation', 'rs113488022', (80, 85))
6237	30926639	In contrast, it was mutated in around 10% of glioblastomas, including secondary glioblastoma (11.8%).	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('mutated', 'Var', (20, 27))	('glioblastomas', 'Phenotype', 'HP:0012174', (45, 58))	('glioblastoma', 'Disease', (45, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('glioblastomas', 'Disease', 'MESH:D005909', (45, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('glioblastomas', 'Disease', (45, 58))
6238	30926639	In TCGA, this gene was mutated in 2% of lower grade gliomas but 8% of glioblastomas (Supplementary Table 1).	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('gliomas', 'Disease', (52, 59))	('glioblastomas', 'Disease', (70, 83))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('mutated', 'Var', (23, 30))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))	('TCGA', 'Gene', (3, 7))
6240	30926639	Higher frequency of EGFR mutations was previously reported in glioblastoma than lower grade glioma.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma', 'Disease', (92, 98))	('glioblastoma', 'Disease', (62, 74))	('reported', 'Reg', (50, 58))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('EGFR', 'Gene', '1956', (20, 24))
6241	30926639	We found EGFR mutations evenly distributed across the groups.	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
6242	30926639	Unlike TCGA that identified EGFR mutations in 6% of lower grade gliomas, we observed 23% mutation in our cohort (FDR=1.6e-4, chi-square test, Fig.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))
6244	30926639	We speculate that the elevated prevalence of EGFR mutation compared to TCGA in lower grade tumors might be due to the different composition of patients in the two studies, and the fact that our sequencing data have a higher depth of coverage.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))
6247	30926639	the fraction of reads carrying variant allele over the total number of reads, across glioma groups (Fig.	('glioma', 'Disease', (85, 91))	('variant', 'Var', (31, 38))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (85, 91))
6249	30926639	We speculate that the lower VAFs suggest EGFR mutations in these groups were likely present in a small subset of cells.	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))
6252	30926639	Mutations in IDH1 and IDH2 predominantly affect amino acid 132 of IDH1 and the analogous amino acid 172 of IDH2.	('IDH1', 'Gene', '3417', (66, 70))	('IDH2', 'Gene', '3418', (107, 111))	('amino acid 132', 'MPA', (48, 62))	('IDH2', 'Gene', (22, 26))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('IDH2', 'Gene', '3418', (22, 26))	('IDH2', 'Gene', (107, 111))	('IDH1', 'Gene', (66, 70))	('affect', 'Reg', (41, 47))
6253	30926639	We detected mutations in IDH1 or IDH2 in 88 tumors, including four hypermutators (Table 1).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('IDH2', 'Gene', (33, 37))	('mutations', 'Var', (12, 21))	('IDH1', 'Gene', '3417', (25, 29))	('IDH2', 'Gene', '3418', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('IDH1', 'Gene', (25, 29))	('detected', 'Reg', (3, 11))
6256	30926639	The 84 non-hypermutators all had only one IDH mutation, affecting either R332 in IDH1 or R172 in IDH2.	('IDH2', 'Gene', (97, 101))	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', (97, 100))	('IDH2', 'Gene', '3418', (97, 101))	('IDH', 'Gene', '3417', (42, 45))	('R332', 'Var', (73, 77))	('R172', 'Var', (89, 93))	('IDH', 'Gene', '3417', (97, 100))	('affecting', 'Reg', (56, 65))	('IDH1', 'Gene', (81, 85))	('IDH', 'Gene', (81, 84))	('IDH1', 'Gene', '3417', (81, 85))	('IDH', 'Gene', '3417', (81, 84))
6257	30926639	The only exception was a recurrent glioblastoma case where a I98T mutation was found in IDH2.	('IDH2', 'Gene', (88, 92))	('I98T', 'Var', (61, 65))	('I98T', 'Mutation', 'rs139512088', (61, 65))	('glioblastoma', 'Disease', (35, 47))	('IDH2', 'Gene', '3418', (88, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))
6258	30926639	The four hypermutators harbored more than one mutations in IDH, but IDH1 R132H was found in all four with higher variant allele fractions than other IDH mutations with borderline significance (P=0.15, t test), suggesting the hotspot mutation was acquired before the hypermutator phenotype.	('IDH', 'Gene', '3417', (68, 71))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', (149, 152))	('R132H', 'Var', (73, 78))	('IDH', 'Gene', '3417', (59, 62))	('IDH', 'Gene', '3417', (149, 152))	('IDH1', 'Gene', (68, 72))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('IDH1', 'Gene', '3417', (68, 72))	('IDH', 'Gene', (68, 71))
6261	30926639	A multivariate analysis controlling for tumor grade, pathology, and age confirmed the significant association between IDH mutation and better outcome (P=0.003, HR=0.25).	('better', 'Disease', (135, 141))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('IDH', 'Gene', (118, 121))	('IDH', 'Gene', '3417', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
6264	30926639	BAF and copy number of 1p and 19 were positively correlated (r=0.64, P<0.001, Pearson correlation) (Fig.	('BAF', 'Gene', (0, 3))	('BAF', 'Gene', '8815', (0, 3))	('copy number', 'Var', (8, 19))
6268	30926639	Despite the limited coverage offered by targeted sequencing, we observed 12 tumors with excessive mutational load (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutational', 'Var', (98, 108))	('tumors', 'Disease', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))
6270	30926639	Seven of the 12 cases demonstrated the temozolomide signature, with C>T substitutions accounting for 95% of all point mutations (Fig.	('temozolomide', 'Chemical', 'MESH:D000077204', (39, 51))	('C>T substitutions', 'Var', (68, 85))	('temozolomide signature', 'MPA', (39, 61))
6271	30926639	No evidence of altered polymerase POLE associated hypermutation (featuring C>A transversion at CpT dinucleotide and C>T transition at CpG dinucleotide) was observed in any of the hypermutators.	('polymerase POLE', 'Enzyme', (23, 38))	('CpT dinucleotide', 'Chemical', '-', (95, 111))	('C>A transversion', 'Var', (75, 91))	('C>T transition', 'Var', (116, 130))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (134, 150))
6273	30926639	C>A mutations are best known to be caused by tobacco consumption and are abundant in lung cancer.	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('tobacco', 'Species', '4097', (45, 52))	('mutations', 'Var', (4, 13))	('C>A', 'Gene', (0, 3))
6283	30926639	Despite a small sample size, these data suggest increased mutational load did not significantly promote tumor aggressiveness.	('mutational load', 'Var', (58, 73))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor aggressiveness', 'Disease', (104, 124))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (104, 124))	('aggressiveness', 'Phenotype', 'HP:0000718', (110, 124))
6301	30926639	Our analysis suggests T200 can recapitulate patterns reported by TCGA and others, most notably histological group associated mutations in glioma genes.	('mutations', 'Var', (125, 134))	('glioma', 'Disease', (138, 144))	('T200', 'Gene', '5788', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('T200', 'Gene', (22, 26))
6302	30926639	Using prospectively collected tumors, we show that IDH mutation is a prognostic marker after adjusting for age, grade, and histology.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('IDH', 'Gene', (51, 54))	('IDH', 'Gene', '3417', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutation', 'Var', (55, 63))
6306	30926639	We identified 12 hypermutators from our cohort, seven demonstrated temozolomide related mutational signature, suggesting cytotoxic agents can serve as potent mutagens.	('temozolomide', 'MPA', (67, 79))	('mutational', 'Var', (88, 98))	('temozolomide', 'Chemical', 'MESH:D000077204', (67, 79))
6308	30926639	Interestingly, the hypermutators had comparable outcome than non-hypermutators, in fact, slightly better (P=0.08, Cox proportional-hazards model, correcting for pathology and age; Hazard Ratio 0.16, 95% CI 0.02-1.2), suggesting the additional mutations acquired did not confer significant growth incentive or evolutionary advantage to the tumor.	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('mutations', 'Var', (243, 252))	('tumor', 'Disease', (339, 344))	('tumor', 'Disease', 'MESH:D009369', (339, 344))
6309	30926639	Recent studies suggest excessive somatic mutations may facilitate the generation of more neoantigens thus elicit stronger immune cell infiltration to the tumor niche, resulting in a more hostile growth environment.	('somatic mutations', 'Var', (33, 50))	('generation', 'MPA', (70, 80))	('hostile growth environment', 'MPA', (187, 213))	('stronger', 'PosReg', (113, 121))	('immune cell infiltration to the', 'CPA', (122, 153))	('facilitate', 'PosReg', (55, 65))	('elicit', 'Reg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('neoantigens', 'MPA', (89, 100))	('more', 'PosReg', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
6315	30926639	Overall, single agent targeted therapy to date has been extremely disappointing due to the inherent heterogeneity of the disease and due to multiple driver mutations in different cell populations within a tumor.	('mutations', 'Var', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (205, 210))
6320	30926639	Future therapeutic strategies in clinical trials should ideally be informed by molecular profiling results and employ combination therapies with targeted drugs to attack subsets of tumor cells harboring different driver mutations while using treatments with less specificity to target cells with passenger and/or secondary mutations.	('mutations', 'Var', (220, 229))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
6334	30344715	Temozolomide (TMZ) is a prodrug that forms O6-methylguanine (O6-MeG) adducts, causing cytotoxicity via mismatch with deoxythymidine residues, inducing apoptosis following processing by the mismatch repair system.	('TMZ', 'Chemical', 'MESH:D000077204', (14, 17))	('cytotoxicity', 'Disease', 'MESH:D064420', (86, 98))	('inducing', 'Reg', (142, 150))	('O6-MeG', 'Chemical', 'MESH:C008449', (61, 67))	('mismatch', 'Var', (103, 111))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (43, 59))	('deoxythymidine', 'Chemical', 'MESH:D013936', (117, 131))	('cytotoxicity', 'Disease', (86, 98))	('apoptosis', 'CPA', (151, 160))	('causing', 'Reg', (78, 85))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
6347	30344715	The U251MG and U-87MG ATCC cell lines were purchased from the American Type Culture Collection (ATCC) and cultured in Dulbecco's modified Eagle's medium (DMEM) with nutrient mixture: F12 (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA), supplemented with 10% fetal bovine serum (FBS; Gibco; Thermo Fisher Scientific, Inc.), without antibiotics.	("'s modified Eagle's medium", 'Chemical', '-', (126, 152))	('F12', 'Gene', '2161', (183, 186))	('DMEM', 'Chemical', '-', (154, 158))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (15, 26))	('U251MG', 'Var', (4, 10))	('U251MG', 'CellLine', 'CVCL:0021', (4, 10))	('F12', 'Gene', (183, 186))	('bovine', 'Species', '9913', (274, 280))
6348	30344715	U-87MG ATCC cells were of CNS origin and are likely to be a bonafide human glioblastoma cell line considering their mRNA expression profile.	('glioblastoma', 'Disease', (75, 87))	('U-87MG', 'Var', (0, 6))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('human', 'Species', '9606', (69, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (0, 11))
6353	30344715	S1237) were purchased from Selleck Chemicals (Houston, Texas, USA) and used to treat U251MG and U-87MG ATCC cells.	('U251MG', 'Var', (85, 91))	('U251MG', 'CellLine', 'CVCL:0021', (85, 91))	('U-87MG', 'Var', (96, 102))	('S1237', 'CellLine', 'CVCL:9E68', (0, 5))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (96, 107))
6364	30344715	U251MG and U-87MG ATCC cells were plated in 96-well plates at 1x103 cells/well), following treatment with 0, 5, 10 or 20 microM apatinib, and 20 microM TMZ as a previous study indicated treatment for 48 h, the viability was determined using Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc., Kumamoto, Japan).	('TMZ', 'Chemical', 'MESH:D000077204', (152, 155))	('U-87MG', 'Var', (11, 17))	('U251MG', 'CellLine', 'CVCL:0021', (0, 6))	('U251MG', 'Var', (0, 6))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (11, 22))	('apatinib', 'Chemical', 'MESH:C553458', (128, 136))
6368	30344715	U251MG and U-87MG ATCC cells were plated in a 6-well plate at 4x105 cells/well.	('U251MG', 'CellLine', 'CVCL:0021', (0, 6))	('U251MG', 'Var', (0, 6))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (11, 22))	('U-87MG', 'Var', (11, 17))
6373	30344715	U251MG and U-87MG ATCC cells were grown to 90% confluency in 6-well plates.	('U251MG', 'CellLine', 'CVCL:0021', (0, 6))	('U251MG', 'Var', (0, 6))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (11, 22))	('U-87MG', 'Var', (11, 17))
6376	30344715	Image J software (National Institutes of Health, Bethesda, MD, USA) was used to evaluate the migration rate of U251MG and U-87MG ATCC cells.	('U-87MG', 'Var', (122, 128))	('U251MG', 'Var', (111, 117))	('U251MG', 'CellLine', 'CVCL:0021', (111, 117))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (122, 133))
6379	30344715	Apatinib significantly inhibited p-VEGFR2 protein expression in a concentration-dependent manner in U251MG and U-87MG ATCC cells (Fig.	('U-87MG', 'Var', (111, 117))	('inhibited', 'NegReg', (23, 32))	('protein', 'Protein', (42, 49))	('VEGFR2', 'Gene', '3791', (35, 41))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('U251MG', 'Var', (100, 106))	('VEGFR2', 'Gene', (35, 41))	('U251MG', 'CellLine', 'CVCL:0021', (100, 106))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (111, 122))
6385	30344715	Inhibition of colony formation of U251MG and U-87MG ATCC cells was also identified following apatinib treatment (P<0.01; Fig.	('apatinib', 'Chemical', 'MESH:C553458', (93, 101))	('Inhibition', 'NegReg', (0, 10))	('U-87MG', 'Var', (45, 51))	('U251MG', 'Var', (34, 40))	('U251MG', 'CellLine', 'CVCL:0021', (34, 40))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (45, 56))	('colony formation', 'CPA', (14, 30))
6386	30344715	To determine the mechanism underlying apatinib-mediated inhibition of glioma-cell proliferation, flow cytometry was performed to investigate U251MG and U-87MG ATCC-cell apoptosis with or without apatinib.	('glioma', 'Disease', (70, 76))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (152, 163))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('U251MG', 'Var', (141, 147))	('U-87MG', 'Var', (152, 158))	('U251MG', 'CellLine', 'CVCL:0021', (141, 147))	('apatinib', 'Chemical', 'MESH:C553458', (195, 203))	('apatinib', 'Chemical', 'MESH:C553458', (38, 46))
6387	30344715	The results revealed an increased rate of apoptosis both in U251MG and U-87MG ATCC cells treated with apatinib compared with untreated cells (P<0.01; Fig.	('U251MG', 'Var', (60, 66))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (71, 82))	('U251MG', 'CellLine', 'CVCL:0021', (60, 66))	('U-87MG', 'Var', (71, 77))	('apoptosis', 'CPA', (42, 51))	('apatinib', 'Chemical', 'MESH:C553458', (102, 110))
6389	30344715	Invasion and wound-healing assays were performed to investigate the invasion and migration abilities of U251MG and U-87MG ATCC cells upon apatinib treatment.	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (115, 126))	('apatinib', 'Chemical', 'MESH:C553458', (138, 146))	('U-87MG', 'Var', (115, 121))	('U251MG', 'CellLine', 'CVCL:0021', (104, 110))	('U251MG', 'Var', (104, 110))	('migration', 'CPA', (81, 90))
6390	30344715	3A and B, apatinib-treated U251MG and U-87MG ATCC cells were less invasive than untreated cells (P<0.01; Fig.	('invasive', 'CPA', (66, 74))	('U-87MG', 'Var', (38, 44))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (38, 49))	('U251MG', 'CellLine', 'CVCL:0021', (27, 33))	('U251MG', 'Var', (27, 33))	('less', 'NegReg', (61, 65))	('apatinib', 'Chemical', 'MESH:C553458', (10, 18))
6391	30344715	Furthermore, apatinib significantly inhibited the migratory ability of U251MG and U-87MG ATCC cells compared with control (P<0.01; Fig.	('U251MG', 'CellLine', 'CVCL:0021', (71, 77))	('inhibited', 'NegReg', (36, 45))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (82, 93))	('apatinib', 'Gene', (13, 21))	('apatinib', 'Chemical', 'MESH:C553458', (13, 21))	('U251MG', 'Var', (71, 77))	('migratory ability', 'CPA', (50, 67))
6413	30344715	Phosphorylation of VEGFR2 by autocrine or paracrine VEGF has been demonstrated to activate the ERK, Akt, FAK, and MAPK pathways, which regulate cell proliferation and migration.	('VEGF', 'Gene', (52, 56))	('Akt', 'Gene', (100, 103))	('FAK', 'Gene', (105, 108))	('VEGFR2', 'Gene', (19, 25))	('activate', 'PosReg', (82, 90))	('FAK', 'Gene', '5747', (105, 108))	('ERK', 'Gene', '5594', (95, 98))	('Phosphorylation', 'Var', (0, 15))	('cell', 'CPA', (144, 148))	('ERK', 'Gene', (95, 98))	('VEGF', 'Gene', (19, 23))	('VEGF', 'Gene', '7422', (52, 56))	('Akt', 'Gene', '207', (100, 103))	('VEGFR2', 'Gene', '3791', (19, 25))	('MAPK pathways', 'Pathway', (114, 127))	('VEGF', 'Gene', '7422', (19, 23))
6416	30344715	In the present study, it was demonstrated that VEGFR2 is highly expressed in glioma cells, and apatinib was revealed to inhibit p-VEGFR2, p-Akt and p-ERK protein expression in U251MG and U-87MG ATCC cells in a concentration-dependent manner.	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (187, 198))	('VEGFR2', 'Gene', (130, 136))	('VEGFR2', 'Gene', (47, 53))	('p-ERK', 'Gene', '9451', (148, 153))	('p-ERK', 'Gene', (148, 153))	('Akt', 'Gene', '207', (140, 143))	('apatinib', 'Chemical', 'MESH:C553458', (95, 103))	('inhibit', 'NegReg', (120, 127))	('glioma', 'Disease', (77, 83))	('U251MG', 'Var', (176, 182))	('VEGFR2', 'Gene', '3791', (130, 136))	('U251MG', 'CellLine', 'CVCL:0021', (176, 182))	('VEGFR2', 'Gene', '3791', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('Akt', 'Gene', (140, 143))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
6417	30344715	Apatinib also significantly inhibited glioma cell proliferation and colony formation, and induced cell apoptosis in p53- and EGFR-mutated U251MG and wild-type U-87MG ATCC cells.	('cell apoptosis', 'CPA', (98, 112))	('EGFR', 'Gene', '1956', (125, 129))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('colony formation', 'CPA', (68, 84))	('U251MG', 'CellLine', 'CVCL:0021', (138, 144))	('EGFR', 'Gene', (125, 129))	('inhibited', 'NegReg', (28, 37))	('p53', 'Gene', '7157', (116, 119))	('U251MG', 'Var', (138, 144))	('induced', 'Reg', (90, 97))	('glioma', 'Disease', (38, 44))	('U-87MG ATCC', 'CellLine', 'CVCL:0022', (159, 170))	('p53', 'Gene', (116, 119))
6443	26713744	Aberrant epigenomes define many childhood and adult brain cancers, as demonstrated by widespread changes to DNA methylation patterns, redistribution of histone marks, and disruption of chromatin structure.	('brain cancers', 'Disease', 'MESH:D001932', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('brain cancers', 'Disease', (52, 65))	('DNA methylation patterns', 'MPA', (108, 132))	('Aberrant', 'Var', (0, 8))	('chromatin structure', 'MPA', (185, 204))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('redistribution', 'MPA', (134, 148))	('disruption', 'Reg', (171, 181))	('brain cancer', 'Phenotype', 'HP:0030692', (52, 64))	('changes', 'Reg', (97, 104))	('histone', 'Protein', (152, 159))
6444	26713744	In this review, we describe the convergence of genetic, metabolic, and micro-environmental factors upon mechanisms of epigenetic deregulation in brain cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('brain cancer', 'Disease', (145, 157))	('brain cancer', 'Disease', 'MESH:D001932', (145, 157))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('epigenetic deregulation', 'Var', (118, 141))	('brain cancer', 'Phenotype', 'HP:0030692', (145, 157))
6445	26713744	We discuss how aberrant epigenetic pathways identified in brain tumors affect cell identity, cell state, and neoplastic transformation, in addition to the potential to exploit these alterations as novel therapeutic strategies for the treatment of brain cancer.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('brain cancer', 'Disease', 'MESH:D001932', (247, 259))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('brain cancer', 'Phenotype', 'HP:0030692', (247, 259))	('neoplastic transformation', 'CPA', (109, 134))	('affect', 'Reg', (71, 77))	('cell state', 'CPA', (93, 103))	('epigenetic', 'Gene', (24, 34))	('brain tumors', 'Disease', 'MESH:D001932', (58, 70))	('cell identity', 'CPA', (78, 91))	('aberrant', 'Var', (15, 23))	('brain tumors', 'Phenotype', 'HP:0030692', (58, 70))	('brain cancer', 'Disease', (247, 259))	('brain tumor', 'Phenotype', 'HP:0030692', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('brain tumors', 'Disease', (58, 70))
6448	26713744	In adult glioblastoma (GBM, World Health Organization grade IV glioma), the most aggressive and prevalent adult primary intrinsic brain cancer, nearly 46% of patients harbor at least one mutation of an epigenetic regulator amidst a diversity of oncogenic pathway mutations.	('brain cancer', 'Disease', 'MESH:D001932', (130, 142))	('adult glioblastoma', 'Disease', 'MESH:D005909', (3, 21))	('adult glioblastoma', 'Disease', (3, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (9, 21))	('brain cancer', 'Phenotype', 'HP:0030692', (130, 142))	('harbor', 'Reg', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('mutation', 'Var', (187, 195))	('patients', 'Species', '9606', (158, 166))	('brain cancer', 'Disease', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('glioma', 'Disease', (63, 69))
6449	26713744	Equally striking is the pediatric counterpart of glioblastoma where one highly prevalent mutation occurs in a histone protein.	('occurs', 'Reg', (98, 104))	('mutation', 'Var', (89, 97))	('glioblastoma', 'Disease', (49, 61))	('histone protein', 'Protein', (110, 125))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))
6450	26713744	Somatic mutations and structural variations that target regulators of epigenetic modifications and functional regulatory elements have been reported across several aggressive pediatric and adult brain cancers such as glioblastoma , medulloblastoma , ependymoma, atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine gliomas (DIPG) , and embryonal tumors with multilayered rosettes (ETMR) .	('gliomas', 'Disease', (330, 337))	('rosettes', 'Phenotype', 'HP:0031925', (386, 394))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('teratoid rhabdoid tumors', 'Disease', 'MESH:C000597569', (271, 295))	('brain cancer', 'Phenotype', 'HP:0030692', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('variations', 'Var', (33, 43))	('gliomas', 'Disease', 'MESH:D005910', (330, 337))	('embryonal tumors', 'Disease', (351, 367))	('embryonal tumors', 'Phenotype', 'HP:0002898', (351, 367))	('ependymoma', 'Disease', (250, 260))	('reported', 'Reg', (140, 148))	('glioma', 'Phenotype', 'HP:0009733', (330, 336))	('tumors', 'Phenotype', 'HP:0002664', (361, 367))	('embryonal tumors', 'Disease', 'MESH:D009373', (351, 367))	('teratoid rhabdoid tumors', 'Disease', (271, 295))	('glioblastoma', 'Disease', 'MESH:D005909', (217, 229))	('gliomas', 'Phenotype', 'HP:0009733', (330, 337))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('ependymoma', 'Phenotype', 'HP:0002888', (250, 260))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('glioblastoma', 'Disease', (217, 229))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('medulloblastoma', 'Disease', 'MESH:D008527', (232, 247))	('medulloblastoma', 'Phenotype', 'HP:0002885', (232, 247))	('brain cancers', 'Disease', (195, 208))	('medulloblastoma', 'Disease', (232, 247))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('ependymoma', 'Disease', 'MESH:D004806', (250, 260))	('brain cancers', 'Disease', 'MESH:D001932', (195, 208))
6454	26713744	Further, we will highlight the therapeutic potential of targeting brain tumor cell state by modulation of epigenetic signatures.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('modulation', 'Reg', (92, 102))	('epigenetic signatures', 'Var', (106, 127))	('brain tumor', 'Disease', 'MESH:D001932', (66, 77))	('brain tumor', 'Disease', (66, 77))	('brain tumor', 'Phenotype', 'HP:0030692', (66, 77))
6463	26713744	While these studies and others demonstrate in a laboratory setting that epigenetic regulation can drive or inhibit cancer growth, human tumors are not formed from the exogenous introduction of transcription factors.	('inhibit', 'NegReg', (107, 114))	('epigenetic regulation', 'Var', (72, 93))	('cancer', 'Disease', (115, 121))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('drive', 'PosReg', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('human', 'Species', '9606', (130, 135))
6467	26713744	Molecular alterations within cancer cells promote cancer growth, but multiple deregulated pathways may converge to create an oncologic epigenome: the altered epigenome may lock cells in a stem-like state, inhibiting normal differentiation.	('inhibiting', 'NegReg', (205, 215))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('promote', 'PosReg', (42, 49))	('epigenome', 'Protein', (158, 167))	('altered', 'Var', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('normal differentiation', 'CPA', (216, 238))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
6473	26713744	In brain cancer, mutations have been identified at nearly all levels of chromatin regulation from mutations of histones, to enzymes that catalyze histone modification, to proteins that facilitate larger-order chromatin structure (Figure 2).	('facilitate', 'PosReg', (185, 195))	('brain cancer', 'Disease', (3, 15))	('brain cancer', 'Disease', 'MESH:D001932', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (98, 107))	('brain cancer', 'Phenotype', 'HP:0030692', (3, 15))	('histones', 'Gene', (111, 119))
6476	26713744	Of the few recurrent mutations identified in brain cancer genomes, many target chromatin associated proteins or histone proteins themselves, termed 'landscaping genes', due to their potential widespread effects on transcriptional programs.	('brain cancer', 'Disease', 'MESH:D001932', (45, 57))	('effects', 'Reg', (203, 210))	('transcriptional', 'MPA', (214, 229))	('chromatin associated proteins', 'Protein', (79, 108))	('histone proteins', 'Protein', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('brain cancer', 'Phenotype', 'HP:0030692', (45, 57))	('target', 'Reg', (72, 78))	('brain cancer', 'Disease', (45, 57))	('mutations', 'Var', (21, 30))
6477	26713744	ATRTs harbor remarkably silent genomes, yet exhibit recurrent mutations or deletions of the SMARCB1 gene (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily B)  (Figure 2).	('SNF', 'Gene', (110, 113))	('SWI', 'Gene', '31120', (106, 109))	('deletions', 'Var', (75, 84))	('SWI', 'Gene', (106, 109))	('SMARCB1', 'Gene', (92, 99))	('SNF', 'Gene', '31442', (110, 113))	('mutations', 'Var', (62, 71))
6479	26713744	Homozygous deletion of SMARCB1 in mice leads to embryonic lethality, while heterozygous loss leads to aggressive tumors that recapitulate human rhabdoid tumors.	('mice', 'Species', '10090', (34, 38))	('rhabdoid tumors', 'Disease', (144, 159))	('aggressive tumors', 'Disease', 'MESH:D001523', (102, 119))	('human', 'Species', '9606', (138, 143))	('embryonic lethality', 'Disease', 'MESH:D020964', (48, 67))	('embryonic lethality', 'Disease', (48, 67))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (144, 159))	('SMARCB1', 'Gene', (23, 30))	('leads to', 'Reg', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('aggressive tumors', 'Disease', (102, 119))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('deletion', 'Var', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('leads to', 'Reg', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
6484	26713744	Importantly, hypermethylated genes converged upon embryonic stem cell (ESC) targets regulated by the Polycomb Repressor Complex 2 (PRC2), suggesting that epigenomic alterations could be disrupting cell state and differentiation programs important to ependymoma development.	('epigenomic alterations', 'Var', (154, 176))	('ependymoma', 'Phenotype', 'HP:0002888', (250, 260))	('ependymoma', 'Disease', (250, 260))	('ependymoma', 'Disease', 'MESH:D004806', (250, 260))	('disrupting', 'NegReg', (186, 196))
6485	26713744	A link between ESC programs and cancer is further demonstrated in the embryonal brain tumor ETMR, which harbors a fusion between a highly amplified microRNA cluster (C19MC) and TTYH1 (Tweety family member 1).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('brain tumor', 'Phenotype', 'HP:0030692', (80, 91))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('TTYH1', 'Gene', (177, 182))	('TTYH1', 'Gene', '57348', (177, 182))	('embryonal brain tumor', 'Disease', (70, 91))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('fusion', 'Var', (114, 120))	('embryonal brain tumor', 'Disease', 'MESH:D001932', (70, 91))
6489	26713744	Recurrent genetic lesions linking epigenomic programs to brain tumor formation is perhaps best exemplified in pediatric glioblastoma and DIPG, which harbor frequent mutation of H3F3A, encoding the H3.3 histone variant, and to a lesser extent HISTH1B and HISTH1C, encoding the H3.1 variant.	('brain tumor', 'Disease', (57, 68))	('H3F3A', 'Gene', (177, 182))	('genetic lesions', 'Disease', 'MESH:D020022', (10, 25))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (110, 132))	('mutation', 'Var', (165, 173))	('brain tumor', 'Phenotype', 'HP:0030692', (57, 68))	('brain tumor', 'Disease', 'MESH:D001932', (57, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('genetic lesions', 'Disease', (10, 25))	('H3F3A', 'Gene', '3020', (177, 182))	('pediatric glioblastoma', 'Disease', (110, 132))
6490	26713744	These mutations target the histone H3 lysine 27th position (K27M), a direct site important for epigenetic post-translational modifications, and the neighboring residue G34R or G34V, which is thought to affect a nearby lysine residue at the 36th position (H3K36) (Figure 2).	('K27M', 'Mutation', 'p.K27M', (60, 64))	('G34R', 'Mutation', 'rs1057519902', (168, 172))	('target', 'Reg', (16, 22))	('G34R', 'Var', (168, 172))	('lysine', 'Chemical', 'MESH:D008239', (218, 224))	('K27M', 'Var', (60, 64))	('G34V', 'Mutation', 'p.G34V', (176, 180))	('lysine', 'Chemical', 'MESH:D008239', (38, 44))	('G34V', 'Var', (176, 180))	('affect', 'Reg', (202, 208))	('mutations', 'Var', (6, 15))
6491	26713744	The H3.3 K27M mutation affects a site of post-translational modification and is associated with global decreased K27 methylation and increased K27 acetylation.	('increased', 'PosReg', (133, 142))	('affects', 'Reg', (23, 30))	('decreased', 'NegReg', (103, 112))	('K27', 'Protein', (113, 116))	('K27 acetylation', 'MPA', (143, 158))	('H3.3 K27M', 'Var', (4, 13))	('site of post-translational modification', 'MPA', (33, 72))	('K27M', 'Mutation', 'p.K27M', (9, 13))
6492	26713744	Further, the K27M mutant results in aberrant redistribution of residual patterns of H3K27me3 within the tumor epigenome.	('H3K27me3', 'Protein', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('K27M', 'Mutation', 'p.K27M', (13, 17))	('redistribution', 'MPA', (45, 59))	('tumor', 'Disease', (104, 109))	('patterns of', 'MPA', (72, 83))	('K27M', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
6493	26713744	ESC-derived neural precursor cells (NPCs) can be transformed with a combination of H3.3-K27M over-expression, shRNA knockdown of TP53, and over-expression of PDGFRA (platelet-derived growth factor receptor A).	('K27M', 'Mutation', 'p.K27M', (88, 92))	('PDGFRA', 'Gene', '5156', (158, 164))	('platelet-derived growth factor receptor A', 'Gene', '5156', (166, 207))	('TP53', 'Gene', (129, 133))	('knockdown', 'Var', (116, 125))	('TP53', 'Gene', '7157', (129, 133))	('over-expression', 'PosReg', (93, 108))	('platelet-derived growth factor receptor A', 'Gene', (166, 207))	('H3.3-K27M', 'Var', (83, 92))	('over-expression', 'PosReg', (139, 154))	('PDGFRA', 'Gene', (158, 164))
6495	26713744	The temporally and anatomically distinct tumors defined by K27M and G34R/V mutations, suggest unique cells of origin and/or cell states that are required for tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (41, 46))	('K27M', 'Mutation', 'p.K27M', (59, 63))	('G34R/V mutations', 'Var', (68, 84))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('G34R', 'Mutation', 'rs1057519902', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('K27M', 'Var', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
6496	26713744	Mutations have also been reported in the proteins that facilitate histone H3.3 incorporation, such as alpha thalassemia/mental retardation syndrome X-linked (ATRX) and death-domain associated protein (DAXX).	('histone H3.3', 'Gene', (66, 78))	('death-domain associated protein', 'Gene', (168, 199))	('ATRX', 'Gene', (158, 162))	('incorporation', 'MPA', (79, 92))	('DAXX', 'Gene', '1616', (201, 205))	('facilitate', 'PosReg', (55, 65))	('histone H3.3', 'Gene', '3020', (66, 78))	('Mutations', 'Var', (0, 9))	('ATRX', 'Gene', '546', (158, 162))	('DAXX', 'Gene', (201, 205))	('mental retardation', 'Phenotype', 'HP:0001249', (120, 138))	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (102, 156))	('death-domain associated protein', 'Gene', '1616', (168, 199))
6497	26713744	Enzymes that catalyze the addition or removal of modifications are recurrently mutated, amplified, or deleted in brain cancer genomes.	('deleted', 'Var', (102, 109))	('brain cancer', 'Phenotype', 'HP:0030692', (113, 125))	('modifications', 'Var', (49, 62))	('brain cancer', 'Disease', (113, 125))	('brain cancer', 'Disease', 'MESH:D001932', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
6498	26713744	These include MLL2 and MLL3 (mixed-lineage leukemia 2/3 in medulloblastoma and adult glioblastoma), SMARCB1 (ATRT), SMARCA4 (glioblastoma, medulloblastoma, ATRT), and SETD2 (SET domain containing 2 in both pediatric and adult glioblastoma) mutations occurring in a diverse set of adult and pediatric brain tumors (Figure 2).	('SMARCB1', 'Gene', (100, 107))	('adult glioblastoma', 'Disease', 'MESH:D005909', (79, 97))	('leukemia 2', 'Disease', (43, 53))	('glioblastoma', 'Disease', 'MESH:D005909', (226, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('MLL2', 'Gene', '9757', (14, 18))	('glioblastoma', 'Disease', (125, 137))	('adult glioblastoma', 'Disease', (220, 238))	('MLL3', 'Gene', (23, 27))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('leukemia 2', 'Disease', 'MESH:D007938', (43, 53))	('SMARCA4', 'Gene', '6597', (116, 123))	('glioblastoma', 'Disease', (226, 238))	('SETD2', 'Gene', (167, 172))	('glioblastoma', 'Disease', (85, 97))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('MLL2', 'Gene', (14, 18))	('pediatric brain tumors', 'Disease', (290, 312))	('brain tumor', 'Phenotype', 'HP:0030692', (300, 311))	('SETD2', 'Gene', '29072', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('adult glioblastoma', 'Disease', 'MESH:D005909', (220, 238))	('medulloblastoma', 'Disease', 'MESH:D008527', (59, 74))	('medulloblastoma', 'Phenotype', 'HP:0002885', (59, 74))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (290, 312))	('brain tumors', 'Phenotype', 'HP:0030692', (300, 312))	('adult glioblastoma', 'Disease', (79, 97))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('medulloblastoma', 'Disease', (59, 74))	('SMARCA4', 'Gene', (116, 123))	('medulloblastoma', 'Disease', 'MESH:D008527', (139, 154))	('medulloblastoma', 'Phenotype', 'HP:0002885', (139, 154))	('medulloblastoma', 'Disease', (139, 154))	('MLL3', 'Gene', '58508', (23, 27))	('mutations', 'Var', (240, 249))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
6501	26713744	Poor prognosis medulloblastomas (Groups 3 and 4, which are not driven by sonic hedgehog and wnt signaling) also harbor subgroup-associated mutations in CHD7 (chromodomain helicase DNA binding protein 7) and ZMYM3 (zinc finger, MYM-type 3), which converge on regulation of gene expression by H3K4me3.	('medulloblastomas', 'Disease', (15, 31))	('chromodomain helicase DNA binding protein 7', 'Gene', '55636', (158, 201))	('sonic hedgehog', 'Gene', '6469', (73, 87))	('medulloblastoma', 'Phenotype', 'HP:0002885', (15, 30))	('mutations', 'Var', (139, 148))	('ZMYM3', 'Gene', '9203', (207, 212))	('CHD7', 'Gene', '55636', (152, 156))	('chromodomain helicase DNA binding protein 7', 'Gene', (158, 201))	('sonic hedgehog', 'Gene', (73, 87))	('CHD7', 'Gene', (152, 156))	('medulloblastomas', 'Disease', 'MESH:D008527', (15, 31))	('ZMYM3', 'Gene', (207, 212))
6504	26713744	A major effort moving forward will be functional characterization of these epigenetic alterations and identification of specific developmental cell types where their epigenetic deregulation promotes tumor formation.	('tumor', 'Disease', (199, 204))	('epigenetic deregulation', 'Var', (166, 189))	('epigenetic alterations', 'Var', (75, 97))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('promotes', 'PosReg', (190, 198))
6506	26713744	In tumors, such as pediatric glioblastoma and ependymoma, histone modification mapping by chromatin immunoprecipitation followed by high density sequencing (ChIP-seq) has demonstrated aberrant epigenetic patterns of histone H3K27 tri-methylation.	('pediatric glioblastoma', 'Disease', (19, 41))	('epigenetic patterns', 'MPA', (193, 212))	('ependymoma', 'Phenotype', 'HP:0002888', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('ependymoma', 'Disease', (46, 56))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (19, 41))	('ependymoma', 'Disease', 'MESH:D004806', (46, 56))	('histone H3K27', 'Protein', (216, 229))	('tri-methylation', 'Var', (230, 245))
6507	26713744	The linkage between epigenetic modifications and cell identity and lineage specification underscores the importance of understanding the epigenetic landscape in brain cancer.	('brain cancer', 'Disease', 'MESH:D001932', (161, 173))	('brain cancer', 'Phenotype', 'HP:0030692', (161, 173))	('epigenetic modifications', 'Var', (20, 44))	('cell identity', 'CPA', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('brain cancer', 'Disease', (161, 173))
6508	26713744	These epigenomic features can be co-opted in cancer by mutations and structural variations.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutations', 'Var', (55, 64))	('structural variations', 'Var', (69, 90))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
6509	26713744	In Group 3 medulloblastoma, Super-Enhancers are hijacked by structural variations, which lead to aberrant activation of GFI1 and GFI1b (growth factor independent 1 transcription repressor) oncogenes.	('medulloblastoma', 'Disease', 'MESH:D008527', (11, 26))	('GFI1b', 'Gene', '8328', (129, 134))	('growth factor independent 1 transcription repressor', 'Gene', '2672', (136, 187))	('medulloblastoma', 'Phenotype', 'HP:0002885', (11, 26))	('GFI1', 'Gene', (129, 133))	('GFI1b', 'Gene', (129, 134))	('GFI1', 'Gene', '2672', (129, 133))	('medulloblastoma', 'Disease', (11, 26))	('GFI1', 'Gene', '2672', (120, 124))	('activation', 'PosReg', (106, 116))	('GFI1', 'Gene', (120, 124))	('variations', 'Var', (71, 81))
6511	26713744	The consequence of these mutations in glioblastoma is the aberrant recruitment of the GABP (GA Binding Protein) transcription factor.	('mutations', 'Var', (25, 34))	('recruitment', 'MPA', (67, 78))	('glioblastoma', 'Disease', (38, 50))	('glioblastoma', 'Disease', 'MESH:D005909', (38, 50))	('GABP', 'Protein', (86, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))
6514	26713744	Examples include widespread accumulation of DNA methylation in IDH1 (Isocitrate dehydrogenase 1) mutated gliomas (see metabolism section below), and the establishment of CIMP phenotypes in other tumors, such as ependymoma (Figure 2).	('accumulation', 'PosReg', (28, 40))	('IDH1', 'Gene', (63, 67))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (69, 95))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('gliomas', 'Disease', (105, 112))	('ependymoma', 'Disease', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('Isocitrate dehydrogenase 1', 'Gene', (69, 95))	('tumors', 'Disease', (195, 201))	('CIMP', 'Chemical', '-', (170, 174))	('IDH1', 'Gene', '3417', (63, 67))	('ependymoma', 'Phenotype', 'HP:0002888', (211, 221))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('DNA methylation', 'MPA', (44, 59))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('mutated', 'Var', (97, 104))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('ependymoma', 'Disease', 'MESH:D004806', (211, 221))
6519	26713744	In addition to influences on cell state, epigenetic alterations have been shown to have widespread effects on the genetic landscape of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('genetic landscape', 'MPA', (114, 131))	('tumor', 'Disease', (135, 140))	('effects', 'Reg', (99, 106))	('epigenetic alterations', 'Var', (41, 63))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
6520	26713744	For example, methylated cytosine bases are highly prone to mutation by spontaneous deamination to thymine, thus creating opportunities for deregulation of tumor suppressor genes and oncogenes in the absence of intact DNA repair mechanisms.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('methylated', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (139, 151))	('thymine', 'Chemical', 'MESH:D013941', (98, 105))	('tumor', 'Disease', (155, 160))	('cytosine', 'Chemical', 'MESH:D003596', (24, 32))	('prone', 'Reg', (50, 55))	('oncogenes', 'Gene', (182, 191))	('mutation', 'MPA', (59, 67))
6521	26713744	Furthermore, it has been shown that hypomethylation of transposable elements have been observed widely in cancer, and may contribute significantly to genomic instability through aberrant translocation of DNA sequences.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('contribute', 'Reg', (122, 132))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('hypomethylation', 'Var', (36, 51))	('aberrant translocation', 'Var', (178, 200))	('observed', 'Reg', (87, 95))	('genomic', 'MPA', (150, 157))
6522	26713744	At the chromatin level a direct association between histone modifications and genetic alteration is evidenced in tumors that overexpress the H3K9/36me3 lysine demethylase KDM4A/JMJD2A, which leads to regional DNA copy gain in the absence of global chromosomal instability.	('tumors', 'Disease', (113, 119))	('regional DNA', 'MPA', (200, 212))	('JMJD2A', 'Gene', (177, 183))	('KDM4A', 'Gene', (171, 176))	('JMJD2A', 'Gene', '9682', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('lysine', 'Chemical', 'MESH:D008239', (152, 158))	('chromosomal instability', 'Phenotype', 'HP:0040012', (248, 271))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('H3K9/36me3', 'Var', (141, 151))	('overexpress', 'PosReg', (125, 136))	('gain', 'PosReg', (218, 222))	('KDM4A', 'Gene', '9682', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
6535	26713744	Although cells in nutrient-rich environments have the resources to facilitate rapid proliferation and tumor growth, it may be the cells within the hypoxic niche that actually drive tumor progression and recurrence due to the stem-like transcriptional and epigenetic adaptations they undergo in this environment (Figure 3).	('tumor', 'Disease', (181, 186))	('drive', 'PosReg', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('iron', 'Chemical', 'MESH:D007501', (302, 306))	('recurrence', 'CPA', (203, 213))	('iron', 'Chemical', 'MESH:D007501', (35, 39))	('epigenetic', 'Var', (255, 265))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
6543	26713744	In glioblastoma, the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is induced by hypoxia; and loss of MLL1 reduces the expression of HIF transcripts and HIF2alpha protein, indicating a potential feedback loop sustaining hypoxic response.	('MLL1', 'Gene', (73, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('HIF2alpha', 'Gene', '2034', (165, 174))	('MLL1', 'Gene', (114, 118))	('loss', 'Var', (106, 110))	('MLL1', 'Gene', '4297', (73, 77))	('glioblastoma', 'Disease', (3, 15))	('expression', 'MPA', (131, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('mixed-lineage leukemia 1', 'Gene', (47, 71))	('HIF2alpha', 'Gene', (165, 174))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('HIF', 'Protein', (145, 148))	('MLL1', 'Gene', '4297', (114, 118))	('mixed-lineage leukemia 1', 'Gene', '4297', (47, 71))	('reduces', 'NegReg', (119, 126))	('hypoxia', 'Disease', (93, 100))	('leukemia', 'Phenotype', 'HP:0001909', (61, 69))
6544	26713744	Depletion of MLL1 inhibited the expression of HIF2alpha and target genes, including vascular endothelial growth factor (VEGF), and reduced BTSC self-renewal, growth, and tumorigenicity.	('vascular endothelial growth factor', 'Gene', '7422', (84, 118))	('reduced BTSC', 'Phenotype', 'HP:0032198', (131, 143))	('HIF2alpha', 'Gene', (46, 55))	('VEGF', 'Gene', '7422', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('MLL1', 'Gene', '4297', (13, 17))	('BTSC self-renewal', 'CPA', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Depletion', 'Var', (0, 9))	('reduced', 'NegReg', (131, 138))	('tumor', 'Disease', (170, 175))	('inhibited', 'NegReg', (18, 27))	('MLL1', 'Gene', (13, 17))	('vascular endothelial growth factor', 'Gene', (84, 118))	('VEGF', 'Gene', (120, 124))	('HIF2alpha', 'Gene', '2034', (46, 55))	('expression', 'MPA', (32, 42))	('growth', 'CPA', (158, 164))
6545	26713744	In other cancers, HIF-independent hypoxia mediated epigenetic silencing of tumor suppressor genes has been described.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('HIF-independent hypoxia', 'Disease', (18, 41))	('cancers', 'Disease', (9, 16))	('epigenetic silencing', 'Var', (51, 71))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('HIF-independent hypoxia', 'Disease', 'MESH:D000860', (18, 41))	('tumor', 'Disease', (75, 80))
6546	26713744	Specifically, the BRCA1 and RAD51 promoters have been shown to be repressed by local chromatin restructuring via H3K4 demethylation, H3K9 methylation, and H3K9 deacetylation.	('BRCA1', 'Gene', '672', (18, 23))	('RAD51', 'Gene', (28, 33))	('H3K4', 'Protein', (113, 117))	('H3K9', 'Protein', (133, 137))	('RAD51', 'Gene', '5888', (28, 33))	('BRCA1', 'Gene', (18, 23))	('deacetylation', 'MPA', (160, 173))	('methylation', 'Var', (138, 149))	('H3K9', 'Protein', (155, 159))	('demethylation', 'Var', (118, 131))
6570	26713744	Whereas co-xenograft of brain tumor cells and endothelial cells increases tumor initiation and growth, knockdown of Notch ligands in the co-injected endothelial cells reduces tumor growth.	('reduces', 'NegReg', (167, 174))	('tumor', 'Disease', (175, 180))	('knockdown', 'Var', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('brain tumor', 'Disease', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('brain tumor', 'Disease', 'MESH:D001932', (24, 35))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('brain tumor', 'Phenotype', 'HP:0030692', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('increases tumor initiation', 'Disease', 'MESH:D009369', (64, 90))	('growth', 'CPA', (95, 101))	('tumor', 'Disease', (30, 35))	('increases tumor initiation', 'Disease', (64, 90))
6574	26713744	Entry and exit from cancer dormancy is mediated by epigenetic alterations, signaling pathways, and transcriptional circuits that are also known to drive stem cell reprogramming and maintenance.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('signaling', 'CPA', (75, 84))	('mediated', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('epigenetic alterations', 'Var', (51, 73))
6584	26713744	Mutations of metabolic pathways have been observed in several cancers, in addition to brain tumors, as a means of disrupting epigenetic and cellular state.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('disrupting', 'NegReg', (114, 124))	('metabolic pathways', 'Pathway', (13, 31))	('brain tumors', 'Disease', 'MESH:D001932', (86, 98))	('brain tumors', 'Phenotype', 'HP:0030692', (86, 98))	('cancers', 'Disease', (62, 69))	('brain tumor', 'Phenotype', 'HP:0030692', (86, 97))	('observed', 'Reg', (42, 50))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('brain tumors', 'Disease', (86, 98))
6585	26713744	In glioma, one of the most common recurrent mutations occurs in IDH1, resulting in the accumulation of an oncometabolite (R-2-hydroxyglutarate, R-2-HG), which functions to inhibit the activity of multiple alpha-ketoglutarate (alpha-KG) dependent dixoygenases.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (205, 224))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('IDH1', 'Gene', (64, 68))	('activity', 'MPA', (184, 192))	('accumulation', 'PosReg', (87, 99))	('R-2-hydroxyglutarate', 'Chemical', '-', (122, 142))	('IDH1', 'Gene', '3417', (64, 68))	('mutations', 'Var', (44, 53))	('glioma', 'Disease', (3, 9))	('inhibit', 'NegReg', (172, 179))
6587	26713744	However, these widespread effects also increase the difficulty of deciphering the functional consequence(s) of the IDH mutations, specifically whether some of these effects are a mere product of increased R-2-HG production.	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('increased', 'PosReg', (195, 204))	('mutations', 'Var', (119, 128))	('R-2-HG production', 'MPA', (205, 222))
6588	26713744	One of several consequences from IDH mutations is aberrant methylation of histones at several lysine residues, and acquisition of a CpG island methylator phenotype through DNA hypermethylation.	('methylation', 'MPA', (59, 70))	('lysine', 'Chemical', 'MESH:D008239', (94, 100))	('histones', 'Protein', (74, 82))	('mutations', 'Var', (37, 46))	('IDH', 'Gene', (33, 36))	('IDH', 'Gene', '3417', (33, 36))
6589	26713744	While the function of IDH1 mutations in glioblastoma remains to be fully characterized, the result of increased histone methylation prevents lineage-specific progenitors from differentiating into terminally differentiated cells.	('mutations', 'Var', (27, 36))	('prevents', 'NegReg', (132, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('lineage-specific progenitors', 'CPA', (141, 169))	('IDH1', 'Gene', (22, 26))	('increased', 'PosReg', (102, 111))	('IDH1', 'Gene', '3417', (22, 26))	('glioblastoma', 'Disease', (40, 52))	('histone methylation', 'MPA', (112, 131))
6590	26713744	Furthermore, chemical inhibition of IDH1 has been shown to promote glioma differentiation.	('IDH1', 'Gene', (36, 40))	('glioma', 'Disease', (67, 73))	('IDH1', 'Gene', '3417', (36, 40))	('promote', 'PosReg', (59, 66))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('chemical inhibition', 'Var', (13, 32))
6591	26713744	Like pediatric glioblastomas, which harbor K27M mutations, the convergence on epigenetic programs elicited by metabolic state changes, suggests that these types of mutations may function to activate a stem- or progenitor- cell states required for tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('glioblastomas', 'Disease', (15, 28))	('tumor', 'Disease', (247, 252))	('glioblastoma', 'Phenotype', 'HP:0012174', (15, 27))	('K27M', 'Var', (43, 47))	('pediatric glioblastoma', 'Disease', (5, 27))	('activate', 'PosReg', (190, 198))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (5, 27))	('stem- or progenitor- cell states', 'CPA', (201, 233))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('glioblastomas', 'Phenotype', 'HP:0012174', (15, 28))	('glioblastomas', 'Disease', 'MESH:D005909', (15, 28))	('K27M', 'Mutation', 'p.K27M', (43, 47))
6598	26713744	It is possible that cancer cells can gain GLUT3 expression and stem cell properties simultaneously by epigenetically de-repressing this region of chromatin during stem cell reprogramming.	('stem cell properties', 'CPA', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('epigenetically', 'Var', (102, 116))	('GLUT3', 'Gene', '6515', (42, 47))	('de-repressing', 'NegReg', (117, 130))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('GLUT3', 'Gene', (42, 47))	('cancer', 'Disease', (20, 26))	('gain', 'PosReg', (37, 41))
6600	26713744	Acetate and co-enzyme A are oxidized by ACSS2 to form the central metabolite Acetyl-CoA necessary for a wide variety of cellular processes including epigenetic modulation through histone acetylation.	('epigenetic modulation', 'Var', (149, 170))	('ACSS2', 'Gene', '55902', (40, 45))	('ACSS2', 'Gene', (40, 45))	('Acetyl-CoA', 'Chemical', 'MESH:D000105', (77, 87))	('Acetate', 'Chemical', 'MESH:D000085', (0, 7))	('histone acetylation', 'MPA', (179, 198))
6604	26713744	Numerous preclinical studies have shown that brain tumors are sensitive to a variety of inhibitors of epigenetic modifications, several of which are FDA approved (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('epigenetic modifications', 'Var', (102, 126))	('brain tumors', 'Phenotype', 'HP:0030692', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('brain tumors', 'Disease', 'MESH:D001932', (45, 57))	('brain tumors', 'Disease', (45, 57))	('inhibitors', 'Var', (88, 98))	('brain tumor', 'Phenotype', 'HP:0030692', (45, 56))
6605	26713744	These include DNA methylation and HDAC inhibitors, such as decitabine and vorinostat, respectively.	('DNA', 'Var', (14, 17))	('methylation', 'Var', (18, 29))	('vorinostat', 'Chemical', 'MESH:D000077337', (74, 84))	('decitabine', 'Chemical', 'MESH:D000077209', (59, 69))
6606	26713744	Targeted epigenetic modulation has already shown promise in numerous pre-clinical models of brain tumors characterized by aberrant epigenetic programs.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (92, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (92, 104))	('Targeted epigenetic modulation', 'Var', (0, 30))	('brain tumors', 'Disease', (92, 104))	('brain tumor', 'Phenotype', 'HP:0030692', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
6607	26713744	In the case of DIPGs that harbor the H3.3 K27M mutant, and global loss of H3K27 tri-methylation, a H3K27 demethylase (JMJD3) inhibitor (GSK-J4) has been shown to be effective for reducing tumor growth by elevating H3K27 tri-methylation.	('tumor', 'Disease', (188, 193))	('loss', 'NegReg', (66, 70))	('tri-methylation', 'MPA', (80, 95))	('JMJD3', 'Gene', (118, 123))	('reducing', 'NegReg', (179, 187))	('H3K27', 'Protein', (74, 79))	('H3.3 K27M', 'Var', (37, 46))	('H3K27', 'Protein', (214, 219))	('elevating', 'PosReg', (204, 213))	('DIPGs', 'Chemical', 'MESH:C060938', (15, 20))	('K27M', 'Mutation', 'p.K27M', (42, 46))	('JMJD3', 'Gene', '23135', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tri-methylation', 'MPA', (220, 235))
6613	26713744	This represents a collection of early studies examining an emerging concept of reversing epigenetic signatures in brain tumors using novel small molecule epigenetic inhibitors.	('brain tumors', 'Disease', (114, 126))	('brain tumor', 'Phenotype', 'HP:0030692', (114, 125))	('epigenetic signatures', 'Var', (89, 110))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('brain tumors', 'Phenotype', 'HP:0030692', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('brain tumors', 'Disease', 'MESH:D001932', (114, 126))
6617	26713744	Glioblastoma and other brain tumors harbor mutations that are infrequent in isolation but disrupt normal function of a limited cohort of pathways (p53, retinoblastoma, receptor tyrosine kinase signaling, and chromatin-associated molecules).	('Glioblastoma', 'Disease', (0, 12))	('brain tumors', 'Disease', 'MESH:D001932', (23, 35))	('brain tumors', 'Phenotype', 'HP:0030692', (23, 35))	('retinoblastoma', 'Phenotype', 'HP:0009919', (152, 166))	('disrupt', 'NegReg', (90, 97))	('retinoblastoma', 'Disease', 'MESH:D012175', (152, 166))	('retinoblastoma', 'Disease', (152, 166))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('brain tumors', 'Disease', (23, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('mutations', 'Var', (43, 52))	('p53', 'Gene', '7157', (147, 150))	('brain tumor', 'Phenotype', 'HP:0030692', (23, 34))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('receptor tyrosine kinase signaling', 'MPA', (168, 202))	('function', 'MPA', (105, 113))	('p53', 'Gene', (147, 150))
6622	26713744	The convergence of genomic alterations, microenvironmental conditions, and metabolic reprogramming to create an epigenetic landscape that promotes aberrant activation and maintenance of stem cell-like transcriptional programs may offer a coherent strategy to improve diagnosis, prediction of prognosis, and therapies.	('activation', 'PosReg', (156, 166))	('iron', 'Chemical', 'MESH:D007501', (48, 52))	('aberrant', 'Var', (147, 155))	('promotes', 'PosReg', (138, 146))	('stem cell-like', 'CPA', (186, 200))
6630	26713744	inhibitors of IDH1 or BRD4 - may offer benefit, sustained tumor control will be most likely achieved with combinatorial targeting strategies with conventional or targeted therapies.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('BRD4', 'Gene', (22, 26))	('inhibitors', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('IDH1', 'Gene', (14, 18))	('BRD4', 'Gene', '23476', (22, 26))	('IDH1', 'Gene', '3417', (14, 18))
6631	26713744	Potentially, inhibitors of chromatin-associated proteins could induce synthetic lethality with other treatments, disrupt the growth of heterogeneous tumor populations, and attenuate mechanisms of progression.	('chromatin-associated proteins', 'Protein', (27, 56))	('attenuate', 'NegReg', (172, 181))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('mechanisms of progression', 'CPA', (182, 207))	('inhibitors', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('growth', 'MPA', (125, 131))	('induce', 'PosReg', (63, 69))	('tumor', 'Disease', (149, 154))	('disrupt', 'NegReg', (113, 120))	('synthetic lethality', 'MPA', (70, 89))
6650	26517510	Moreover, epigenetic changes such as the O6-methylguanine DNA methyltransferase (Mgmt) gene methylation patterning, have been shown to modulate responses to temozolomide in GBM.	('temozolomide', 'Chemical', 'MESH:D000077204', (157, 169))	('modulate', 'Reg', (135, 143))	('methylation', 'Var', (92, 103))	('O6-methylguanine DNA methyltransferase', 'Gene', (41, 79))	('Mgmt', 'Gene', (81, 85))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (41, 79))	('responses to temozolomide', 'MPA', (144, 169))	('Mgmt', 'Gene', '4255', (81, 85))
6652	26517510	Genetically divergent GBM cell populations might have evolved from GSCs of different origins that expressed variable patterns of stem-cell markers, such as CD133, CD15, A2B5, and CD44, due to which they might harbor different tumorigenic potential.	('CD15', 'Gene', '2526', (163, 167))	('CD44', 'Gene', '960', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('CD133', 'Gene', (156, 161))	('CD133', 'Gene', '8842', (156, 161))	('A2B5', 'Var', (169, 173))	('CD44', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CD15', 'Gene', (163, 167))	('tumor', 'Disease', (226, 231))
6671	26517510	U87 cells exposed to U373 CM showed an almost doubling of their CFU, whereas with the slow-growing U373 cells there was only a 30% increase in CFU upon exposure to U87 CM.	('U87', 'Gene', '641648', (0, 3))	('U373', 'CellLine', 'CVCL:2219', (21, 25))	('U87', 'Gene', (164, 167))	('U373', 'CellLine', 'CVCL:2219', (99, 103))	('U373 CM', 'Var', (21, 28))	('U87', 'Gene', (0, 3))	('U87', 'Gene', '641648', (164, 167))	('CFU', 'CPA', (64, 67))
6683	26517510	When exposing these GBM cells to the CM of the other cell type(s), the number of MN in U87 cells decreased with exposure to U373 CM, whereas the number of MN in U373 cells increased with exposure to U87 CM (Figure 4d).	('U373 CM', 'Var', (124, 131))	('U87', 'Gene', '641648', (87, 90))	('U373', 'CellLine', 'CVCL:2219', (161, 165))	('decreased', 'NegReg', (97, 106))	('U87', 'Gene', (199, 202))	('U373', 'CellLine', 'CVCL:2219', (124, 128))	('U87', 'Gene', '641648', (199, 202))	('U87', 'Gene', (87, 90))
6684	26517510	This decrease in the chromosomal instability in U87 cells correlated with the demonstrated inhibition of proliferation of these U87 cells by U373 CM (compare Figure 3a with Figure 4d).	('U87', 'Gene', '641648', (48, 51))	('U87', 'Gene', '641648', (128, 131))	('chromosomal', 'MPA', (21, 32))	('chromosomal instability', 'Phenotype', 'HP:0040012', (21, 44))	('inhibition', 'NegReg', (91, 101))	('proliferation', 'CPA', (105, 118))	('U373 CM', 'Var', (141, 148))	('U373', 'CellLine', 'CVCL:2219', (141, 145))	('U87', 'Gene', (128, 131))	('decrease', 'NegReg', (5, 13))	('U87', 'Gene', (48, 51))
6687	26517510	Consistent with this, the Bax (Bcl-2 associated X protein)/Bcl2 (B-cell CLL/lymphoma 2) ratio was decreased in U87 cells exposed to U373 CM (Figure 4f).	('U373 CM', 'Var', (132, 139))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('Bcl2', 'Gene', (59, 63))	('U87', 'Gene', (111, 114))	('Bcl-2', 'Gene', (31, 36))	('Bax', 'Gene', (26, 29))	('Bcl-2', 'Gene', '596', (31, 36))	('U373', 'CellLine', 'CVCL:2219', (132, 136))	('U87', 'Gene', '641648', (111, 114))	('Bcl2', 'Gene', '596', (59, 63))	('lymphoma', 'Disease', (76, 84))	('lymphoma', 'Disease', 'MESH:D008223', (76, 84))	('decreased', 'NegReg', (98, 107))	('Bax', 'Gene', '581', (26, 29))
6689	26517510	Together, these data imply that U251 CM and U373 CM act towards increased genomic stability of U87 cells, whereas U87 CM might have opposite effects; i.e., it might decrease genomic stability of U251 and U373 cells, and enhance their apoptotic tendency.	('genomic stability', 'CPA', (174, 191))	('U251', 'Var', (32, 36))	('U373', 'CellLine', 'CVCL:2219', (44, 48))	('U373', 'CellLine', 'CVCL:2219', (204, 208))	('enhance', 'PosReg', (220, 227))	('apoptotic tendency', 'CPA', (234, 252))	('U87', 'Gene', '641648', (114, 117))	('U87', 'Gene', (95, 98))	('decrease', 'NegReg', (165, 173))	('U87', 'Gene', '641648', (95, 98))	('increased', 'PosReg', (64, 73))	('U87', 'Gene', (114, 117))
6701	26517510	As in the cell cycle analysis, TMZ increased the proliferation rates of U87 cells in direct co-culture, whereas it decreased the proliferation rates of U373 cells, when compared to non-treated directly co-cultured cells (Figure 5f-5h).	('U87', 'Gene', (72, 75))	('increased', 'PosReg', (35, 44))	('U373', 'CellLine', 'CVCL:2219', (152, 156))	('proliferation rates', 'CPA', (49, 68))	('decreased', 'NegReg', (115, 124))	('U87', 'Gene', '641648', (72, 75))	('TMZ', 'Var', (31, 34))	('proliferation rates', 'CPA', (129, 148))	('TMZ', 'Chemical', 'MESH:D000077204', (31, 34))
6702	26517510	This was most evident for 1:1 direct co-culture (Figure 5g), which again implies that U87 cells sensitize U373 cells to TMZ, and U373 cells protect U87 cells from TMZ toxicity, a concept that was also observed in the indirect co-cultures (Figure 5d).	('U87', 'Gene', '641648', (86, 89))	('toxicity', 'Disease', 'MESH:D064420', (167, 175))	('toxicity', 'Disease', (167, 175))	('U87', 'Gene', (148, 151))	('U373', 'CellLine', 'CVCL:2219', (129, 133))	('TMZ', 'Chemical', 'MESH:D000077204', (163, 166))	('U87', 'Gene', '641648', (148, 151))	('U373', 'CellLine', 'CVCL:2219', (106, 110))	('U373', 'Var', (129, 133))	('TMZ', 'Chemical', 'MESH:D000077204', (120, 123))	('U87', 'Gene', (86, 89))
6707	26517510	CD29 (integrin b1/fibronectin receptor), CD90 (Thy-1 cell surface antigen) and CD105 (endoglin, TGF-b receptor), when compared to U87 cells.	('CD90', 'Gene', (41, 45))	('CD105', 'Var', (79, 84))	('CD29', 'Gene', '3688', (0, 4))	('U87', 'Gene', (130, 133))	('CD29', 'Gene', (0, 4))	('U87', 'Gene', '641648', (130, 133))	('CD90', 'Gene', '7070', (41, 45))
6725	26517510	Thus, we believe that the interactions between these U87 and U373 (and similarly for U251) model GBM cell lines might well mirror these two GBM subtypes in vivo.	('interactions', 'Interaction', (26, 38))	('U373', 'Var', (61, 65))	('U87', 'Gene', (53, 56))	('U373', 'CellLine', 'CVCL:2219', (61, 65))	('U87', 'Gene', '641648', (53, 56))
6738	26517510	In contrast, decreased numbers of MN and decreased Bax/Bcl-2 ratios in U87 cells exposed to U251/U373 CM indicate a higher apoptotic threshold of U87 cells.	('decreased', 'NegReg', (13, 22))	('Bcl-2', 'Gene', (55, 60))	('Bcl-2', 'Gene', '596', (55, 60))	('U87', 'Gene', (71, 74))	('higher', 'PosReg', (116, 122))	('U87', 'Gene', (146, 149))	('decreased', 'NegReg', (41, 50))	('U251/U373 CM', 'Var', (92, 104))	('U87', 'Gene', '641648', (146, 149))	('Bax', 'Gene', '581', (51, 54))	('U87', 'Gene', '641648', (71, 74))	('apoptotic threshold', 'CPA', (123, 142))	('Bax', 'Gene', (51, 54))	('U373', 'CellLine', 'CVCL:2219', (97, 101))
6746	26517510	The wild type p53 status of U87 cells might underlie the observed decrease in proliferation of U87 cells exposed to U251/U373 CM.	('U87', 'Gene', '641648', (28, 31))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('U87', 'Gene', (95, 98))	('U251/U373 CM', 'Var', (116, 128))	('proliferation', 'CPA', (78, 91))	('U87', 'Gene', '641648', (95, 98))	('decrease', 'NegReg', (66, 74))	('U373', 'CellLine', 'CVCL:2219', (121, 125))	('U87', 'Gene', (28, 31))
6748	26517510	On the other hand, the mutated p53 gene status in U373 cells might underlie the increased genomic instability and apoptosis in U373 cells exposed to U87 CM.	('U87', 'Gene', (149, 152))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('U373', 'CellLine', 'CVCL:2219', (50, 54))	('U87', 'Gene', '641648', (149, 152))	('genomic instability', 'CPA', (90, 109))	('U373', 'CellLine', 'CVCL:2219', (127, 131))	('increased', 'PosReg', (80, 89))	('mutated', 'Var', (23, 30))	('apoptosis', 'CPA', (114, 123))
6750	26517510	These apoptotic threshold alterations might result in changed sensitivity of the GBM cells to TMZ, a DNA alkylating agent that is known to impair GBM cell growth and increase survival of patients from 6 months up to 1 year.	('patients', 'Species', '9606', (187, 195))	('TMZ', 'Chemical', 'MESH:D000077204', (94, 97))	('result', 'Reg', (44, 50))	('survival', 'CPA', (175, 183))	('sensitivity', 'MPA', (62, 73))	('increase', 'PosReg', (166, 174))	('alterations', 'Var', (26, 37))	('impair', 'NegReg', (139, 145))	('changed', 'Reg', (54, 61))
6761	26517510	When exposed to U373 CM, U87 cell invasion decreased in the indirect 2D co-cultures using matrigel, whereas it increased in the 3D-collagen-embedded U87 spheroids.	('indirect 2D co-cultures using', 'CPA', (60, 89))	('U373 CM', 'Var', (16, 23))	('U87', 'Gene', (149, 152))	('U87', 'Gene', '641648', (25, 28))	('increased', 'PosReg', (111, 120))	('U87', 'Gene', '641648', (149, 152))	('U373', 'CellLine', 'CVCL:2219', (16, 20))	('U87', 'Gene', (25, 28))	('decreased', 'NegReg', (43, 52))
6765	26517510	Knock-down of Csf2 expression also reduces invasion of GL261 cells in vivo.	('reduces', 'NegReg', (35, 42))	('invasion of GL261 cells in vivo', 'CPA', (43, 74))	('Knock-down', 'Var', (0, 10))	('GL261', 'CellLine', 'CVCL:Y003', (55, 60))	('Csf2', 'Gene', (14, 18))
6810	26517510	Real-time PCR reactions were performed using 1:10 dilutions (1 mul/well) of each cDNA, TaqMan Universal PCR Master Mix (Applied Biosystems, USA) and the TaqMan Gene Expression assays (all from Applied Biosystems, USA): Ccl20 (chemokine (C-C motif) ligand 20), Hs01011368_m1; Egflam (EGF-like, fibronecting type III and laminin G domains), Hs00794831_m1; Dpp4 (dipeptidyl-peptidase 4), Hs00175210_m1, Bcl2 (B-cell CLL/lymphoma2), Hs00608023_m1; Bax (Bcl-2 associated X protein), Hs99999001_m1.	('Hs00175210_m1', 'Var', (385, 398))	('Hs00608023_m1', 'Var', (429, 442))	('B-cell CLL/lymphoma2', 'Gene', (406, 426))	('dipeptidyl-peptidase 4', 'Gene', '1803', (360, 382))	('Hs99999001_m1', 'Var', (478, 491))	('chemokine (C-C motif) ligand 20', 'Gene', '6364', (226, 257))	('Dpp4', 'Gene', '1803', (354, 358))	('Egflam', 'Gene', '133584', (275, 281))	('Dpp4', 'Gene', (354, 358))	('Bcl2', 'Gene', (400, 404))	('Bcl-2', 'Gene', (449, 454))	('Bcl2', 'Gene', '596', (400, 404))	('Bax', 'Gene', (444, 447))	('Ccl20', 'Gene', (219, 224))	('Bcl-2', 'Gene', '596', (449, 454))	('Egflam', 'Gene', (275, 281))	('Ccl20', 'Gene', '6364', (219, 224))	('Bax', 'Gene', '581', (444, 447))	('lymphoma', 'Phenotype', 'HP:0002665', (417, 425))	('B-cell CLL/lymphoma2', 'Gene', '596', (406, 426))	('dipeptidyl-peptidase 4', 'Gene', (360, 382))
6837	23977117	Among the remaining 39 patients, 10 patients had GBMs with an oligodendroglial component and four patients had a 1p 19q deletion, which are known to be associated with a more favorable prognosis than in those patients having general GBMs.	('1p 19q deletion', 'Var', (113, 128))	('patients', 'Species', '9606', (36, 44))	('oligodendroglial component', 'Disease', 'MESH:C562869', (62, 88))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (209, 217))	('oligodendroglial component', 'Disease', (62, 88))
6848	23977117	Among the genetic alterations, there were two proliferation markers (epidermal growth factor receptor [EGFR] and Ki-67), one DNA repair gene (O6-methylguanine-DNA methyltransferase [MGMT]) and two tumor-suppressor genes (phosphatase and tensin homologue [PTEN] and p53).	('p53', 'Gene', (265, 268))	('MGMT', 'Gene', (182, 186))	('alterations', 'Var', (18, 29))	('EGFR', 'Gene', '1956', (103, 107))	('p53', 'Gene', '7157', (265, 268))	('O6-methylguanine-DNA methyltransferase', 'Gene', (142, 180))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('epidermal growth factor receptor', 'Gene', (69, 101))	('EGFR', 'Gene', (103, 107))	('phosphatase and tensin homologue', 'Gene', '5728', (221, 253))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('PTEN', 'Gene', (255, 259))	('epidermal growth factor receptor', 'Gene', '1956', (69, 101))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (142, 180))	('PTEN', 'Gene', '5728', (255, 259))	('tumor', 'Disease', (197, 202))	('Ki-67', 'Gene', (113, 118))	('MGMT', 'Gene', '4255', (182, 186))
6858	23977117	In the ROC analysis, cutoff values that provided a balance between sensitivity and specificity for prediction of the genetic profiles were determined by selecting the coordinate that was nearest the left upper corner (ie, [0,1 ]) on each ROC curve, and values higher than the cutoff values were considered to indicate loss of PTEN expression or nonmethylation of MGMT promoter.	('loss', 'NegReg', (318, 322))	('expression', 'MPA', (331, 341))	('PTEN', 'Gene', (326, 330))	('MGMT', 'Gene', (363, 367))	('PTEN', 'Gene', '5728', (326, 330))	('MGMT', 'Gene', '4255', (363, 367))	('nonmethylation', 'Var', (345, 359))
6884	23977117	EGFR amplification is associated with EGFR overexpression.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', (38, 42))	('overexpression', 'PosReg', (43, 57))	('associated', 'Reg', (22, 32))	('EGFR', 'Gene', '1956', (0, 4))
6888	23977117	PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to the second-messenger molecule phosphatidylinositol-3,4,5-triphosphate (PIP3), which activates Akt.	('PI3K', 'Var', (0, 4))	('activates', 'PosReg', (146, 155))	('Akt', 'Gene', (156, 159))	('PIP3', 'Chemical', '-', (133, 137))	('phosphatidylinositol-3,4,5-triphosphate', 'Chemical', 'MESH:C060974', (92, 131))	('PIP2', 'Chemical', 'MESH:D019269', (53, 57))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (14, 51))	('Akt', 'Gene', '207', (156, 159))
6895	23977117	Loss of MGMT expression may be caused by the methylation of promoter CpG islands.	('expression', 'MPA', (13, 23))	('MGMT', 'Gene', '4255', (8, 12))	('Loss', 'NegReg', (0, 4))	('MGMT', 'Gene', (8, 12))	('methylation', 'Var', (45, 56))
6898	23977117	Mutations in p53, a famous tumor suppressor gene, are found in a diverse variety of human tumors.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('found', 'Reg', (54, 59))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('human', 'Species', '9606', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('p53', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('p53', 'Gene', '7157', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
6901	23977117	Ki-67 is a well-known biomarker representing the proliferative activity of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ki-67', 'Var', (0, 5))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
6930	32608374	The prodrug is activated by the HSV-TK and incorporated into the DNA of the tumor cells, where it causes damage to the genome and tumor apoptosis.,  Since 1991, multiple phase I and II clinical trials tested the HSVTK/Nucleoside-analogue system in GBM treatment, conveyed by replication-defective retroviruses and adenoviruses.- Cerepro  (Ark Therapeutics; UK and Finland) and adenoviral vector-based HSV-TK/valacyclovir were studied in some preclinical and phase I/II clinical trials (www.clinicaltrials.gov, #NCT03603405, #NCT03596086), where they proved to increase the patients' overall survival, also with a good safety profile.	('#NCT03603405', 'Var', (510, 522))	('valacyclovir', 'Chemical', 'MESH:D000077483', (408, 420))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('#NCT03596086', 'Var', (524, 536))	('Ark', 'Gene', (339, 342))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Ark', 'Gene', '558', (339, 342))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('GBM', 'Phenotype', 'HP:0012174', (248, 251))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patients', 'Species', '9606', (573, 581))	('overall survival', 'CPA', (583, 599))	('tumor', 'Disease', (130, 135))	('increase', 'PosReg', (560, 568))	('adenovirus', 'Species', '10508', (314, 324))
6931	32608374	CD converts 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), which exerts its antitumor effect, irreversibly inhibiting the synthesis of DNA.,  Several preclinical and phase I-III clinical trials tested the efficacy and safety profile of CD/5-FC for high grade gliomas (#NCT01985256, #NCT01156584, #NCT01470794).	('tumor', 'Disease', (85, 90))	('5-FU', 'Chemical', 'MESH:D005472', (57, 61))	('gliomas', 'Disease', (264, 271))	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('5-FC', 'Chemical', 'MESH:D005437', (30, 34))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('5-FC', 'Chemical', 'MESH:D005437', (244, 248))	('5-fluorocytosine', 'Chemical', 'MESH:D005437', (12, 28))	('#NCT01985256', 'Var', (273, 285))	('tested', 'Reg', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('#NCT01156584', 'Var', (287, 299))
6932	32608374	A further enhancement of the cytotoxicity comes from the combination of CD/5-FC with Uracil Phosphoribosyl Transferase (UPRT).	('enhancement', 'PosReg', (10, 21))	('cytotoxicity', 'Disease', (29, 41))	('UPRT', 'Gene', '139596', (120, 124))	('CD/5-FC', 'Var', (72, 79))	('combination', 'Interaction', (57, 68))	('Uracil Phosphoribosyl Transferase', 'Gene', '139596', (85, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('Uracil Phosphoribosyl Transferase', 'Gene', (85, 118))	('UPRT', 'Gene', (120, 124))	('5-FC', 'Chemical', 'MESH:D005437', (75, 79))
6937	32608374	p53, p16 and Phosphatase and Tensin Homologue (PTEN) pathways are frequently mutated in high-grade gliomas, consequently resulting in the loss of both DNA repair and the regulation of cell proliferation.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('loss', 'NegReg', (138, 142))	('p16', 'Gene', (5, 8))	('regulation', 'CPA', (170, 180))	('mutated', 'Var', (77, 84))	('gliomas', 'Disease', (99, 106))	('p16', 'Gene', '1029', (5, 8))	('PTEN', 'Gene', (47, 51))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('DNA repair', 'MPA', (151, 161))	('PTEN', 'Gene', '5728', (47, 51))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('Phosphatase and Tensin Homologue', 'Gene', '5728', (13, 45))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
6939	32608374	It is found to be inactivated in 25-30% of primary GBMs, and 60-70% of recurrent ones.,  Tumor suppressor gene strategies involve a non-replicating adenovirus, combined with the cytomegalovirus promoter (CMV), in which the E1 gene is replaced by the p53 gene (AD5CMV-P53).- Adenovirus-mediated p53 gene transfer showed an oncolytic effect against recurrent GBMs in many phase I trials, where it was administered by stereotactic injection, resulting in a median progression-free survival of 13 weeks and an overall survival of 43 weeks (#NCT00004041, #NCT00004080).	('gene transfer', 'Var', (298, 311))	('Adenovirus', 'Species', '10508', (274, 284))	('Tumor', 'Phenotype', 'HP:0002664', (89, 94))	('adenovirus', 'Species', '10508', (148, 158))	('GBM', 'Phenotype', 'HP:0012174', (357, 360))	('p53', 'Gene', (250, 253))	('p53', 'Gene', '7157', (250, 253))	('Tumor suppressor', 'Gene', '7248', (89, 105))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('p53', 'Gene', '7157', (294, 297))	('p53', 'Gene', (294, 297))	('Tumor suppressor', 'Gene', (89, 105))
6941	32608374	The adenovirus-mediated restoration of its function proved to reduce cancer growth, but also to counteract the spreading of GBM cells through the inhibition of the matrix metalloprotease 2 activity within the tumor microenvironment.	('function', 'MPA', (43, 51))	('adenovirus-mediated', 'Var', (4, 23))	('tumor', 'Disease', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('reduce', 'NegReg', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))	('matrix', 'Enzyme', (164, 170))	('cancer', 'Disease', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('adenovirus', 'Species', '10508', (4, 14))	('activity', 'MPA', (189, 197))
6953	32608374	HSV G207 and HSV1716 are the main engineered HSVs used in the treatment of malignant gliomas.	('malignant gliomas', 'Disease', 'MESH:D005910', (75, 92))	('HSV G207', 'Var', (0, 8))	('gliomas', 'Phenotype', 'HP:0009733', (85, 92))	('HSV1716', 'Var', (13, 20))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('malignant gliomas', 'Disease', (75, 92))
6954	32608374	HSV G207, deleted for the gamma34.5 gene, selectively targets replicating cells.,  In many phase I/II clinical trials, HSV G207 was locally administered, with limited evidence of anti-tumor activity (#NCT00157703, #NCT00028158).	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('#NCT00028158', 'Var', (214, 226))	('tumor', 'Disease', (184, 189))	('#NCT00157703', 'Var', (200, 212))	('HSV', 'Var', (119, 122))
6962	32608374	Carcinogenic embryonic antigen (MV-CEA) and the human thyroidal sodium iodide symporter gene (MV-NIS) were added to enhance its antitumoral action.,  Oncolytic PVS-RIPO is an attenuated type 1 Sabin poliovirus in which the internal ribosomal entry site (IRES) has been replaced with the IRES of human rhinovirus type 2.,  PVS-RIPO targets and destroys glioma cells with a classic oncolytic mechanism.	('poliovirus', 'Species', '138950', (199, 209))	('human', 'Species', '9606', (295, 300))	('Carcinogenic embryonic', 'Disease', 'MESH:D020964', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Carcinogenic embryonic', 'Disease', (0, 22))	('human', 'Species', '9606', (48, 53))	('human rhinovirus', 'Species', '169066', (295, 311))	('glioma', 'Disease', (352, 358))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('destroys', 'NegReg', (343, 351))	('glioma', 'Disease', 'MESH:D005910', (352, 358))	('glioma', 'Phenotype', 'HP:0009733', (352, 358))	('sodium iodide', 'Chemical', 'MESH:D012974', (64, 77))	('PVS-RIPO', 'Var', (322, 330))
6963	32608374	Data collected from the PVS-RIPO clinical trials confirmed the antitumoral activity, however, limited by low tolerability (#NCT02986178; #NCT01491893).	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('#NCT02986178', 'Var', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
6964	32608374	Many viruses have proven to hold a specific neurotropism, which makes them perfect vehicles for targeting the glioma cells, transferring gene copies, codifying antitumor factors and, ultimately, fulfilling the therapeutic action.	('tumor', 'Disease', (164, 169))	('glioma', 'Disease', (110, 116))	('transferring gene copies', 'Var', (124, 148))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
6966	32608374	These are capable of delivering specific transgenes, reprogramming genetic expression and selectively lysing the tumor cells.	('tumor', 'Disease', (113, 118))	('delivering', 'Reg', (21, 31))	('reprogramming', 'Var', (53, 66))	('transgenes', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
7010	33204830	The anatomical structure of a tissue or organ is essential to its function, and the structural change could result in organ dysfunction and disease.	('result in', 'Reg', (108, 117))	('organ dysfunction', 'Disease', (118, 135))	('organ dysfunction', 'Disease', 'MESH:D009102', (118, 135))	('structural change', 'Var', (84, 101))	('disease', 'Disease', (140, 147))
7021	33204830	Low cell density can cause cornea swelling and vision blurred, namely Fuchs' corneal dystrophy.	('Low cell density', 'Var', (0, 16))	('swelling', 'Disease', 'MESH:D004487', (34, 42))	('swelling', 'Disease', (34, 42))	('corneal dystrophy', 'Phenotype', 'HP:0001131', (77, 94))	('corneal dystrophy', 'Disease', (77, 94))	('cause', 'Reg', (21, 26))	('corneal dystrophy', 'Disease', 'MESH:D003317', (77, 94))	('vision blurred', 'Phenotype', 'HP:0000622', (47, 61))	('cornea', 'Disease', (27, 33))
7053	33204830	The nanotoxicity study on the lung chip reveals that the mechanical stretch elevates the toxicity of nanoparticles by accentuating the endothelial and epithelial uptake of nanoparticles.	('accentuating', 'PosReg', (118, 130))	('chip', 'Gene', (35, 39))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('elevates', 'PosReg', (76, 84))	('chip', 'Gene', '287155', (35, 39))	('toxicity', 'Disease', 'MESH:D064420', (8, 16))	('toxicity', 'Disease', (8, 16))	('mechanical', 'Var', (57, 67))
7054	33204830	The mechanical stretch has also been shown to enhance the IL2-induced vascular leakage, which highlights the crucial role of mechanical stretch in lung diseases such as pulmonary edema.	('pulmonary edema', 'Disease', 'MESH:D011654', (169, 184))	('lung diseases', 'Disease', 'MESH:D008171', (147, 160))	('enhance', 'PosReg', (46, 53))	('mechanical', 'Var', (4, 14))	('lung diseases', 'Phenotype', 'HP:0002088', (147, 160))	('pulmonary edema', 'Phenotype', 'HP:0100598', (169, 184))	('IL2', 'Gene', '3558', (58, 61))	('vascular leakage', 'Disease', 'MESH:D003763', (70, 86))	('IL2', 'Gene', (58, 61))	('stretch in lung', 'Phenotype', 'HP:0100598', (136, 151))	('pulmonary edema', 'Disease', (169, 184))	('edema', 'Phenotype', 'HP:0000969', (179, 184))	('vascular leakage', 'Disease', (70, 86))	('lung diseases', 'Disease', (147, 160))
7070	33204830	Additionally, cancer exhibits a large variety of genetic mutations among patients and the genetic variations can impact the efficiency of drug treatment.	('cancer', 'Disease', (14, 20))	('efficiency', 'MPA', (124, 134))	('impact', 'Reg', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('patients', 'Species', '9606', (73, 81))	('genetic variations', 'Var', (90, 108))
7178	33204830	On the aligned PLGA nanofibers containing polypyrrole functionalized graphene the ganglion cells grow along the fiber direction up to 160 mum in the cell length with electrical stimulation, compared to randomly oriented cells with 100 mum in length on random nanofibers.	('ganglion cells grow', 'CPA', (82, 101))	('graphene', 'Chemical', 'MESH:D006108', (69, 77))	('polypyrrole functionalized', 'Var', (42, 68))	('polypyrrole', 'Chemical', 'MESH:C067635', (42, 53))
7192	33204830	In addition, the vacuum modulated deformation of the two side walls generates 1-D, cyclic mechanical stretch.	('rat', 'Species', '10116', (72, 75))	('cyclic mechanical stretch', 'MPA', (83, 108))	('deformation', 'Var', (34, 45))
7245	33204830	The study helps identify GM6001 (an MMP inhibitor) as a promising candidate for inhibiting the CAFs-promoted ACC invasion (Figure 8A-iii).	('CAFs', 'Chemical', '-', (95, 99))	('GM6001', 'Chemical', 'MESH:C078131', (25, 31))	('CAFs-promoted', 'Disease', (95, 108))	('GM6001', 'Var', (25, 31))	('inhibiting', 'NegReg', (80, 90))
7247	33204830	In this chip, the presence of macrophages or the simulation of TNF-alpha impairs endothelial barrier, leading to elevated tumor cell intravasation rates.	('TNF-alpha', 'Gene', (63, 72))	('simulation', 'Var', (49, 59))	('endothelial', 'MPA', (81, 92))	('chip', 'Gene', '287155', (8, 12))	('elevated tumor', 'Disease', 'MESH:D006973', (113, 127))	('chip', 'Gene', (8, 12))	('impairs', 'NegReg', (73, 80))	('rat', 'Species', '10116', (147, 150))	('elevated tumor', 'Disease', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('TNF-alpha', 'Gene', '7124', (63, 72))
7264	33204830	For example, liver-kidney chips are built to predict the chemical toxicity in a high-throughput manner and the studies highlight the metabolic cooperation between liver and kidney in response to small molecules such as ammonia, dimethylsulfoxide, N-acetyl-para-aminophenol and aristolochic acid I.	('ammonia', 'Chemical', 'MESH:D000641', (219, 226))	('rat', 'Species', '10116', (148, 151))	('ammonia', 'MPA', (219, 226))	('liver-kidney', 'Disease', 'MESH:D017093', (13, 25))	('N-acetyl-para-aminophenol', 'Chemical', '-', (247, 272))	('dimethylsulfoxide', 'Chemical', 'MESH:D004121', (228, 245))	('dimethylsulfoxide', 'MPA', (228, 245))	('chip', 'Gene', (26, 30))	('N-acetyl-para-aminophenol', 'MPA', (247, 272))	('aristolochic', 'Var', (277, 289))	('toxicity', 'Disease', (66, 74))	('toxicity', 'Disease', 'MESH:D064420', (66, 74))	('aristolochic acid', 'Chemical', 'MESH:C000228', (277, 294))	('chip', 'Gene', '287155', (26, 30))	('response', 'MPA', (183, 191))	('liver-kidney', 'Disease', (13, 25))
7268	33204830	However, one of the major issues is that the pump may generate bubbles in the chip, which could cause cell death and fail the drug test.	('bubbles', 'MPA', (63, 70))	('generate', 'Reg', (54, 62))	('death', 'Disease', 'MESH:D003643', (107, 112))	('cause', 'Reg', (96, 101))	('chip', 'Gene', (78, 82))	('chip', 'Gene', '287155', (78, 82))	('pump', 'Var', (45, 49))	('rat', 'Species', '10116', (58, 61))	('death', 'Disease', (107, 112))
7282	33204830	The mechanical stimulation is critical to the development and normal function of human organs; alterations in the mechanical stimulation can result in dysfunction and even disease of the organ.	('result in', 'Reg', (141, 150))	('rat', 'Species', '10116', (99, 102))	('alterations', 'Var', (95, 106))	('dysfunction', 'CPA', (151, 162))	('human', 'Species', '9606', (81, 86))	('disease', 'Disease', (172, 179))
7294	33204830	During the culture period, the alterations in physicochemical properties of the system could induce the unexpected variation of the outcomes such as inaccurate prediction of drug efficiency.	('alterations', 'Var', (31, 42))	('rat', 'Species', '10116', (35, 38))	('induce', 'Reg', (93, 99))	('drug efficiency', 'MPA', (174, 189))	('rat', 'Species', '10116', (155, 158))
7312	32468052	We have expanded on our observations by including data relating to mutations and copy number alterations at pan-cancer level.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('copy number alterations', 'Var', (81, 104))
7314	32468052	Based on increasing data, older age and male sex predispose to severe COVID-19, whilst a number of underlying diseases/conditions are also directly related with significantly higher risk for adverse clinical outcomes from COVID-19.	('severe', 'Var', (63, 69))	('COVID-19', 'Disease', (70, 78))	('COVID-19', 'Disease', 'MESH:C000657245', (222, 230))	('COVID-19', 'Disease', (222, 230))	('COVID-19', 'Disease', 'MESH:C000657245', (70, 78))
7334	32468052	Furthermore, using the cBioportal pan-cancer panel, the region and the types of mutations were identified which these two genes have in all the examined cancer types (Figs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (38, 44))
7335	32468052	Most of the CTSL mutations are lying on the peptidase region and are mostly found in CESC, ESCA, Mature B-cell Neoplasms, Melanoma and COAD (Fig.	('ESCA', 'Disease', (91, 95))	('B-cell Neoplasms', 'Disease', 'MESH:D016393', (104, 120))	('Melanoma', 'Disease', 'MESH:D008545', (122, 130))	('Melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('found', 'Reg', (76, 81))	('CTSL', 'Gene', '1514', (12, 16))	('COAD', 'Disease', 'MESH:D029424', (135, 139))	('Melanoma', 'Disease', (122, 130))	('CTSL', 'Gene', (12, 16))	('B-cell Neoplasms', 'Disease', (104, 120))	('Neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('CESC', 'Disease', (85, 89))	('COAD', 'Disease', (135, 139))	('mutations', 'Var', (17, 26))
7336	32468052	Of note, in most of the cancers the majority of the patients had deletions and partly some gains and amplifications (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gains', 'PosReg', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('deletions', 'Var', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))	('patients', 'Species', '9606', (52, 60))
7337	32468052	TMPRSS2 mutations were lying across the whole gene region and mostly consist of gene fusions (TMPRSS2-ERG) in prostate adenocarcinoma (Fig.	('TMPRSS2', 'Gene', '7113', (94, 101))	('prostate adenocarcinoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (110, 133))	('TMPRSS2', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('TMPRSS2', 'Gene', (94, 101))	('consist', 'Reg', (69, 76))	('TMPRSS2', 'Gene', '7113', (0, 7))
7340	32468052	Of note, neither of the two proteins were differentially regulated in LUAD; a comorbidity of severe COVID-19 contrary to ACE-2.	('ACE-2', 'Gene', '59272', (121, 126))	('LUAD', 'Disease', (70, 74))	('severe', 'Var', (93, 99))	('COVID-19', 'Disease', (100, 108))	('COVID-19', 'Disease', 'MESH:C000657245', (100, 108))	('ACE-2', 'Gene', (121, 126))
7345	32468052	In our analysis we also demonstrate that the pancreas is riddled with deep deletions for TMPRSS2 where ACE-2 is co-expressed.	('ACE-2', 'Gene', '59272', (103, 108))	('deletions', 'Var', (75, 84))	('TMPRSS2', 'Gene', (89, 96))	('TMPRSS2', 'Gene', '7113', (89, 96))	('ACE-2', 'Gene', (103, 108))
7385	32368056	Previous studies by Kumur and collaborators showed that RVG peptide significantly increased oligonucleotide delivery to the brain (p=0.001) in comparison to other organs (liver and spleen), making it an excellent candidate to improve RNA delivery to the brain.	('RVG', 'Chemical', '-', (56, 59))	('oligonucleotide delivery to the brain', 'MPA', (92, 129))	('RNA delivery', 'MPA', (234, 246))	('improve', 'PosReg', (226, 233))	('RVG', 'Var', (56, 59))	('increased', 'PosReg', (82, 91))	('oligonucleotide', 'Chemical', 'MESH:D009841', (92, 107))
7562	32368056	Even though nanoparticles with positive charge interact easier with cell membranes, they can increase macrophage entrapment and immune response, as well as increasing the production of reactive oxygen species (ROS).	('increase', 'PosReg', (93, 101))	('nanoparticles', 'Var', (12, 25))	('macrophage entrapment', 'Disease', (102, 123))	('ROS', 'Chemical', 'MESH:D017382', (210, 213))	('increase macrophage', 'Phenotype', 'HP:0004311', (93, 112))	('production of reactive oxygen species', 'MPA', (171, 208))	('immune response', 'CPA', (128, 143))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (185, 208))	('macrophage entrapment', 'Disease', 'MESH:D055501', (102, 123))	('increasing', 'PosReg', (156, 166))
7592	30322863	Likewise, as a potential clinical biomarker, the detection of CTCs has correlated with poor prognosis, lack of treatment response, or rapid tumor recurrence in patients with a variety of cancers including glioblastoma (GBM).	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('patients', 'Species', '9606', (160, 168))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('cancers', 'Disease', (187, 194))	('GBM', 'Phenotype', 'HP:0012174', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('CTCs', 'Var', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('glioblastoma', 'Disease', (205, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	('detection', 'Var', (49, 58))	('tumor', 'Disease', (140, 145))
7665	30322863	We took advantage of an orthotopic, genetically engineered murine GBM model with a native microenvironment, induced by the RCAS/N-tva-mediated somatic pdgfb gene transfer in Ink4a-Arf-/-;Pten-/- neural stem/progenitor cells.	('Pten', 'Gene', '19211', (187, 191))	('Ink4a-Arf', 'Gene', (174, 183))	('N', 'Chemical', 'MESH:D009584', (128, 129))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('murine', 'Species', '10090', (59, 65))	('Ink4a-Arf', 'Gene', '12578', (174, 183))	('pdgfb', 'Gene', (151, 156))	('gene transfer', 'Var', (157, 170))	('Pten', 'Gene', (187, 191))
7675	30322863	Real-time RT-PCR analysis of pooled single cells revealed that GBM CTCs, and to a lesser extent, NSCLC CTCs, robustly expressed SOX2, OCT4, and NANOG, in contrast to a much lower expression of these genes in normal astrocytes (Fig.	('NANOG', 'Var', (144, 149))	('NSCLC', 'Disease', (97, 102))	('SOX2', 'Gene', (128, 132))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('OCT4', 'Gene', (134, 138))
7685	30322863	Furthermore, mice with intracranial implantation of CTCs exhibited shorter survival than mice received tumor cell injection (Supplementary Fig.	('mice', 'Species', '10090', (13, 17))	('survival', 'CPA', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('mice', 'Species', '10090', (89, 93))	('shorter', 'NegReg', (67, 74))	('CTCs', 'Var', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
7716	30322863	Interestingly, treatment of CTCs, but not tumor cells, with XAV939, a selective pharmacological inhibitor of Wnt pathway, remarkedly inhibited sphere formation (Fig.	('tumor', 'Disease', (42, 47))	('inhibited', 'NegReg', (133, 142))	('sphere formation', 'CPA', (143, 159))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('XAV939', 'Var', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
7717	30322863	Likewise, limited dilution analysis showed that XAV939 treatment abrogated the stem cell frequency in CTCs but not in tumor cells (Fig.	('XAV939', 'Var', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('stem cell frequency', 'CPA', (79, 98))	('tumor', 'Disease', (118, 123))	('CTCs', 'Disease', (102, 106))	('abrogated', 'NegReg', (65, 74))
7718	30322863	Furthermore, XAV939 treatment sensitized CTCs, but not tumor cells, to TMZ chemotherapy (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('TMZ', 'Chemical', 'MESH:C047246', (71, 74))	('sensitized', 'Reg', (30, 40))	('XAV939', 'Var', (13, 19))
7719	30322863	In addition, XAV939 also inhibited neurosphere formation in human GBM CSCs (Supplementary Fig.	('XAV939', 'Var', (13, 19))	('inhibited', 'NegReg', (25, 34))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('neurosphere formation', 'CPA', (35, 56))	('human', 'Species', '9606', (60, 65))
7750	30314897	Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production.	('cell proliferation', 'CPA', (109, 127))	('GLUD2', 'Gene', (77, 82))	('differences', 'Var', (62, 73))	('ROS', 'Chemical', 'MESH:D017382', (224, 227))	('cell cycle phases', 'CPA', (178, 195))	('migration', 'CPA', (129, 138))	('invasion', 'CPA', (140, 148))	('affected', 'Reg', (100, 108))	('ROS production', 'MPA', (224, 238))	('mitochondrial function', 'CPA', (197, 219))	('colony formation abilities', 'CPA', (150, 176))
7752	30314897	The involvement of GLUD2 in glioma metabolism and growth has already been suggested, but only in the presence of IDH1 mutations (Cancer Res, 2018 and Proc Natl Acad Sci U S A, 2014).	('glioma metabolism', 'Disease', (28, 45))	('growth', 'MPA', (50, 56))	('Cancer', 'Disease', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('IDH1', 'Gene', (113, 117))	('glioma metabolism', 'Disease', 'MESH:D005910', (28, 45))	('mutations', 'Var', (118, 127))	('Cancer', 'Disease', 'MESH:D009369', (129, 135))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('IDH1', 'Gene', '3417', (113, 117))	('involvement', 'Reg', (4, 15))
7753	30314897	It has been described that GLUD1 and GLUD2 are overexpressed in IDH1 mutant tumors.	('mutant', 'Var', (69, 75))	('IDH1', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('IDH1', 'Gene', '3417', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('GLUD1', 'Gene', '2746', (27, 32))	('GLUD1', 'Gene', (27, 32))	('overexpressed', 'PosReg', (47, 60))
7754	30314897	In this context, the expression of GLUD2 makes cells resistant to the inhibitory effects of growth of the IDH1R132H mutation, by providing a-KG to feed the citric acid cycle and support the synthesis of lipids.	('lipids', 'Chemical', 'MESH:D008055', (203, 209))	('citric acid cycle', 'MPA', (156, 173))	('citric acid', 'Chemical', 'MESH:D019343', (156, 167))	('mutation', 'Var', (116, 124))	('synthesis of lipids', 'MPA', (190, 209))	('IDH1', 'Gene', (106, 110))	('support', 'PosReg', (178, 185))	('feed', 'PosReg', (147, 151))	('IDH1', 'Gene', '3417', (106, 110))
7760	30314897	Moreover, differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production.	('ROS', 'Chemical', 'MESH:D017382', (172, 175))	('differences', 'Var', (10, 21))	('cell cycle phases', 'CPA', (126, 143))	('invasion', 'CPA', (88, 96))	('mitochondrial function', 'CPA', (145, 167))	('GLUD2', 'Gene', (25, 30))	('migration', 'CPA', (77, 86))	('ROS production', 'CPA', (172, 186))	('affected', 'Reg', (48, 56))	('colony formation abilities', 'CPA', (98, 124))	('cell proliferation', 'CPA', (57, 75))
7761	30314897	In support of these findings, we also demonstrated that GLUD2 overexpression decreases glial cell proliferation without affecting neurons development in zebrafish embryos.	('overexpression', 'Var', (62, 76))	('GLUD2', 'Gene', (56, 61))	('zebrafish', 'Species', '7955', (153, 162))	('glial cell proliferation', 'CPA', (87, 111))	('decreases', 'NegReg', (77, 86))
7778	30314897	We investigated, through in-vitro and in-vivo functional studies, how an alteration of GLUD2 expression could affect the behavior of human glioblastoma cells.	('glioblastoma', 'Disease', 'MESH:D005909', (139, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('affect', 'Reg', (110, 116))	('GLUD2', 'Gene', (87, 92))	('expression', 'MPA', (93, 103))	('glioblastoma', 'Disease', (139, 151))	('human', 'Species', '9606', (133, 138))	('alteration', 'Var', (73, 83))
7796	30314897	T98G and U118 were grown as monolayers in Dulbecco's Modified Eagle Medium (DMEM) low glucose and high glucose respectively, supplemented with 10% FBS and 1% Penicillin-Streptomycin.	('glucose', 'Chemical', 'MESH:D005947', (103, 110))	('FBS', 'Gene', (147, 150))	('Penicillin', 'Chemical', 'MESH:D010406', (158, 168))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (42, 74))	('U118', 'Chemical', '-', (9, 13))	('T98G', 'CellLine', 'CVCL:0556', (0, 4))	('FBS', 'Gene', '26269', (147, 150))	('Streptomycin', 'Chemical', 'MESH:D013307', (169, 181))	('DMEM', 'Chemical', '-', (76, 80))	('T98G', 'Var', (0, 4))	('high glucose', 'Phenotype', 'HP:0003074', (98, 110))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))
7827	30314897	To assess oxidative stress/reactive oxygen species (ROS), cells were transfected with GLUD2 overexpression vector and silencing siRNA and relative controls for two days in a 96 well plate.	('oxidative stress', 'Phenotype', 'HP:0025464', (10, 26))	('silencing', 'Var', (118, 127))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (27, 50))	('siRNA', 'Gene', (128, 133))
7845	30314897	Moreover, immunohistochemical analysis revealed that the protein expression of GLUD2 detected in long RFS GBM tissues was higher than that in short GBM (Fig.	('RFS', 'Chemical', '-', (102, 105))	('higher', 'PosReg', (122, 128))	('GLUD2', 'Gene', (79, 84))	('long RFS', 'Var', (97, 105))	('protein expression', 'MPA', (57, 75))
7855	30314897	Moreover, mutations in codon 132 of IDH1 and codons 140 or 172 of IDH2 have not been identified.	('IDH2', 'Gene', '3418', (66, 70))	('IDH1', 'Gene', (36, 40))	('IDH1', 'Gene', '3417', (36, 40))	('IDH2', 'Gene', (66, 70))	('mutations', 'Var', (10, 19))
7857	30314897	Cell proliferation rate in T98G at four different time points, T0, T1 (24 h), T2 (48 h) and T3 (72 h), as shown in Supplementary Fig.	('T98G', 'CellLine', 'CVCL:0556', (27, 31))	('T98G', 'Var', (27, 31))	('Cell proliferation rate', 'CPA', (0, 23))
7859	30314897	Colony-forming assay revealed a higher colonies number in T98G cells compared to U118 cells (Supplementary Fig.	('higher', 'PosReg', (32, 38))	('U118', 'Chemical', '-', (81, 85))	('colonies number', 'CPA', (39, 54))	('T98G', 'CellLine', 'CVCL:0556', (58, 62))	('T98G', 'Var', (58, 62))
7865	30314897	GLUD2 overexpression reduced the T98G colony formation ability (Fig.	('T98G', 'Var', (33, 37))	('reduced', 'NegReg', (21, 28))	('T98G', 'CellLine', 'CVCL:0556', (33, 37))
7871	30314897	GLUD2 silencing increased the U118 colony formation ability (Fig.	('increased', 'PosReg', (16, 25))	('silencing', 'Var', (6, 15))	('U118', 'Chemical', '-', (30, 34))	('U118 colony formation ability', 'CPA', (30, 59))
7873	30314897	GLUD2 overexpression in T98G cells showed a significant increase in G0/G1 phase and a statistically significant decrease in S and G2/M phases when compared to control cells (Fig.	('increase', 'PosReg', (56, 64))	('decrease', 'NegReg', (112, 120))	('T98G', 'CellLine', 'CVCL:0556', (24, 28))	('overexpression', 'PosReg', (6, 20))	('G0/G1 phase', 'CPA', (68, 79))	('T98G', 'Var', (24, 28))
7874	30314897	GLUD2 silencing in U118 cells with siRNA did not lead to a statistically significant change in the cell cycle (Fig.	('U118', 'Chemical', '-', (19, 23))	('cell cycle', 'CPA', (99, 109))	('silencing', 'Var', (6, 15))
7876	30314897	GLUD2 silencing in U118 cells showed an overexpression of both cyclin D1 and cyclin E (Fig.	('U118', 'Chemical', '-', (19, 23))	('cyclin E', 'MPA', (77, 85))	('overexpression', 'PosReg', (40, 54))	('cyclin D1', 'Gene', '595', (63, 72))	('silencing', 'Var', (6, 15))	('cyclin D1', 'Gene', (63, 72))
7878	30314897	We examined GLUD2 overexpression and silencing effects on basal respiration, ATP-linked respiration, H+ (Proton) leak, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration, using the Seahorse XFp Cell Mito Stress Test Kit (Supplementary Fig.	('basal respiration', 'MPA', (58, 75))	('maximal respiration', 'MPA', (119, 138))	('Mito', 'Species', '262676', (231, 235))	('silencing', 'Var', (37, 46))	('ATP-linked', 'MPA', (77, 87))	('spare respiratory capacity', 'MPA', (140, 166))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('non-mitochondrial respiration', 'MPA', (172, 201))
7879	30314897	GLUD2 overexpression in T98G cells led to a statistically significant increase in the basal levels of mitochondrial respiration (p = 0.0015) and maximal respiration (p < 0.0001) compared to empty vector control (Fig.	('increase', 'PosReg', (70, 78))	('T98G', 'CellLine', 'CVCL:0556', (24, 28))	('overexpression', 'PosReg', (6, 20))	('T98G', 'Var', (24, 28))	('mitochondrial respiration', 'MPA', (102, 127))
7881	30314897	Non-mitochondrial respiration was also statistically increased in T98G cells with GLUD2 overexpression (p = 0.0004) and decreased in U118 cells with GLUD2 silencing (p = 0.0057) compared to respective controls (Fig.	('decreased', 'NegReg', (120, 129))	('T98G', 'Var', (66, 70))	('Non-mitochondrial respiration', 'MPA', (0, 29))	('U118', 'Chemical', '-', (133, 137))	('T98G', 'CellLine', 'CVCL:0556', (66, 70))	('increased', 'PosReg', (53, 62))
7882	30314897	Despite proton leak and ATP production were increased in T98G cells with GLUD2 overexpression and decreased in U118 cells with GLUD2 silencing, compared to the respective controls, differences were not statistically significant (Fig.	('T98G', 'CellLine', 'CVCL:0556', (57, 61))	('ATP production', 'MPA', (24, 38))	('proton leak', 'MPA', (8, 19))	('T98G', 'Var', (57, 61))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('U118', 'Chemical', '-', (111, 115))	('increased', 'PosReg', (44, 53))	('decreased', 'NegReg', (98, 107))
7883	30314897	Spare respiratory capacity was significantly increased in GLUD2 overexpressed T98G cells (p = 0.0006) whereas no significant differences were observed in the spare respiratory capacity in GLUD2 silenced U118 cells.	('increased', 'PosReg', (45, 54))	('Spare respiratory capacity', 'MPA', (0, 26))	('U118', 'Chemical', '-', (203, 207))	('T98G', 'Var', (78, 82))	('T98G', 'CellLine', 'CVCL:0556', (78, 82))
7921	30314897	We also evaluated the consequences of GLUD2 expression levels variation on mitochondrial function and metabolic phenotype, by measuring oxygen consumption rate (OCR) after GLUD2 overexpression and silencing.	('silencing', 'Var', (197, 206))	('oxygen consumption rate', 'MPA', (136, 159))	('oxygen', 'Chemical', 'MESH:D010100', (136, 142))
7922	30314897	Statistically significant effects, in both overexpression and silencing of GLUD2 with opposite trends, were observed in the baseline oxygen consumption and non-mitochondrial respiration.	('non-mitochondrial respiration', 'MPA', (156, 185))	('GLUD2', 'Gene', (75, 80))	('silencing', 'Var', (62, 71))	('oxygen', 'Chemical', 'MESH:D010100', (133, 139))	('overexpression', 'PosReg', (43, 57))	('baseline oxygen consumption', 'MPA', (124, 151))	('effects', 'Reg', (26, 33))
7928	30314897	In particular, it has been demonstrated that increased glutamate oxidation by an enhanced GLUD2 activation by the Ala445 variant in the regulatory domain, may improperly boost mitochondrial oxidative metabolism with consequent increased ROS production.	('Ala445', 'Var', (114, 120))	('increased', 'PosReg', (227, 236))	('glutamate oxidation', 'MPA', (55, 74))	('increased glutamate', 'Phenotype', 'HP:0500149', (45, 64))	('enhanced', 'PosReg', (81, 89))	('increased', 'PosReg', (45, 54))	('boost', 'PosReg', (170, 175))	('ROS', 'Chemical', 'MESH:D017382', (237, 240))	('ROS production', 'MPA', (237, 251))	('Ala445', 'Chemical', '-', (114, 120))	('increased ROS production', 'Phenotype', 'HP:0025464', (227, 251))	('activation', 'MPA', (96, 106))	('glutamate', 'Chemical', 'MESH:D018698', (55, 64))	('mitochondrial oxidative metabolism', 'MPA', (176, 210))	('GLUD2', 'Enzyme', (90, 95))
7939	30314897	GLUD2 enzymatic activity could be increased through the induction of an activating mutation, for example the Ala445 variant in the regulatory domain, with a highly advanced genome editing system such as CRISPR/Cas9.	('activating', 'PosReg', (72, 82))	('increased', 'PosReg', (34, 43))	('Ala445 variant', 'Var', (109, 123))	('Ala445', 'Chemical', '-', (109, 115))
7955	30354145	Alkylation occurs primarily at O6 positions of guanine residues, generating DNA mismatch errors, which lead to apoptosis.	('guanine', 'Chemical', 'MESH:D006147', (47, 54))	('Alkylation', 'Var', (0, 10))	('apoptosis', 'CPA', (111, 120))	('lead to', 'Reg', (103, 110))
7960	30354145	Furthermore, these copolymers enhanced TMZ solution stability, indicating the potential advantages of this simple and reproducible polymerization strategy.	('TMZ solution', 'Chemical', '-', (39, 51))	('TMZ solution stability', 'MPA', (39, 61))	('enhanced', 'PosReg', (30, 38))	('copolymers', 'Var', (19, 29))
7991	30354145	The concentrated polymer was dissolved in aqueous 0.1 M HCl, and lyophilization afforded polymers D1-D2 as pink solids in yields >60%.	('D1-D2', 'Chemical', '-', (98, 103))	('polymers D1-D2', 'Var', (89, 103))	('D1-D2', 'Var', (98, 103))
8029	29081735	Abnormalities in WNT signaling are associated with many pathologies in multiple organ systems, including the nervous system.	('associated', 'Reg', (35, 45))	('WNT', 'Gene', (17, 20))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (17, 20))	('Abnormalities', 'Var', (0, 13))
8077	29081735	Mutations in WNT's co-receptor, LRP-6, lead to hypoplasia of the dorsal thalamus, and lack of thalamocortical projections in mice (Zhou et al.,).	('WNT', 'Gene', (13, 16))	('LRP-6', 'Gene', '16974', (32, 37))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (13, 16))	('lack', 'NegReg', (86, 90))	('hypoplasia of the dorsal thalamus', 'Disease', (47, 80))	('mice', 'Species', '10090', (125, 129))	('Mutations', 'Var', (0, 9))	('LRP-6', 'Gene', (32, 37))	('hypoplasia of the dorsal thalamus', 'Disease', 'MESH:C538109', (47, 80))
8078	29081735	Knockout of WNT3a leads to absence of the hippocampus in mice (Lee et al.,).	('mice', 'Species', '10090', (57, 61))	('Knockout', 'Var', (0, 8))	('WNT3a', 'Gene', (12, 17))	('absence', 'NegReg', (27, 34))
8079	29081735	The hippocampus also fails to develop in mouse models when WNT expression is transcriptionally disrupted in the cortical hem, a signaling center in the embryonic brain (Mulligan and Cheyette,).	('embryonic brain', 'Disease', (152, 167))	('mouse', 'Species', '10090', (41, 46))	('WNT', 'Gene', (59, 62))	('disrupted', 'Var', (95, 104))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (59, 62))	('embryonic brain', 'Disease', 'MESH:D001927', (152, 167))
8083	29081735	Disruption of WNT7a, normally found in cerebellar granular cells, inhibits mossy fiber growth cone modulation.	('WNT7a', 'Gene', '7476', (14, 19))	('mossy fiber growth cone modulation', 'CPA', (75, 109))	('inhibits', 'NegReg', (66, 74))	('WNT7a', 'Gene', (14, 19))	('Disruption', 'Var', (0, 10))
8091	29081735	CNS-specific deletion of wnt7a and wnt7b as well as endothelial cell-specific deletion of ss-catenin in mice, resulted in severe CNS-specific hemorrhage due to dilated PNVP and defective INVP endothelial cells and pericytes in the neural tube.	('defective', 'NegReg', (177, 186))	('ss-catenin', 'Chemical', '-', (90, 100))	('deletion', 'Var', (78, 86))	('mice', 'Species', '10090', (104, 108))	('deletion', 'Var', (13, 21))	('hemorrhage', 'Disease', (142, 152))	('wnt7a', 'Gene', (25, 30))	('ss-catenin', 'Gene', (90, 100))	('wnt7b', 'Gene', '22422', (35, 40))	('resulted in', 'Reg', (110, 121))	('hemorrhage', 'Disease', 'MESH:D006470', (142, 152))	('wnt7b', 'Gene', (35, 40))	('wnt7a', 'Gene', '22421', (25, 30))
8093	29081735	CNS-specific hemorrhage observed in tumors with these mutations highlights the role of canonical Wnt signaling in the BBB formation.	('Wnt', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (97, 100))	('hemorrhage', 'Disease', 'MESH:D006470', (13, 23))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('hemorrhage', 'Disease', (13, 23))	('Wnt', 'Gene', (97, 100))
8097	29081735	One of the hallmarks of pathologic retinal neovascularization is disruption of the blood-retinal barrier, which results in significant vascular leakiness (Lobo et al.,; Schulenburg and Tsanaktsidis,).	('vascular leakiness', 'Disease', (135, 153))	('results in', 'Reg', (112, 122))	('retinal neovascularization', 'Phenotype', 'HP:0030666', (35, 61))	('disruption', 'Var', (65, 75))	('vascular leakiness', 'Disease', 'MESH:C535298', (135, 153))
8099	29081735	Intriguingly, disruption of WNT signaling in the same models leads to a less severe retinopathy (Chen et al.,).	('WNT', 'Gene', (28, 31))	('severe retinopathy', 'Phenotype', 'HP:0001141', (77, 95))	('retinopathy', 'Disease', 'MESH:D012164', (84, 95))	('retinopathy', 'Disease', (84, 95))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (28, 31))	('retinopathy', 'Phenotype', 'HP:0000488', (84, 95))	('disruption', 'Var', (14, 24))
8108	29081735	It is proposed that FAT1 function promotes dysregulated WNT/beta-catenin signaling, allowing more free beta-catenin to enter the nucleus.	('function', 'Var', (25, 33))	('promotes', 'PosReg', (34, 42))	('WNT', 'Gene', (56, 59))	('FAT1', 'Gene', '2195', (20, 24))	('free beta-catenin', 'MPA', (98, 115))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (56, 59))	('FAT1', 'Gene', (20, 24))	('dysregulated', 'MPA', (43, 55))
8115	29081735	Preclinical studies demonstrated that inhibition of c-MET in GBM cells decreased the nuclear translocation of beta-catenin (Kim et al.,).	('c-MET', 'Gene', (52, 57))	('c-MET', 'Gene', '4233', (52, 57))	('nuclear translocation of beta-catenin', 'MPA', (85, 122))	('inhibition', 'Var', (38, 48))	('decreased', 'NegReg', (71, 80))
8158	29081735	In contrast, post-radiation glioma cells exhibited much higher radiation sensitivity when irradiated after treatment with the WNT inhibitor XAV939 than did post-radiation glioma cells irradiated in the presence of a vehicle control (Kim et al.,).	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('WNT', 'Gene', (126, 129))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('XAV939', 'Chemical', 'MESH:C544261', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('XAV939', 'Var', (140, 146))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (126, 129))	('glioma', 'Disease', (171, 177))	('higher', 'PosReg', (56, 62))	('glioma', 'Disease', (28, 34))	('radiation sensitivity', 'MPA', (63, 84))
8169	29081735	The WNT subtype medulloblastoma carries a WNT mutation which promotes abnormal nuclear beta-catenin localization, inducing abnormal cellular proliferation (Baryawno et al.,).	('cellular proliferation', 'CPA', (132, 154))	('inducing', 'PosReg', (114, 122))	('WNT', 'Gene', (4, 7))	('abnormal cellular proliferation', 'Phenotype', 'HP:0031377', (123, 154))	('promotes', 'PosReg', (61, 69))	('WNT', 'Gene', (42, 45))	('WNT subtype medulloblastoma', 'Disease', 'MESH:D008527', (4, 31))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (4, 7))	('nuclear', 'MPA', (79, 86))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (42, 45))	('WNT subtype medulloblastoma', 'Disease', (4, 31))	('mutation', 'Var', (46, 54))	('medulloblastoma', 'Phenotype', 'HP:0002885', (16, 31))
8179	29081735	Importantly, the same mutation in CTNNB1 that drives oncogenic WNT signaling and tumorigenesis in WNT medulloblastomas also induces secretion of locally active WNT inhibitors, such as WIF1 and DKK1.	('mutation', 'Var', (22, 30))	('WNT medulloblastomas', 'Disease', 'MESH:D008527', (98, 118))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (98, 101))	('medulloblastoma', 'Phenotype', 'HP:0002885', (102, 117))	('CTNNB1', 'Gene', (34, 40))	('induces', 'Reg', (124, 131))	('WNT medulloblastomas', 'Disease', (98, 118))	('drives', 'PosReg', (46, 52))	('WNT', 'Gene', (98, 101))	('tumor', 'Disease', (81, 86))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (63, 66))	('WIF1', 'Gene', '11197', (184, 188))	('WNT', 'Gene', (160, 163))	('secretion of', 'MPA', (132, 144))	('WNT', 'Gene', (63, 66))	('WIF1', 'Gene', (184, 188))	('CTNNB1', 'Gene', '1499', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
8182	29081735	Specifically, experimental knockout of beta-catenin in mice leads to increased expression of PLVAP, and increased BBB permeability.	('BBB permeability', 'CPA', (114, 130))	('PLVAP', 'Gene', (93, 98))	('increased', 'PosReg', (69, 78))	('expression', 'MPA', (79, 89))	('increased', 'PosReg', (104, 113))	('mice', 'Species', '10090', (55, 59))	('beta-catenin', 'Protein', (39, 51))	('knockout', 'Var', (27, 35))
8191	29081735	Aspirin, thought to antagonize WNT by phosphorylating key residues on beta-catenin and promoting its degradation, has been the most rigorously studied of the NSAID family for its anti-cancer properties.	('cancer', 'Disease', (184, 190))	('promoting', 'PosReg', (87, 96))	('degradation', 'MPA', (101, 112))	('Aspirin', 'Chemical', 'MESH:D001241', (0, 7))	('phosphorylating', 'Var', (38, 53))	('WNT', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('WNT', 'Gene', '22408;7473;89780;22416;7474;7476;22421;22422;7480', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
8192	29081735	A retrospective clinical study of celecoxib (COX2-selective NSAID) in recurrent glioblastoma found that 6 month progression-free survival was 43% for patients receiving low-dose temozolomide plus celecoxib, as opposed to the 21% typically seen with standard temozolomide maintenance therapy.	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('temozolomide', 'Chemical', 'MESH:D000077204', (178, 190))	('temozolomide', 'Chemical', 'MESH:D000077204', (258, 270))	('celecoxib', 'Chemical', 'MESH:D000068579', (34, 43))	('celecoxib', 'Chemical', 'MESH:D000068579', (196, 205))	('patients', 'Species', '9606', (150, 158))	('COX2', 'Gene', (45, 49))	('COX2', 'Gene', '4513', (45, 49))	('low-dose', 'Var', (169, 177))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))
8291	28442916	Dysregulation of the uPAR interactome has been implicated as an important component of the pathogenesis of numerous human central nervous system disorders including Alzheimer's disease, autism, brain tumors, and epilepsy.	('brain tumors', 'Disease', 'MESH:D001932', (194, 206))	('brain tumors', 'Phenotype', 'HP:0030692', (194, 206))	('numerous human central nervous system disorders', 'Disease', (107, 154))	('epilepsy', 'Disease', (212, 220))	('Dysregulation', 'Var', (0, 13))	('nervous system disorders', 'Phenotype', 'HP:0000707', (130, 154))	('brain tumor', 'Phenotype', 'HP:0030692', (194, 205))	('numerous human central nervous system disorders', 'Disease', 'MESH:D002493', (107, 154))	('central nervous system disorders', 'Phenotype', 'HP:0002011', (122, 154))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (165, 184))	("Alzheimer's disease", 'Disease', (165, 184))	('brain tumors', 'Disease', (194, 206))	('uPAR', 'Gene', (21, 25))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (165, 184))	('autism', 'Phenotype', 'HP:0000717', (186, 192))	('autism', 'Disease', 'MESH:D001321', (186, 192))	('implicated', 'Reg', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('epilepsy', 'Disease', 'MESH:D004827', (212, 220))	('uPAR', 'Gene', '5329', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('autism', 'Disease', (186, 192))	('epilepsy', 'Phenotype', 'HP:0001250', (212, 220))
8314	26563484	Finally, interfering with PRMT5 activity impaired target gene activation by Myc whereas it restrained Omomyc-dependent repression.	('Omomyc-dependent repression', 'MPA', (102, 129))	('target gene activation', 'MPA', (50, 72))	('activity', 'MPA', (32, 40))	('PRMT5', 'Gene', (26, 31))	('restrained', 'NegReg', (91, 101))	('impaired', 'NegReg', (41, 49))	('PRMT5', 'Gene', '10419', (26, 31))	('Myc', 'Gene', (76, 79))	('Myc', 'Gene', '4609', (76, 79))	('Omomyc', 'Chemical', '-', (102, 108))	('interfering', 'Var', (9, 20))
8329	26563484	Dysregulation of epigenetic mechanisms is a distinct feature of cancer.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
8334	26563484	PRMT5 is able to mono-methylate or symmetrically di-methylate non-histone and histone proteins, being the latter usually repressive of transcription.	('mono-methylate', 'Var', (17, 31))	('PRMT5', 'Gene', '10419', (0, 5))	('transcription', 'MPA', (135, 148))	('PRMT5', 'Gene', (0, 5))
8337	26563484	Consistently, PRMT5 knock out decreases the proliferation rate of glioblastoma cells as well as their survival and migratory capacity.	('decreases', 'NegReg', (30, 39))	('survival', 'CPA', (102, 110))	('knock out', 'Var', (20, 29))	('glioblastoma', 'Disease', (66, 78))	('PRMT5', 'Gene', (14, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('proliferation rate', 'CPA', (44, 62))	('PRMT5', 'Gene', '10419', (14, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('migratory capacity', 'CPA', (115, 133))
8341	26563484	Further, inhibiting PRMT5 activity in the nucleus rescued Omomyc-dependent transcriptional repression of Myc target genes and impaired their activation by Myc.	('Myc', 'Gene', (105, 108))	('rescued', 'PosReg', (50, 57))	('transcriptional repression', 'MPA', (75, 101))	('Myc', 'Gene', '4609', (155, 158))	('inhibiting', 'Var', (9, 19))	('PRMT5', 'Gene', (20, 25))	('impaired', 'NegReg', (126, 134))	('Myc', 'Gene', (155, 158))	('Myc', 'Gene', '4609', (105, 108))	('activation by', 'MPA', (141, 154))	('PRMT5', 'Gene', '10419', (20, 25))	('Omomyc', 'Chemical', '-', (58, 64))
8346	26563484	Among the other modifications tested, we observed an increase in H4R3me2s, which paralleled Omomyc expression (Fig.	('increase', 'PosReg', (53, 61))	('Omomyc expression', 'Disease', (92, 109))	('H4R3me2s', 'Var', (65, 73))	('Omomyc', 'Chemical', '-', (92, 98))	('H4R3me2s', 'Chemical', '-', (65, 73))	('expression', 'Species', '29278', (99, 109))
8363	26563484	Figure 3 shows an almost complete overlap between Omomyc:revealed by Flag antibody:and either PRMT5, H4R3me2s or Myc.	('Myc', 'Gene', (113, 116))	('PRMT5', 'Gene', (94, 99))	('PRMT5', 'Gene', '10419', (94, 99))	('H4R3me2s', 'Chemical', '-', (101, 109))	('Omomyc', 'Disease', (50, 56))	('Omomyc', 'Chemical', '-', (50, 56))	('Myc', 'Gene', '4609', (113, 116))	('H4R3me2s', 'Var', (101, 109))
8368	26563484	In U87MG and BT168 wild type cells, cultured in the presence of doxycycline, no changes in symmetric di-methylation of R3 on histone H4 were found (Supplementary Figures S2 and S3).	('U87MG', 'Var', (3, 8))	('doxycycline', 'Chemical', 'MESH:D004318', (64, 75))	('U87MG', 'CellLine', 'CVCL:0022', (3, 8))	('symmetric di-methylation', 'MPA', (91, 115))
8375	26563484	Moreover, ChIP experiments indicated a local enrichment of H4R3me2s histone residues at Omomyc-bound upstream chromatin domains of cycD1 and nucleolin (Ncl) gene promoters (Supplementary Fig.	('nucleolin', 'Gene', '4691', (141, 150))	('histone', 'Protein', (68, 75))	('Omomyc', 'Chemical', '-', (88, 94))	('H4R3me2s', 'Var', (59, 67))	('Ncl', 'Gene', '4691', (152, 155))	('nucleolin', 'Gene', (141, 150))	('H4R3me2s', 'Chemical', '-', (59, 67))	('Ncl', 'Gene', (152, 155))
8385	26563484	Further, PRMT5 associates with N-Myc in neuroblastoma cells, promoting its stability, presumably by methylating a specific arginine (R242).	('PRMT5', 'Gene', (9, 14))	('arginine', 'Chemical', 'MESH:D001120', (123, 131))	('PRMT5', 'Gene', '10419', (9, 14))	('R242', 'Var', (133, 137))	('methylating', 'Var', (100, 111))	('neuroblastoma', 'Disease', 'MESH:D009447', (40, 53))	('neuroblastoma', 'Disease', (40, 53))	('N-Myc', 'Gene', (31, 36))	('promoting', 'PosReg', (61, 70))	('neuroblastoma', 'Phenotype', 'HP:0003006', (40, 53))	('stability', 'MPA', (75, 84))	('N-Myc', 'Gene', '4613', (31, 36))
8388	26563484	This effect correlates with the local enrichment of H4R3me2s histones and Omomyc at the chromatin domains upstream of Myc target gene promoters (Supplementary Fig.	('H4R3me2s', 'Chemical', '-', (52, 60))	('Omomyc', 'Chemical', '-', (74, 80))	('Myc', 'Gene', '4609', (118, 121))	('Myc', 'Gene', (118, 121))	('H4R3me2s', 'Var', (52, 60))
8392	26563484	Indeed, inhibition of PRMT5 activity by a shRNA against its co-factor COPR5 restrained Myc transactivating properties, while recovered Omomyc-dependent repression of Myc targets (Fig.	('restrained', 'PosReg', (76, 86))	('COPR5', 'Gene', '55352', (70, 75))	('COPR5', 'Gene', (70, 75))	('PRMT5', 'Gene', (22, 27))	('recovered', 'NegReg', (125, 134))	('Omomyc', 'Chemical', '-', (135, 141))	('Myc', 'Gene', '4609', (87, 90))	('Myc', 'Gene', '4609', (166, 169))	('PRMT5', 'Gene', '10419', (22, 27))	('Myc', 'Gene', (87, 90))	('inhibition', 'Var', (8, 18))	('Myc', 'Gene', (166, 169))
8394	26563484	PRMT5-mediated symmetric di-methylation of H3R2 keeps genes poised for transcriptional activation.	('PRMT5', 'Gene', (0, 5))	('PRMT5', 'Gene', '10419', (0, 5))	('symmetric', 'Var', (15, 24))	('H3R2', 'Gene', (43, 47))
8403	26563484	Based on this finding, we propose that Omomyc may perturb the Myc/PRMT5 interaction and that this may have a role in its potent anti-oncogenic properties.	('Myc', 'Gene', '4609', (62, 65))	('PRMT5', 'Gene', '10419', (66, 71))	('interaction', 'Interaction', (72, 83))	('Myc', 'Gene', (62, 65))	('Omomyc', 'Chemical', '-', (39, 45))	('Omomyc', 'Var', (39, 45))	('perturb', 'NegReg', (50, 57))	('anti-oncogenic properties', 'CPA', (128, 153))	('PRMT5', 'Gene', (66, 71))
8438	26563484	Anti-H4R3me2s, anti-MEP50 and anti-PRMT5 antibodies were from Abcam (Abcam, Cambridge, UK); anti-Flag and anti-H3 antibodies were from SIGMA.	('PRMT5', 'Gene', (35, 40))	('PRMT5', 'Gene', '10419', (35, 40))	('Anti-H4R3me2s', 'Var', (0, 13))	('H4R3me2s', 'Chemical', '-', (5, 13))	('MEP50', 'Gene', '79084', (20, 25))	('MEP50', 'Gene', (20, 25))
8456	26563484	Oligonucleotides were: hCCND1prom-4129F GCTTTCCATTCAGAGGTGTGTTT (-871 from TSS) hCCND1prom-4228R CTACCTTGACCAGTCGGTCCTT (-722 bp from TSS) hNCLprom-4390F TCACAGAAAACCTCGCACAGA (-610 bp from TSS) hNCLprom-4524R CCGTTGGCCCTTTTGGA (-476 bp from TSS).	('hCCND1prom-4228R', 'Var', (80, 96))	('-722', 'Var', (121, 125))	('Oligonucleotides', 'Chemical', 'MESH:D009841', (0, 16))	('-871', 'Var', (65, 69))
8493	23458621	Generally the obtained nanoparticles have very large negative Z-potential values due to deprotonated Si-OH groups on the surface that strongly stabilized the resulting colloidal suspension by electrostatic repulsion.	('Z-potential values', 'MPA', (62, 80))	('deprotonated', 'Var', (88, 100))	('Si-OH', 'Chemical', '-', (101, 106))	('Si-OH', 'Protein', (101, 106))	('negative', 'NegReg', (53, 61))
8517	23458621	These modifications are carried out in the pristine Pluronic 127 surfactant, then used in the nanoparticles synthesis in the desired amount, so that no post nanoparticle functionalization is needed to introduce chemical functionalities (-COOH, -NH2, -SH, -N3, alkynes, etc.)	('alkynes', 'Var', (260, 267))	('alkynes', 'Chemical', 'MESH:D000480', (260, 267))	('-COOH', 'Var', (237, 242))	('COOH', 'Chemical', 'MESH:D002255', (238, 242))
8548	23458621	The PEG tails on the external face of the nanoparticles were functionalized with metastasis specific peptides (i.e., H2N-CGIYRLRSC-COOH and H2N-CGVYSLRSC-COOH), identified in our laboratory by phage display screenings on human biopsies of liver metastases.	('liver metastases', 'Disease', 'MESH:D009362', (239, 255))	('COOH', 'Chemical', 'MESH:D002255', (154, 158))	('human', 'Species', '9606', (221, 226))	('metastasis', 'Disease', (81, 91))	('peptides', 'Chemical', 'MESH:D010455', (101, 109))	('liver metastases', 'Disease', (239, 255))	('COOH', 'Chemical', 'MESH:D002255', (131, 135))	('PEG', 'Chemical', 'MESH:D011092', (4, 7))	('H2N-CGVYSLRSC-COOH', 'Var', (140, 158))	('H2N-CGIYRLRSC-COOH', 'Var', (117, 135))
8599	23458621	In a second example, nanoprobes constituted by a core of Fe3O4 (for MRI) and by multiple silica layers embedding visible-fluorescent quantum dots (600 nm emission) and near infrared-fluorescent quantum dots (780 nm emission), were surface-conjugated with an anti-HER2 (human epidermal growth factor receptor 2) antibody.	('HER2', 'Gene', (263, 267))	('epidermal growth factor receptor 2', 'Gene', '2064', (275, 309))	('HER2', 'Gene', '2064', (263, 267))	('epidermal growth factor receptor 2', 'Gene', (275, 309))	('human', 'Species', '9606', (269, 274))	('Fe3O4', 'Var', (57, 62))	('Fe3O4', 'Chemical', '-', (57, 62))	('silica', 'Chemical', 'MESH:D012822', (89, 95))
8699	25228443	Correspondingly, a misbalance between HAT and HDAC is subsequently associated with oncogenic transformation processes.	('HDAC', 'Gene', (46, 50))	('HDAC', 'Gene', '9734', (46, 50))	('associated', 'Reg', (67, 77))	('misbalance', 'Var', (19, 29))	('oncogenic transformation processes', 'CPA', (83, 117))
8700	25228443	In this context, the option of blocking the activity of HDACs through specific small molecule inhibitors opens up new avenues of pharmacological intervention in gene transcription through epigenetic regulation.	('epigenetic regulation', 'Var', (188, 209))	('HDAC', 'Gene', '9734', (56, 60))	('HDAC', 'Gene', (56, 60))
8738	25228443	In contrast, MS-275 altered xCT levels in healthy brain parenchyma, indicating that MS-275 exhibits general toxic effects (Fig.	('MS-275', 'Chemical', 'MESH:C118739', (84, 90))	('MS-275', 'Var', (13, 19))	('altered', 'Reg', (20, 27))	('MS-275', 'Chemical', 'MESH:C118739', (13, 19))	('MS-275', 'Var', (84, 90))	('xCT levels', 'MPA', (28, 38))
8740	25228443	Only at 10 muM MS-275 a significant suppression of the xCT-transporter could be detected, indicating a global effect on gene expression (Fig.	('MS-275', 'Chemical', 'MESH:C118739', (15, 21))	('muM', 'Gene', (11, 14))	('gene expression', 'MPA', (120, 135))	('suppression', 'NegReg', (36, 47))	('xCT-transporter', 'MPA', (55, 70))	('MS-275', 'Var', (15, 21))	('muM', 'Gene', '56925', (11, 14))
8778	25228443	Treatment of the tumor implanted brain slice cultures with 8 muM MS-275 did not lead to a significant reduction in peritumoral cell death.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (17, 22))	('muM', 'Gene', (61, 64))	('MS-275', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('MS-275', 'Chemical', 'MESH:C118739', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('muM', 'Gene', '56925', (61, 64))
8799	25228443	Noteworthy, selective deletion of a tumor-specific variant of the CD44 molecule from the complex, CD44v9, leads to loss of the xCT transporter from the surface of the tumor cells with consequent suppression of tumor growth.	('xCT transporter from the surface', 'MPA', (127, 159))	('suppression', 'NegReg', (195, 206))	('CD44', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('loss', 'NegReg', (115, 119))	('CD44', 'Gene', '960', (98, 102))	('deletion', 'Var', (22, 30))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CD44', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CD44', 'Gene', '960', (66, 70))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
8822	25228443	Patients with hypermethylation of the MGMT promotor profit the most from temozolomide-treatment.	('MGMT', 'Gene', '4255', (38, 42))	('hypermethylation', 'Var', (14, 30))	('temozolomide', 'Chemical', 'MESH:D000077204', (73, 85))	('Patients', 'Species', '9606', (0, 8))	('MGMT', 'Gene', (38, 42))
8895	24068912	For example, when CANX has a normalized value greater than -1.05 and MAPK1 is less than 0.50, we can identify 9 of our short-term survivors, though such high sensitivity and specificity are likely indicative of over-fitting.	('less', 'Var', (78, 82))	('MAPK1', 'Gene', '5594', (69, 74))	('CANX', 'Gene', (18, 22))	('MAPK1', 'Gene', (69, 74))	('CANX', 'Gene', '821', (18, 22))
8905	24068912	Of the 309 unique, validated mutations identified through sequencing of the TCGA GBM tumor samples, CTNNB1, EP300, STAT3, and TOP1 also appear in the 50-gene subnetwork signature.	('GBM tumor', 'Disease', (81, 90))	('STAT3', 'Gene', '6774', (115, 120))	('STAT3', 'Gene', (115, 120))	('GBM tumor', 'Disease', 'MESH:D005910', (81, 90))	('mutations', 'Var', (29, 38))	('EP300', 'Gene', (108, 113))	('EP300', 'Gene', '2033', (108, 113))	('CTNNB1', 'Gene', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('CTNNB1', 'Gene', '1499', (100, 106))
8909	24068912	In this light, the presence or absence of common mutations in patient subgroups differentially disrupts network state functions, and a single chemotherapeutic agent is unlikely to be effective in every patient.	('mutations', 'Var', (49, 58))	('patient', 'Species', '9606', (62, 69))	('patient', 'Species', '9606', (202, 209))	('absence', 'NegReg', (31, 38))	('network state functions', 'MPA', (104, 127))	('disrupts', 'NegReg', (95, 103))
8912	24068912	Importantly, deletions of NF-kappaB inhibitor alpha (NFKBIA) and amplifications of EGFR have been shown to be mutually exclusive events in GBM, suggestive of underlying genomic subtypes.	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (83, 87))	('NFKBIA', 'Gene', (53, 59))	('deletions', 'Var', (13, 22))	('GBM', 'Disease', (139, 142))	('NFKBIA', 'Gene', '4792', (53, 59))	('NF-kappaB inhibitor alpha', 'Gene', (26, 51))	('NF-kappaB inhibitor alpha', 'Gene', '4792', (26, 51))
8993	32455831	Other studies demonstrated that the inhibition of HO activity significantly improved the proapoptotic effect of PI and resulted in a significant reduction of the dose of PI.	('inhibition', 'Var', (36, 46))	('reduction', 'NegReg', (145, 154))	('improved', 'PosReg', (76, 84))	('rat', 'Species', '10116', (21, 24))	('proapoptotic effect', 'MPA', (89, 108))
9005	32455831	Indeed, the ploidy status, MYCN oncogene amplification, or allelic loss in chromosome 1p, correlate with different clinical phenotypes.	('MYCN', 'Gene', (27, 31))	('MYCN', 'Gene', '4613', (27, 31))	('allelic loss', 'Var', (59, 71))	('ploidy status', 'Disease', 'MESH:D013226', (12, 25))	('ploidy status', 'Disease', (12, 25))	('amplification', 'Var', (41, 54))
9008	32455831	In fact, the inhibition of proteasome activity increases the apoptotic rate and sensitizes tumor cells to traditional chemo- and radiotherapies.	('sensitizes', 'Reg', (80, 90))	('rat', 'Species', '10116', (71, 74))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('apoptotic rate', 'CPA', (61, 75))	('increases', 'PosReg', (47, 56))	('tumor', 'Disease', (91, 96))	('proteasome', 'Protein', (27, 37))
9013	32455831	Indeed, authors showed that NRF2 and HO-1 silencing sensitizes GI-ME-N cells to BSO stress and then to etoposide.	('etoposide', 'Chemical', 'MESH:D005047', (103, 112))	('silencing', 'Var', (42, 51))	('BSO stress', 'MPA', (80, 90))	('GI-ME-N', 'Chemical', '-', (63, 70))	('BSO', 'Chemical', '-', (80, 83))	('NRF2', 'Gene', (28, 32))	('HO-1', 'Gene', (37, 41))	('sensitizes', 'Reg', (52, 62))	('NRF2', 'Gene', '4780', (28, 32))
9019	32455831	In particular, cell sensitivity to oxidative stress was increased by the impairment of Bach1-dependent HO-1.	('increased', 'PosReg', (56, 65))	('oxidative stress', 'Phenotype', 'HP:0025464', (35, 51))	('impairment', 'Var', (73, 83))	('cell sensitivity to oxidative stress', 'MPA', (15, 51))	('Bach1', 'Gene', '571', (87, 92))	('Bach1', 'Gene', (87, 92))
9022	32455831	HO-1 inhibition significantly reduced tumor growth, volume and liver metastasis, and induced apoptosis, decreasing Bcl2 and Bcl-Xl levels.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('liver metastasis', 'CPA', (63, 79))	('Bcl-Xl', 'Gene', '598', (124, 130))	('inhibition', 'Var', (5, 15))	('Bcl-Xl', 'Gene', (124, 130))	('induced', 'Reg', (85, 92))	('Bcl2', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('decreasing', 'NegReg', (104, 114))	('reduced', 'NegReg', (30, 37))	('apoptosis', 'CPA', (93, 102))	('Bcl2', 'Gene', '596', (115, 119))	('HO-1', 'Gene', (0, 4))
9023	32455831	Moreover, HO-1 inhibition stimulated immune cells to attack tumors promoting NXS2 cell lyse.	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('HO-1', 'Gene', (10, 14))	('inhibition', 'Var', (15, 25))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
9029	32455831	using a vitamin K analog, VK3-OCH3, which caused a G2/M cell cycle arrest and apoptosis through the above-mentioned HO-1 signal transduction pathway.	('vitamin K', 'Chemical', 'MESH:D014812', (8, 17))	('apoptosis', 'CPA', (78, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('VK3-OCH3', 'Var', (26, 34))	('arrest', 'Disease', (67, 73))
9033	32455831	Traditional genetic analysis suggests that isochromosome 17q, which results in the loss of 17p and the gain of 17q, represents the most common aberration in medulloblastomas.	('isochromosome 17q', 'Var', (43, 60))	('gain', 'PosReg', (103, 107))	('medulloblastomas', 'Disease', (157, 173))	('medulloblastoma', 'Phenotype', 'HP:0002885', (157, 172))	('17p', 'Protein', (91, 94))	('rat', 'Species', '10116', (147, 150))	('17q', 'MPA', (111, 114))	('loss', 'NegReg', (83, 87))	('medulloblastomas', 'Disease', 'MESH:D008527', (157, 173))
9038	32455831	Although HO-1 and HO-2 expression also showed no significant association with the different medulloblastoma subtypes, patients with high HO-1 and low HO-2 expression have better survival.	('low', 'NegReg', (146, 149))	('medulloblastoma', 'Phenotype', 'HP:0002885', (92, 107))	('medulloblastoma', 'Disease', 'MESH:D008527', (92, 107))	('HO-2', 'Gene', '3163', (150, 154))	('expression', 'MPA', (155, 165))	('HO-1', 'Gene', (137, 141))	('medulloblastoma', 'Disease', (92, 107))	('survival', 'MPA', (178, 186))	('HO-2', 'Gene', (150, 154))	('HO-2', 'Gene', '3163', (18, 22))	('high', 'Var', (132, 136))	('patients', 'Species', '9606', (118, 126))	('HO-2', 'Gene', (18, 22))	('better', 'PosReg', (171, 177))
9044	32455831	Genetic alterations, such as mutation or loss of the tumor suppressor gene neurofibromatosis 2 (NF2) on chromosome 22, constitute a leading cause of about 50% of meningiomas.	('mutation', 'Var', (29, 37))	('meningiomas', 'Disease', (162, 173))	('neurofibromatosis 2', 'Gene', '4771', (75, 94))	('rat', 'Species', '10116', (12, 15))	('NF2', 'Gene', (96, 99))	('meningiomas', 'Disease', 'MESH:D008577', (162, 173))	('cause', 'Reg', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (75, 92))	('NF2', 'Gene', '4771', (96, 99))	('neurofibromatosis 2', 'Gene', (75, 94))	('tumor', 'Disease', (53, 58))	('meningiomas', 'Phenotype', 'HP:0002858', (162, 173))	('loss', 'NegReg', (41, 45))	('meningioma', 'Phenotype', 'HP:0002858', (162, 172))
9053	32455831	Astrocytomas are most frequently caused by several chromosomal alterations, such as trisomy or polysomy of chromosome 7.	('rat', 'Species', '10116', (67, 70))	('polysomy', 'Var', (95, 103))	('caused', 'Reg', (33, 39))	('trisomy', 'Disease', 'MESH:D014314', (84, 91))	('trisomy', 'Disease', (84, 91))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('Astrocytomas', 'Disease', (0, 12))
9055	32455831	Moreover, losses of 22q, 19q,13q, 11p, 10p, 9p, and 6, as well as the sex chromosomes or the mutations in TP53, CDKN2A, p14ARF, and CDKN2B tumor suppressor genes, also result in a small percentage of diffuse and anaplastic astrocytomas.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CDKN2B', 'Gene', (132, 138))	('mutations', 'Var', (93, 102))	('diffuse', 'Disease', (200, 207))	('CDKN2A', 'Gene', (112, 118))	('result in', 'Reg', (168, 177))	('p14ARF', 'Gene', (120, 126))	('CDKN2B', 'Gene', '1030', (132, 138))	('astrocytoma', 'Phenotype', 'HP:0009592', (223, 234))	('CDKN2A', 'Gene', '1029', (112, 118))	('p14ARF', 'Gene', '1029', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (212, 235))	('TP53', 'Gene', (106, 110))	('TP53', 'Gene', '7157', (106, 110))	('anaplastic astrocytomas', 'Disease', (212, 235))	('losses', 'NegReg', (10, 16))
9056	32455831	Astrocytomas, especially those showing LOH on 17p, are frequently characterized by a higher expression of the platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFa, suggesting an autocrine growth stimulation.	('PDGFa', 'Gene', (176, 181))	('platelet-derived growth factor receptor A', 'Gene', '5156', (110, 151))	('PDGFa', 'Gene', '5154', (176, 181))	('higher', 'PosReg', (85, 91))	('PDGFRA', 'Gene', (153, 159))	('platelet-derived growth factor receptor A', 'Gene', (110, 151))	('LOH on 17p', 'Var', (39, 49))	('Astrocytomas', 'Disease', 'MESH:D001254', (0, 12))	('PDGFRA', 'Gene', '5156', (153, 159))	('expression', 'MPA', (92, 102))	('Astrocytomas', 'Disease', (0, 12))
9063	32455831	Moreover, diffuse gliomas of Grades II and III present a high percentage of IDH1 and IDH2 mutations.	('IDH1', 'Gene', (76, 80))	('gliomas', 'Disease', (18, 25))	('mutations', 'Var', (90, 99))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('IDH1', 'Gene', '3417', (76, 80))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('IDH2', 'Gene', (85, 89))	('IDH2', 'Gene', '3418', (85, 89))
9068	32455831	Malignant transformation is caused by genetic alterations and dysregulations of different growth factor signaling pathways such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and phosphatase and tensin homolog (PTEN).	('phosphatase and tensin homolog', 'Gene', '5728', (248, 278))	('EGF', 'Gene', (199, 202))	('Malignant transformation', 'CPA', (0, 24))	('PTEN', 'Gene', (280, 284))	('EGF', 'Gene', '1950', (168, 171))	('epidermal growth factor', 'Gene', (174, 197))	('vascular endothelial growth factor', 'Gene', '7422', (131, 165))	('epidermal growth factor', 'Gene', '1950', (174, 197))	('VEGF', 'Gene', '7422', (167, 171))	('PDGF', 'Gene', (237, 241))	('PTEN', 'Gene', '5728', (280, 284))	('VEGF', 'Gene', (167, 171))	('vascular endothelial growth factor', 'Gene', (131, 165))	('dysregulations', 'Var', (62, 76))	('EGF', 'Gene', '1950', (199, 202))	('caused', 'Reg', (28, 34))	('rat', 'Species', '10116', (50, 53))	('EGF', 'Gene', (168, 171))	('growth factor signaling pathways', 'Pathway', (90, 122))
9070	32455831	Moreover, the most common triggering events for glioblastoma formation are amplifications of the EGFR gene on chromosome 7, or mutations in the TP53 or the retinoblastoma (RB1) pathways.	('TP53', 'Gene', '7157', (144, 148))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('TP53', 'Gene', (144, 148))	('EGFR', 'Gene', '1956', (97, 101))	('retinoblastoma', 'Disease', 'MESH:D012175', (156, 170))	('retinoblastoma', 'Disease', (156, 170))	('EGFR', 'Gene', (97, 101))	('glioblastoma', 'Disease', (48, 60))	('mutations', 'Var', (127, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('amplifications', 'Var', (75, 89))	('retinoblastoma', 'Phenotype', 'HP:0009919', (156, 170))
9075	32455831	Therefore, Nrf2 inhibition could induce GSC differentiating into non-stem-like glioblastoma cells, reducing tumor growth, and increasing the sensitivity to radiotherapy and chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('reducing', 'NegReg', (99, 107))	('increasing', 'PosReg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('sensitivity', 'MPA', (141, 152))	('Nrf2', 'Gene', '4780', (11, 15))	('tumor', 'Disease', (108, 113))	('glioblastoma', 'Disease', (79, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('Nrf2', 'Gene', (11, 15))	('induce', 'Reg', (33, 39))	('GSC differentiating', 'CPA', (40, 59))	('inhibition', 'Var', (16, 26))
9080	32455831	revealed that upregulated expression of Nrf2 reduced apoptosis in glioma cell line U251 and enhanced expression of HO-1; on the other hand, downregulation of Nrf2 increased apoptosis and reduced expression of HO-1.	('Nrf2', 'Gene', (40, 44))	('glioma', 'Disease', (66, 72))	('downregulation', 'Var', (140, 154))	('Nrf2', 'Gene', '4780', (158, 162))	('apoptosis', 'CPA', (53, 62))	('apoptosis', 'CPA', (173, 182))	('reduced', 'NegReg', (45, 52))	('expression', 'MPA', (195, 205))	('increased', 'PosReg', (163, 172))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('Nrf2', 'Gene', (158, 162))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('reduced', 'NegReg', (187, 194))	('Nrf2', 'Gene', '4780', (40, 44))	('upregulated', 'PosReg', (14, 25))	('expression', 'MPA', (101, 111))	('enhanced', 'PosReg', (92, 100))
9082	32455831	Furthermore, U251 cells treated with ZnPPIX augmented the anticancer effects of arsenic trioxide (ATO), inhibiting NRF2 and HO-1, while these effects were counteracted in cells treated with cobalt protoporphyrin (CoPPIX), a well-known HO-1 inducer.	('HO-1', 'Gene', (124, 128))	('cobalt protoporphyrin', 'Chemical', 'MESH:C007095', (190, 211))	('ATO', 'Chemical', 'MESH:D000077237', (98, 101))	('NRF2', 'Gene', '4780', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ZnPPIX', 'Var', (37, 43))	('CoPPIX', 'Chemical', '-', (213, 219))	('NRF2', 'Gene', (115, 119))	('inhibiting', 'NegReg', (104, 114))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('ZnPPIX', 'Chemical', '-', (37, 43))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (80, 96))	('augmented', 'PosReg', (44, 53))
9083	32455831	demonstrated the role of FTY720 as a potent inhibitor of NFR2 in U251MG and U87MG GBM cell lines.	('NFR2', 'Gene', (57, 61))	('U251MG', 'CellLine', 'CVCL:0021', (65, 71))	('U87MG', 'Var', (76, 81))	('rat', 'Species', '10116', (7, 10))	('U251MG', 'Var', (65, 71))	('inhibitor', 'NegReg', (44, 53))	('U87MG', 'CellLine', 'CVCL:0022', (76, 81))
9084	32455831	Indeed, FTY720 was able to downregulate NFR2 expression increasing susceptibility of GBM cells to the cytotoxic effect of TMZ treatment, while NRF2 induction had an opposite effect.	('downregulate', 'NegReg', (27, 39))	('FTY720', 'Var', (8, 14))	('TMZ', 'Chemical', 'MESH:D000077204', (122, 125))	('NRF2', 'Gene', '4780', (143, 147))	('susceptibility', 'MPA', (67, 81))	('NFR2', 'Gene', (40, 44))	('NRF2', 'Gene', (143, 147))
9090	32455831	Conversely, the inhibition of hBVR activity could overcome hypoxia-induced chemoresistance by regulating the cellular redox grade.	('hBVR', 'Gene', '644', (30, 34))	('hBVR', 'Gene', (30, 34))	('hypoxia', 'Disease', (59, 66))	('overcome', 'PosReg', (50, 58))	('hypoxia', 'Disease', 'MESH:D000860', (59, 66))	('regulating', 'Reg', (94, 104))	('cellular redox grade', 'MPA', (109, 129))	('inhibition', 'Var', (16, 26))
9093	32455831	described pyrimidotriazinedione 35G8, a protein disulfide isomerase (PDI) inhibitor, as toxic for human glioblastoma cell lines.	('35G8', 'Chemical', '-', (32, 36))	('glioblastoma', 'Disease', (104, 116))	('pyrimidotriazinedione', 'Var', (10, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('protein disulfide isomerase', 'Gene', (40, 67))	('human', 'Species', '9606', (98, 103))	('PDI', 'Gene', '5034', (69, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('pyrimidotriazinedione', 'Chemical', '-', (10, 31))	('PDI', 'Gene', (69, 72))	('protein disulfide isomerase', 'Gene', '5034', (40, 67))
9112	31788085	Mutant-allele tumor heterogeneity in malignant glioma effectively predicts neoplastic recurrence Intra-tumor heterogeneity (ITH) is one of the most important causes of therapy resistance, which eventually leads to the poor outcomes observed in patients with glioma.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('glioma', 'Disease', 'MESH:D005910', (258, 264))	('patients', 'Species', '9606', (244, 252))	('leads', 'Reg', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('causes', 'Reg', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('tumor', 'Disease', (103, 108))	('glioma', 'Disease', (47, 53))	('malignant glioma', 'Disease', (37, 53))	('malignant glioma', 'Disease', 'MESH:D005910', (37, 53))	('Mutant-allele', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('Intra-tumor', 'Disease', (97, 108))	('Intra-tumor', 'Disease', 'MESH:D009369', (97, 108))	('glioma', 'Disease', (258, 264))
9113	31788085	Mutant-allele tumor heterogeneity (MATH) values are based on whole-exon sequencing and precisely reflect genetic ITH.	('Mutant-allele', 'Var', (0, 13))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
9119	31788085	MATH values were negatively associated with the 2- and 5-year recurrence-free survival (RFS) rates in patients with glioma, particularly in the IDH1/2-wt and GBM cohorts (P=0.001 and P=0.017, respectively).	('GBM', 'Disease', (158, 161))	('GBM', 'Disease', 'MESH:D005909', (158, 161))	('MATH', 'Var', (0, 4))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', (116, 122))	('recurrence-free survival', 'CPA', (62, 86))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('negatively', 'NegReg', (17, 27))
9130	31788085	Mutant-allele tumor heterogeneity (MATH) values are indicators of gene mutation dispersion that were developed by Mroz and Rocco.	('Mutant-allele', 'Var', (0, 13))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
9159	31788085	These results demonstrated that MATH values were negatively associated with the interval to glioma RFS (Fig.	('negatively', 'NegReg', (49, 59))	('glioma', 'Disease', (92, 98))	('MATH', 'Var', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
9160	31788085	Patients with glioma with IDH1/2-wt are predicted to have a poor prognosis.	('IDH1/2-wt', 'Var', (26, 35))	('glioma', 'Disease', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))
9162	31788085	Similarly, although patients with GBM have been reported to have the shortest interval to recurrence among all patients with malignant glioma, the present study revealed that prognoses were significantly improved in patients with GBM with low MATH levels compared with those with high MATH levels (Fig.	('GBM', 'Disease', (34, 37))	('malignant glioma', 'Disease', 'MESH:D005910', (125, 141))	('GBM', 'Disease', (230, 233))	('malignant glioma', 'Disease', (125, 141))	('GBM', 'Disease', 'MESH:D005909', (34, 37))	('GBM', 'Disease', 'MESH:D005909', (230, 233))	('low', 'Var', (239, 242))	('prognoses', 'CPA', (175, 184))	('patients', 'Species', '9606', (216, 224))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('low MATH', 'Phenotype', 'HP:0001249', (239, 247))	('patients', 'Species', '9606', (20, 28))	('improved', 'PosReg', (204, 212))	('high MATH levels', 'Phenotype', 'HP:0001249', (280, 296))	('patients', 'Species', '9606', (111, 119))
9165	31788085	It was observed that seven genes [IDH1, tumor protein p53 (TP53), titin (TTN), ATRX chromatin remodeler (ATRX), capicua transcriptional repressor, mucin 16 (MUC16) and epidermal growth factor receptor (EGFR)] were hypermutated in the low-MATH group (frequency >10%; Fig.	('EGFR', 'Gene', (202, 206))	('capicua transcriptional repressor', 'Gene', '23152', (112, 145))	('mucin 16', 'Gene', (147, 155))	('TTN', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('IDH1', 'Gene', '3417', (34, 38))	('TP53', 'Gene', (59, 63))	('low-MATH', 'Var', (234, 242))	('p53', 'Gene', '7157', (54, 57))	('ATRX', 'Gene', (105, 109))	('EGFR', 'Gene', '1956', (202, 206))	('MUC16', 'Gene', '94025', (157, 162))	('titin', 'Gene', '7273', (66, 71))	('capicua transcriptional repressor', 'Gene', (112, 145))	('ATRX', 'Gene', '546', (105, 109))	('titin', 'Gene', (66, 71))	('mucin 16', 'Gene', '94025', (147, 155))	('p53', 'Gene', (54, 57))	('tumor', 'Disease', (40, 45))	('TP53', 'Gene', '7157', (59, 63))	('epidermal growth factor receptor', 'Gene', (168, 200))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('low-MATH', 'Phenotype', 'HP:0001249', (234, 242))	('epidermal growth factor receptor', 'Gene', '1956', (168, 200))	('ATRX', 'Gene', (79, 83))	('MUC16', 'Gene', (157, 162))	('ATRX', 'Gene', '546', (79, 83))	('IDH1', 'Gene', (34, 38))	('TTN', 'Gene', '7273', (73, 76))
9168	31788085	Using a chi2 test, it was identified that while the difference in TP53 was not significant (P=0.91), the mutation sample frequencies of IDH1 and ATRX were significantly lower in the high-MATH group, whereas the mutation sample frequencies of TTN, MUC16 and EGFR were significantly higher in the high-MATH group (Fig.	('ATRX', 'Gene', '546', (145, 149))	('TTN', 'Gene', '7273', (242, 245))	('TP53', 'Gene', '7157', (66, 70))	('EGFR', 'Gene', (257, 261))	('TP53', 'Gene', (66, 70))	('MUC16', 'Gene', '94025', (247, 252))	('higher', 'PosReg', (281, 287))	('high-MATH', 'Var', (182, 191))	('IDH1', 'Gene', (136, 140))	('ATRX', 'Gene', (145, 149))	('TTN', 'Gene', (242, 245))	('IDH1', 'Gene', '3417', (136, 140))	('lower', 'NegReg', (169, 174))	('MUC16', 'Gene', (247, 252))	('EGFR', 'Gene', '1956', (257, 261))
9171	31788085	In univariate Cox regression analysis, race and the mutation status of the MUC16 gene had no effect on glioma recurrence.	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('MUC16', 'Gene', (75, 80))	('mutation', 'Var', (52, 60))	('glioma', 'Disease', (103, 109))	('MUC16', 'Gene', '94025', (75, 80))
9172	31788085	The results of the multivariate Cox regression analysis suggested that MATH level, the mutation status of two genes (IDH and TTN), and four clinical characteristics (age, sex, WHO grade and histological classification) had a significant influence on glioma recurrence.	('TTN', 'Gene', '7273', (125, 128))	('glioma', 'Phenotype', 'HP:0009733', (250, 256))	('IDH', 'Gene', (117, 120))	('glioma', 'Disease', (250, 256))	('influence', 'Reg', (237, 246))	('IDH', 'Gene', '3417', (117, 120))	('TTN', 'Gene', (125, 128))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))	('mutation', 'Var', (87, 95))	('glioma', 'Disease', 'MESH:D005910', (250, 256))	('clinical', 'Species', '191496', (140, 148))
9184	31788085	Patients with GBM and IDH1/2-wt glioma had higher MATH levels than the other patients with glioma.	('GBM', 'Disease', (14, 17))	('higher', 'PosReg', (43, 49))	('glioma', 'Disease', (32, 38))	('glioma', 'Disease', (91, 97))	('GBM', 'Disease', 'MESH:D005909', (14, 17))	('MATH levels', 'MPA', (50, 61))	('patients', 'Species', '9606', (77, 85))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (32, 38))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('IDH1/2-wt', 'Var', (22, 31))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
9185	31788085	Furthermore, MATH values were independent predictors of glioma recurrence (P=0.015).	('MATH values', 'Var', (13, 24))	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))
9192	31788085	High ITH levels have been found to increase chemoradiotherapy resistance in glioma.	('increase', 'PosReg', (35, 43))	('chemoradiotherapy resistance', 'MPA', (44, 72))	('glioma', 'Disease', (76, 82))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('High ITH levels', 'Var', (0, 15))
9194	31788085	In patients receiving chemotherapy drugs or radiation, high ITH gliomas will have more residual subclones to replace those that are lost.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('patients', 'Species', '9606', (3, 11))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('high ITH', 'Var', (55, 63))
9195	31788085	Additionally, gene enrichment analysis demonstrated that the gene mutations occurring in patients with high MATH values were enriched in the 'BH3 anti-apoptotic', 'MAD2 inhibitory signal' and 'glutathione biosynthesis' signaling pathways, which act to inhibit apoptosis, mitotic catastrophe and radio-chemotherapy resistance, respectively (Fig.	('mutations', 'Var', (66, 75))	('radio-chemotherapy resistance', 'CPA', (295, 324))	('inhibit', 'NegReg', (252, 259))	("'glutathione biosynthesis' signaling pathways", 'Pathway', (192, 237))	('MAD2', 'Gene', (164, 168))	('apoptosis', 'CPA', (260, 269))	('MAD2', 'Gene', '4085', (164, 168))	('patients', 'Species', '9606', (89, 97))	('mitotic catastrophe', 'CPA', (271, 290))	('glutathione', 'Chemical', 'MESH:D005978', (193, 204))
9198	31788085	In the nomogram, several factors including, MATH level, gene IDH1/2, gene TTN, age, sex, WHO grade and histological classification, were indicated to have a substantial effect on glioma recurrence.	('TTN', 'Gene', (74, 77))	('TTN', 'Gene', '7273', (74, 77))	('gene', 'Var', (69, 73))	('effect', 'Reg', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('gene', 'Var', (56, 60))	('glioma', 'Disease', (179, 185))
9199	31788085	Age has been identified as an independent prognostic factor in high-grade glioma, and elderly patients with glioma exhibit abnormal repair functions, resulting in gene mutations and impaired DNA metabolic functions.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('repair functions', 'CPA', (132, 148))	('patients', 'Species', '9606', (94, 102))	('glioma', 'Disease', (108, 114))	('gene mutations', 'Var', (163, 177))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Disease', (74, 80))	('DNA metabolic functions', 'MPA', (191, 214))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('impaired', 'NegReg', (182, 190))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
9204	31788085	Additionally, while IDH1/2 mutation status, WHO grade and histological classification are generally considered to influence glioma prognosis, the present study revealed that patients with IDH1/2-wt glioma, GBM and WHO grade IV all have high MATH levels.	('IDH1/2-wt', 'Var', (188, 197))	('GBM', 'Disease', (206, 209))	('glioma', 'Disease', (124, 130))	('high MATH levels', 'Phenotype', 'HP:0001249', (236, 252))	('glioma', 'Disease', (198, 204))	('GBM', 'Disease', 'MESH:D005909', (206, 209))	('patients', 'Species', '9606', (174, 182))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (198, 204))
9205	31788085	The mutation status of the TTN gene was strongly associated with glioma recurrence.	('glioma', 'Disease', (65, 71))	('TTN', 'Gene', (27, 30))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('mutation', 'Var', (4, 12))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('associated with', 'Reg', (49, 64))	('TTN', 'Gene', '7273', (27, 30))
9208	31788085	Although, to the best of our knowledge, no studies have yet investigated the association between TTN and tumors, data from the TCGA database revealed that the TTN gene has a high frequency of mutation in a number of tumors, including lung (724 cases), skin (379 cases), uterus (282 cases), stomach (274 cases), colon (264 cases) and breast (291 cases) tumors .	('tumors', 'Disease', (105, 111))	('breast', 'Disease', (333, 339))	('tumors', 'Disease', (216, 222))	('TTN', 'Gene', (159, 162))	('stomach', 'Disease', (290, 297))	('TTN', 'Gene', (97, 100))	('tumors', 'Disease', 'MESH:D009369', (352, 358))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mutation', 'Var', (192, 200))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('colon', 'Disease', (311, 316))	('skin', 'Disease', (252, 256))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('lung', 'Disease', (234, 238))	('uterus', 'Disease', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TTN', 'Gene', '7273', (159, 162))	('tumors', 'Disease', (352, 358))	('TTN', 'Gene', '7273', (97, 100))
9209	31788085	In the present study, the mutation status of the TP53, PTEN, EGFR and ATRX genes was not associated with glioma recurrence.	('associated', 'Reg', (89, 99))	('ATRX', 'Gene', '546', (70, 74))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('PTEN', 'Gene', '5728', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('TP53', 'Gene', '7157', (49, 53))	('mutation', 'Var', (26, 34))	('TP53', 'Gene', (49, 53))	('glioma', 'Disease', (105, 111))	('ATRX', 'Gene', (70, 74))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('PTEN', 'Gene', (55, 59))
9212	31788085	For example, a number of studies have demonstrated that TP53 mutations are significantly associated with short survival times in patients with glioma.	('short', 'NegReg', (105, 110))	('associated', 'Reg', (89, 99))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('patients', 'Species', '9606', (129, 137))	('TP53', 'Gene', '7157', (56, 60))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (56, 60))	('glioma', 'Disease', (143, 149))
9213	31788085	However, not all mutations in TP53 result in a loss in gene transcription; patients with TP53 mutant glioma that retain transcriptional activity exhibit longer survival times.	('survival', 'CPA', (160, 168))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', (89, 93))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Disease', (101, 107))	('patients', 'Species', '9606', (75, 83))	('mutant', 'Var', (94, 100))	('gene transcription', 'MPA', (55, 73))	('TP53', 'Gene', '7157', (30, 34))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('longer', 'PosReg', (153, 159))
9219	31788085	GBM glioblastoma ITH intra-tumor heterogeneity LGG low grade glioma MATH mutant-allele tumor heterogeneity RFS recurrence-free survival	('GBM', 'Disease', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutant-allele', 'Var', (73, 86))	('intra-tumor', 'Disease', (21, 32))	('GBM', 'Disease', 'MESH:D005909', (0, 3))	('tumor', 'Disease', (27, 32))	('LGG low', 'Phenotype', 'HP:0004315', (47, 54))	('glioblastoma', 'Disease', (4, 16))	('tumor', 'Disease', (87, 92))	('glioma', 'Disease', (61, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('intra-tumor', 'Disease', 'MESH:D009369', (21, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('glioma', 'Disease', 'MESH:D005910', (61, 67))
9223	31649250	The inhibition of TGFbeta1 activity by LY2109761 attenuated the migration/invasion of GBM cells by upregulating cell-surface NgR.	('GBM', 'Disease', (86, 89))	('attenuated', 'NegReg', (49, 59))	('LY2109761', 'Chemical', 'MESH:C530108', (39, 48))	('GBM', 'Disease', 'MESH:D005909', (86, 89))	('TGFbeta1', 'Gene', '7040', (18, 26))	('TGFbeta1', 'Gene', (18, 26))	('LY2109761', 'Var', (39, 48))	('NgR', 'Gene', (125, 128))	('inhibition', 'NegReg', (4, 14))	('upregulating', 'PosReg', (99, 111))	('activity', 'MPA', (27, 35))	('NgR', 'Gene', '65078', (125, 128))
9226	31649250	The knockdown of vimentin suppressed the migration/invasion of GBM cells through the increased maturation of NgR.	('vimentin', 'Gene', (17, 25))	('NgR', 'Gene', (109, 112))	('GBM', 'Disease', (63, 66))	('suppressed', 'NegReg', (26, 36))	('NgR', 'Gene', '65078', (109, 112))	('GBM', 'Disease', 'MESH:D005909', (63, 66))	('maturation', 'CPA', (95, 105))	('vimentin', 'Gene', '7431', (17, 25))	('increased', 'PosReg', (85, 94))	('knockdown', 'Var', (4, 13))
9244	31649250	The removal of 26 amino acids from the C-terminal region of NgR results in a 49-kDa mature form of NgR, as predicted by Swissprot.	('NgR', 'Gene', '65078', (60, 63))	('NgR', 'Gene', (99, 102))	('removal', 'Var', (4, 11))	('NgR', 'Gene', (60, 63))	('NgR', 'Gene', '65078', (99, 102))	('results in', 'Reg', (64, 74))
9273	31649250	U87 and U251 were treated with 20 muM LY2109761 or 2 ng/ml TGFbeta1 for 72 h and were subjected to survival analysis by using the WST-1 assay (Boehringer Mannheim) according to the manufacturer's protocol.	('muM', 'Gene', '56925', (34, 37))	('LY2109761', 'Var', (38, 47))	('U87', 'Gene', '641648', (0, 3))	('muM', 'Gene', (34, 37))	('LY2109761', 'Chemical', 'MESH:C530108', (38, 47))	('TGFbeta1', 'Gene', '7040', (59, 67))	('TGFbeta1', 'Gene', (59, 67))	('U87', 'Gene', (0, 3))
9274	31649250	To determine the surface NgR expression and the intracellular expression of NgR and vimentin after treatment with LY2109761 or TGFbeta1, FACS analysis was conducted with a guava easyCyte Systems and InCyte 3.1 software (Merck Millipore, Bedford, MA).	('LY2109761', 'Chemical', 'MESH:C530108', (114, 123))	('TGFbeta1', 'Gene', '7040', (127, 135))	('guava easyCyte Systems', 'Disease', 'MESH:D019578', (172, 194))	('NgR', 'Gene', (25, 28))	('vimentin', 'Gene', '7431', (84, 92))	('LY2109761', 'Var', (114, 123))	('TGFbeta1', 'Gene', (127, 135))	('NgR', 'Gene', '65078', (25, 28))	('vimentin', 'Gene', (84, 92))	('NgR', 'Gene', '65078', (76, 79))	('NgR', 'Gene', (76, 79))	('guava easyCyte Systems', 'Disease', (172, 194))
9275	31649250	U87 and U251 were treated with 20 muM LY2109761 or 2 ng/ml TGFbeta1 for 48 h before the assay, and wounds were created by scratching using a 200-mul pipette tip.	('muM', 'Gene', '56925', (34, 37))	('LY2109761', 'Var', (38, 47))	('U87', 'Gene', '641648', (0, 3))	('muM', 'Gene', (34, 37))	('LY2109761', 'Chemical', 'MESH:C530108', (38, 47))	('TGFbeta1', 'Gene', '7040', (59, 67))	('TGFbeta1', 'Gene', (59, 67))	('U87', 'Gene', (0, 3))
9276	31649250	After being treated with OMgp (100 ng/ml) for 2 h at 37  C, U87 and U251 cells were then seeded onto these components 48 h after treatment with LY2109761 or TGFbeta1.	('LY2109761', 'Var', (144, 153))	('OMgp', 'Gene', '4974', (25, 29))	('LY2109761', 'Chemical', 'MESH:C530108', (144, 153))	('TGFbeta1', 'Gene', '7040', (157, 165))	('U87', 'Gene', (60, 63))	('TGFbeta1', 'Gene', (157, 165))	('U87', 'Gene', '641648', (60, 63))	('OMgp', 'Gene', (25, 29))
9279	31649250	U87 and U251 cells were treated with LY2109761 or TGFbeta1 for 48 h before the assay.	('U87', 'Gene', '641648', (0, 3))	('LY2109761', 'Chemical', 'MESH:C530108', (37, 46))	('TGFbeta1', 'Gene', '7040', (50, 58))	('TGFbeta1', 'Gene', (50, 58))	('LY2109761', 'Var', (37, 46))	('U87', 'Gene', (0, 3))
9284	31649250	U87 and U251 cells were treated with LY2109761 or TGFbeta1 for 48 h before confocal microscopy analysis.	('U87', 'Gene', '641648', (0, 3))	('LY2109761', 'Chemical', 'MESH:C530108', (37, 46))	('TGFbeta1', 'Gene', '7040', (50, 58))	('TGFbeta1', 'Gene', (50, 58))	('LY2109761', 'Var', (37, 46))	('U87', 'Gene', (0, 3))
9286	31649250	All the samples were blocked with 5% goat serum in 0.2% Triton X-100 for 1 h at room temperature (RT) and were then incubated overnight at 4  C with anti-TGFbeta (1:500), E-cadherin (1:500), NgR (1:500), Id1 (1:1000), vimentin (1:1000), and beta-catenin (1:1000) antibodies.	('1:1000', 'Var', (209, 215))	('Id1', 'Gene', (204, 207))	('NgR', 'Gene', '65078', (191, 194))	('Id1', 'Gene', '3397', (204, 207))	('beta-catenin', 'Gene', (241, 253))	('TGFbeta', 'Gene', (154, 161))	('goat', 'Species', '9925', (37, 41))	('E-cadherin', 'Gene', (171, 181))	('E-cadherin', 'Gene', '999', (171, 181))	('vimentin', 'Gene', '7431', (218, 226))	('beta-catenin', 'Gene', '1499', (241, 253))	('vimentin', 'Gene', (218, 226))	('1:500', 'Var', (183, 188))	('TGFbeta', 'Gene', '7040', (154, 161))	('NgR', 'Gene', (191, 194))
9288	31649250	Vimentin small interfering RNA (siRNA) and control siRNA were purchased from Bioneer Co. (Daejeon, Korea).	('Vimentin', 'Gene', '7431', (0, 8))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('small', 'Var', (9, 14))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('Vimentin', 'Gene', (0, 8))
9289	31649250	The primer sequences of vimentin siRNA #1 were sense 5'-UGA AGC UGC UAA CUA CCA ATT-3' and antisense 5'-UUG GUA GUU AGC AGC UUC ATT-3'.	('vimentin', 'Gene', (24, 32))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('antisense', 'Var', (91, 100))	("5'-UUG GUA GUU", 'Chemical', 'MESH:C031631', (101, 115))	('vimentin', 'Gene', '7431', (24, 32))
9290	31649250	The primer sequences of vimentin siRNA #2 were sense 5'-UCA CCU UCG UGA AUA CCA ATT-3' and antisense 5'-UUG GUA UUC ACG AAG GUG ATT-3'.	('vimentin', 'Gene', (24, 32))	('N', 'Chemical', 'MESH:D009584', (36, 37))	("5'-UUG GUA UUC ACG AAG GUG", 'Chemical', 'MESH:C461385', (101, 127))	('antisense', 'Var', (91, 100))	('vimentin', 'Gene', '7431', (24, 32))
9292	31649250	Plasmids containing shRNAs for human vimentin (TRCN0000029119, TRCN0000029120, TRCN0000297192, and TRCN0000297191, Sigma) or a scrambled shRNA (#1864, Addgene, Cambridge, MA) were cotransfected with pVSV-G and a packaging plasmid (SBI, Palo Alto, CA) into HEK293T cells by using the Lipofectamine 3000 transfection reagent (Thermo Scientific, Waltham, MA).	('TRCN0000297191', 'Var', (99, 113))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('TRCN0000297192', 'Var', (79, 93))	('human', 'Species', '9606', (31, 36))	('N', 'Chemical', 'MESH:D009584', (140, 141))	('vimentin', 'Gene', '7431', (37, 45))	('TRCN0000029120', 'Var', (63, 77))	('TRCN0000029119', 'Var', (47, 61))	('vimentin', 'Gene', (37, 45))	('N', 'Chemical', 'MESH:D009584', (66, 67))
9293	31649250	TRCN0000029119, TRCN0000029120, TRCN0000297192, and TRCN0000297191 were designated shVIM1, shVIM2, shVIM3, and shVIM4, respectively.	('VIM', 'Gene', (93, 96))	('VIM', 'Gene', '7431', (85, 88))	('VIM', 'Gene', '7431', (113, 116))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('VIM', 'Gene', (101, 104))	('TRCN0000297191', 'Var', (52, 66))	('VIM', 'Gene', '7431', (93, 96))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('VIM', 'Gene', (85, 88))	('VIM', 'Gene', (113, 116))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('TRCN0000029120', 'Var', (16, 30))	('VIM', 'Gene', '7431', (101, 104))
9301	31649250	Based on UniProt data (https://www.uniprot.org/uniprot/Q9BZR6#expression), NgR is a 473-amino acid protein (52 kDa), and the removal of 26 amino acids on the C terminus results in a 49-kDa mature form.	('NgR', 'Gene', (75, 78))	('NgR', 'Gene', '65078', (75, 78))	('removal', 'Var', (125, 132))	('results in', 'Reg', (169, 179))
9303	31649250	Intriguingly, in U251 cells, the TGFbeta receptor type I inhibitor LY2109761 induced the conversion of the precursor to the mature isoform of NgR (Fig.	('LY2109761', 'Chemical', 'MESH:C530108', (67, 76))	('TGFbeta', 'Gene', (33, 40))	('TGFbeta', 'Gene', '7040', (33, 40))	('NgR', 'Gene', (142, 145))	('LY2109761', 'Var', (67, 76))	('NgR', 'Gene', '65078', (142, 145))	('conversion', 'MPA', (89, 99))
9310	31649250	To investigate the functional role of the increased expression of mature NgR in GBM cells, we induced the maturation of NgR by inhibiting TGFbeta1 with LY2109761 in these cells, and the functional changes were investigated (Fig.	('GBM', 'Disease', 'MESH:D005909', (80, 83))	('LY2109761', 'Var', (152, 161))	('NgR', 'Gene', '65078', (120, 123))	('LY2109761', 'Chemical', 'MESH:C530108', (152, 161))	('inhibiting', 'NegReg', (127, 137))	('NgR', 'Gene', (120, 123))	('GBM', 'Disease', (80, 83))	('TGFbeta1', 'Gene', '7040', (138, 146))	('NgR', 'Gene', (73, 76))	('maturation', 'MPA', (106, 116))	('TGFbeta1', 'Gene', (138, 146))	('NgR', 'Gene', '65078', (73, 76))	('induced', 'Reg', (94, 101))
9312	31649250	2a), the inhibition of TGFbeta1 suppressed the expression of N-cadherin and induced mature NgR and E-cadherin expression (Fig.	('NgR', 'Gene', '65078', (91, 94))	('N-cadherin', 'Gene', '1000', (61, 71))	('TGFbeta1', 'Gene', '7040', (23, 31))	('TGFbeta1', 'Gene', (23, 31))	('induced', 'PosReg', (76, 83))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('suppressed', 'NegReg', (32, 42))	('inhibition', 'Var', (9, 19))	('expression', 'MPA', (47, 57))	('N-cadherin', 'Gene', (61, 71))	('NgR', 'Gene', (91, 94))
9313	31649250	Furthermore, LY2109761 (20 muM) treatment significantly increased the expression of mature cell-surface NgR to 18.67 and 8.05% in U87 and U251 cells, respectively, compared with 8.48 and 2.27% in untreated U87 and U251 cells (Fig.	('LY2109761', 'Var', (13, 22))	('U87', 'Gene', '641648', (206, 209))	('muM', 'Gene', '56925', (27, 30))	('increased', 'PosReg', (56, 65))	('muM', 'Gene', (27, 30))	('expression', 'MPA', (70, 80))	('LY2109761', 'Chemical', 'MESH:C530108', (13, 22))	('NgR', 'Gene', '65078', (104, 107))	('U87', 'Gene', (130, 133))	('U87', 'Gene', (206, 209))	('U87', 'Gene', '641648', (130, 133))	('NgR', 'Gene', (104, 107))
9314	31649250	Thus, these results demonstrate that TGFbeta1 inhibition by LY2109761 leads to the induction of NgR maturation.	('TGFbeta1', 'Gene', '7040', (37, 45))	('TGFbeta1', 'Gene', (37, 45))	('inhibition', 'NegReg', (46, 56))	('LY2109761', 'Chemical', 'MESH:C530108', (60, 69))	('NgR', 'Gene', (96, 99))	('NgR', 'Gene', '65078', (96, 99))	('LY2109761', 'Var', (60, 69))
9316	31649250	A scratch-wound migration assay was performed by using cells treated with LY2109761.	('LY2109761', 'Var', (74, 83))	('LY2109761', 'Chemical', 'MESH:C530108', (74, 83))	('scratch-wound migration assay', 'CPA', (2, 31))
9317	31649250	2d, no movement was observed in cells treated with 20 muM of LY2109761, while PBS-treated cells showed significant movement.	('muM', 'Gene', (54, 57))	('muM', 'Gene', '56925', (54, 57))	('LY2109761', 'Var', (61, 70))	('LY2109761', 'Chemical', 'MESH:C530108', (61, 70))
9321	31649250	Overall, these results provide evidence that the inhibition of TGFbeta1 induced the expression of surface NgR and significantly suppressed the migration ability of U87 and U251 cells.	('NgR', 'Gene', '65078', (106, 109))	('TGFbeta1', 'Gene', '7040', (63, 71))	('NgR', 'Gene', (106, 109))	('U87', 'Gene', (164, 167))	('suppressed', 'NegReg', (128, 138))	('TGFbeta1', 'Gene', (63, 71))	('inhibition', 'Var', (49, 59))	('U87', 'Gene', '641648', (164, 167))	('expression', 'MPA', (84, 94))
9322	31649250	Next, we performed a modified cell-matrix adhesion assay by using OMgp-coated plates to determine whether the upregulated surface NgR induced by LY2109761 interacts with a ligand.	('N', 'Chemical', 'MESH:D009584', (130, 131))	('NgR', 'Gene', (130, 133))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('OMgp', 'Gene', '4974', (66, 70))	('NgR', 'Gene', '65078', (130, 133))	('LY2109761', 'Var', (145, 154))	('upregulated', 'PosReg', (110, 121))	('LY2109761', 'Chemical', 'MESH:C530108', (145, 154))	('interacts', 'Interaction', (155, 164))	('OMgp', 'Gene', (66, 70))
9323	31649250	Two hours after seeding cells on OMgp-coated plates, the number of viable adherent cells had significantly increased to 199.8 or 191.7% in LY2109761-treated U87 and U251 cells, respectively, compared with that in control-treated cells (Fig.	('LY2109761', 'Chemical', 'MESH:C530108', (139, 148))	('LY2109761-treated', 'Var', (139, 156))	('increased', 'PosReg', (107, 116))	('OMgp', 'Gene', (33, 37))	('U87', 'Gene', (157, 160))	('OMgp', 'Gene', '4974', (33, 37))	('U87', 'Gene', '641648', (157, 160))
9324	31649250	These results indicate that the upregulated surface NgR increases the cell adhesion of GBM cells to OMgp-coated Matrigel but does not affect the cell adhesion to OMgp-uncoated Matrigel.	('OMgp', 'Gene', (162, 166))	('increases', 'PosReg', (56, 65))	('OMgp', 'Gene', '4974', (100, 104))	('GBM', 'Disease', (87, 90))	('cell adhesion', 'CPA', (70, 83))	('surface', 'Var', (44, 51))	('OMgp', 'Gene', '4974', (162, 166))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('NgR', 'Gene', (52, 55))	('OMgp', 'Gene', (100, 104))	('NgR', 'Gene', '65078', (52, 55))	('upregulated', 'PosReg', (32, 43))
9325	31649250	Next, we examined whether the upregulation of OMgp responsiveness in GBM cells treated with LY2109761 also affected the migration and invasion abilities of U87 and U251 cells (Fig.	('LY2109761', 'Chemical', 'MESH:C530108', (92, 101))	('U87', 'Gene', (156, 159))	('GBM', 'Disease', (69, 72))	('GBM', 'Disease', 'MESH:D005909', (69, 72))	('OMgp', 'Gene', (46, 50))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('U87', 'Gene', '641648', (156, 159))	('migration', 'CPA', (120, 129))	('affected', 'Reg', (107, 115))	('upregulation', 'PosReg', (30, 42))	('LY2109761', 'Var', (92, 101))	('OMgp', 'Gene', '4974', (46, 50))	('invasion abilities', 'CPA', (134, 152))
9326	31649250	2h, 20 muM LY2109761 significantly reduced the percentage of migrating cells to 33.2 and 30.4% in U87 and U251 cells, respectively, compared with untreated U87 (97%) and U251 (99.7%) cells.	('muM', 'Gene', '56925', (7, 10))	('U87', 'Gene', (156, 159))	('reduced', 'NegReg', (35, 42))	('LY2109761', 'Var', (11, 20))	('muM', 'Gene', (7, 10))	('U87', 'Gene', '641648', (156, 159))	('U87', 'Gene', (98, 101))	('LY2109761', 'Chemical', 'MESH:C530108', (11, 20))	('U87', 'Gene', '641648', (98, 101))
9327	31649250	However, in the migration chamber without OMgp, the percentage of migrating cells in LY2109761-treated U87 or U251 cells decreased to 72.3 or 86.3%, respectively, compared with 100% in untreated cells.	('OMgp', 'Gene', (42, 46))	('U87', 'Gene', '641648', (103, 106))	('LY2109761', 'Chemical', 'MESH:C530108', (85, 94))	('LY2109761-treated', 'Var', (85, 102))	('decreased', 'NegReg', (121, 130))	('OMgp', 'Gene', '4974', (42, 46))	('U87', 'Gene', (103, 106))
9328	31649250	Consistently, LY2109761 suppressed the percentage of invasive U87 and U251 cells to 65.3 or 69.7%, respectively, compared with untreated cells (100%), as demonstrated by the Matrigel with OMgp-coated invasion assay (Fig.	('LY2109761', 'Var', (14, 23))	('suppressed', 'NegReg', (24, 34))	('LY2109761', 'Chemical', 'MESH:C530108', (14, 23))	('U251 cells', 'CPA', (70, 80))	('OMgp', 'Gene', (188, 192))	('U87', 'Gene', (62, 65))	('U87', 'Gene', '641648', (62, 65))	('OMgp', 'Gene', '4974', (188, 192))
9329	31649250	However, in the Matrigel without OMgp-coated invasion chamber, the percentage of invasive U87 and U251 cells after treatment with LY2109761 decreased to 25.4 and 16.6%, respectively, compared with that in untreated control cells (Fig.	('U87', 'Gene', (90, 93))	('decreased', 'NegReg', (140, 149))	('U87', 'Gene', '641648', (90, 93))	('LY2109761', 'Chemical', 'MESH:C530108', (130, 139))	('OMgp', 'Gene', (33, 37))	('OMgp', 'Gene', '4974', (33, 37))	('LY2109761', 'Var', (130, 139))
9330	31649250	Overall, the enhanced OMgp responsiveness of U87 or U251 cells after treatment with LY2109761 caused a 2-4-fold decrease in cell migration and invasive activity compared with cells cultured without OMgp.	('OMgp', 'Gene', '4974', (22, 26))	('LY2109761', 'Chemical', 'MESH:C530108', (84, 93))	('enhanced', 'PosReg', (13, 21))	('U87', 'Gene', '641648', (45, 48))	('decrease', 'NegReg', (112, 120))	('invasive activity', 'CPA', (143, 160))	('cell migration', 'CPA', (124, 138))	('OMgp', 'Gene', (198, 202))	('LY2109761', 'Var', (84, 93))	('OMgp', 'Gene', (22, 26))	('U87', 'Gene', (45, 48))	('OMgp', 'Gene', '4974', (198, 202))
9331	31649250	These results suggest that the induction of mature NgR in GBM cells suppresses OMgp-coated transwell migration and invasive activity by enhancing OMgp responsiveness.	('OMgp', 'Gene', (146, 150))	('enhancing', 'PosReg', (136, 145))	('GBM', 'Disease', 'MESH:D005909', (58, 61))	('OMgp', 'Gene', '4974', (79, 83))	('suppresses', 'NegReg', (68, 78))	('induction', 'Var', (31, 40))	('NgR', 'Gene', (51, 54))	('OMgp', 'Gene', '4974', (146, 150))	('NgR', 'Gene', '65078', (51, 54))	('invasive activity', 'CPA', (115, 132))	('OMgp', 'Gene', (79, 83))	('GBM', 'Disease', (58, 61))
9334	31649250	As anticipated, the addition of recombinant human TGFbeta1 reduced the expression of mature NgR and E-cadherin (Fig.	('human', 'Species', '9606', (44, 49))	('expression', 'MPA', (71, 81))	('reduced', 'NegReg', (59, 66))	('TGFbeta1', 'Gene', '7040', (50, 58))	('TGFbeta1', 'Gene', (50, 58))	('NgR', 'Gene', (92, 95))	('NgR', 'Gene', '65078', (92, 95))	('E-cadherin', 'Gene', (100, 110))	('E-cadherin', 'Gene', '999', (100, 110))	('addition', 'Var', (20, 28))
9344	31649250	Importantly, we observed a decrease in the colocalization of intracellular NgR and vimentin in U87 and U251 cells after treatment with LY2109761 (Fig.	('NgR', 'Gene', (75, 78))	('vimentin', 'Gene', (83, 91))	('NgR', 'Gene', '65078', (75, 78))	('decrease', 'NegReg', (27, 35))	('U87', 'Gene', (95, 98))	('LY2109761', 'Var', (135, 144))	('vimentin', 'Gene', '7431', (83, 91))	('U87', 'Gene', '641648', (95, 98))	('colocalization', 'MPA', (43, 57))	('LY2109761', 'Chemical', 'MESH:C530108', (135, 144))	('intracellular', 'MPA', (61, 74))
9347	31649250	Together, these results indicate that the inhibition of TGFbeta1 by LY2109761 enhances the surface expression of NgR via the vimentin-mediated maturation of NgR.	('LY2109761', 'Var', (68, 77))	('NgR', 'Gene', (113, 116))	('vimentin', 'Gene', '7431', (125, 133))	('NgR', 'Gene', '65078', (113, 116))	('enhances', 'PosReg', (78, 86))	('NgR', 'Gene', (157, 160))	('vimentin', 'Gene', (125, 133))	('LY2109761', 'Chemical', 'MESH:C530108', (68, 77))	('NgR', 'Gene', '65078', (157, 160))	('surface expression', 'MPA', (91, 109))	('TGFbeta1', 'Gene', '7040', (56, 64))	('inhibition', 'NegReg', (42, 52))	('TGFbeta1', 'Gene', (56, 64))
9349	31649250	In both the LY2109761 and TGFbeta1 treatments, we found that vimentin coprecipitated with NgR, which is consistent with the colocalization results shown in Fig.	('LY2109761', 'Chemical', 'MESH:C530108', (12, 21))	('TGFbeta1', 'Gene', '7040', (26, 34))	('TGFbeta1', 'Gene', (26, 34))	('LY2109761', 'Var', (12, 21))	('vimentin', 'Gene', '7431', (61, 69))	('NgR', 'Gene', (90, 93))	('vimentin', 'Gene', (61, 69))	('NgR', 'Gene', '65078', (90, 93))
9350	31649250	5a, the expression of the precursor form of NgR decreased upon the inactivation of the TGFbeta1 pathway by LY2109761 treatment, indicating that LY2109761 increased the mature form of NgR.	('NgR', 'Gene', (44, 47))	('LY2109761', 'Var', (144, 153))	('NgR', 'Gene', '65078', (44, 47))	('LY2109761', 'Var', (107, 116))	('TGFbeta1', 'Gene', '7040', (87, 95))	('LY2109761', 'Chemical', 'MESH:C530108', (144, 153))	('decreased', 'NegReg', (48, 57))	('NgR', 'Gene', '65078', (183, 186))	('increased', 'PosReg', (154, 163))	('expression', 'MPA', (8, 18))	('LY2109761', 'Chemical', 'MESH:C530108', (107, 116))	('NgR', 'Gene', (183, 186))	('TGFbeta1', 'Gene', (87, 95))	('inactivation', 'NegReg', (67, 79))
9352	31649250	To further study the involvement of EMT in GBM cells treated with LY2109761 or TGFbeta1, we examined the expression of vimentin, Slug, and Snail.	('Slug', 'Gene', '6591', (129, 133))	('Slug', 'Gene', (129, 133))	('GBM', 'Disease', 'MESH:D005909', (43, 46))	('examined', 'Reg', (92, 100))	('LY2109761', 'Var', (66, 75))	('LY2109761', 'Chemical', 'MESH:C530108', (66, 75))	('vimentin', 'Gene', '7431', (119, 127))	('TGFbeta1', 'Gene', '7040', (79, 87))	('TGFbeta1', 'Gene', (79, 87))	('GBM', 'Disease', (43, 46))	('vimentin', 'Gene', (119, 127))	('Snail', 'Gene', (139, 144))	('Snail', 'Gene', '6615', (139, 144))
9353	31649250	5c, d) revealed that the transcriptional level of vimentin was significantly downregulated in LY2109761-treated U87 and U251 cells compared with untreated cells.	('downregulated', 'NegReg', (77, 90))	('LY2109761-treated', 'Var', (94, 111))	('vimentin', 'Gene', '7431', (50, 58))	('transcriptional level', 'MPA', (25, 46))	('U87', 'Gene', (112, 115))	('vimentin', 'Gene', (50, 58))	('U87', 'Gene', '641648', (112, 115))	('LY2109761', 'Chemical', 'MESH:C530108', (94, 103))
9361	31649250	Similar results were also found in cells that underwent permanent vimentin knockdown by using shRNA (Supplementary Fig.	('knockdown', 'Var', (75, 84))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('vimentin', 'Gene', (66, 74))	('vimentin', 'Gene', '7431', (66, 74))
9364	31649250	For NgR, the survival rate was better in the group with high expression than in the group with low expression (log-rank p = 3.33 x 10-4, Fig.	('survival rate', 'CPA', (13, 26))	('NgR', 'Gene', '65078', (4, 7))	('NgR', 'Gene', (4, 7))	('better', 'PosReg', (31, 37))	('high expression', 'Var', (56, 71))
9386	31649250	In addition, we performed in vitro experiments by using LY2109761 in primary glioma stem cells (GBMSC), such as X01 and X03, as shown in Supplementary Fig.	('GBM', 'Disease', (96, 99))	('LY2109761', 'Var', (56, 65))	('GBM', 'Disease', 'MESH:D005909', (96, 99))	('glioma', 'Disease', (77, 83))	('LY2109761', 'Chemical', 'MESH:C530108', (56, 65))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
9387	31649250	The results of cell viability, Western blot, FACS, and scratch-wound migration assays after LY2109761 treatment in two primary GBMSCs were similar to those in U87 and U251.	('LY2109761', 'Chemical', 'MESH:C530108', (92, 101))	('U87', 'Gene', '641648', (159, 162))	('U87', 'Gene', (159, 162))	('GBM', 'Disease', 'MESH:D005909', (127, 130))	('scratch-wound migration assays', 'CPA', (55, 85))	('LY2109761', 'Var', (92, 101))	('GBM', 'Disease', (127, 130))
9397	29304038	Our subsequent in vivo investigation in the STS26T MPNST sciatic nerve tumor model indicated that IL13 conjugated liposomal doxorubicin (IL13LIPDXR) was more effective in inhibiting tumor progression compared to unconjugated liposomal doxorubicin (LIPDXR).	('STS26T MPNST', 'CellLine', 'CVCL:8917', (44, 56))	('sciatic nerve tumor', 'Disease', 'MESH:D020426', (57, 76))	('IL13', 'Var', (98, 102))	('tumor', 'Disease', (182, 187))	('inhibiting', 'NegReg', (171, 181))	('doxorubicin', 'Chemical', 'MESH:D004317', (235, 246))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('nerve tumor', 'Phenotype', 'HP:0030430', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('tumor', 'Disease', (71, 76))	('sciatic nerve tumor', 'Disease', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
9412	29304038	Drug resistance associated with cancer cells expressing IL13Ralpha2 may be due in part to the anti-apoptotic nature of this receptor.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Drug resistance', 'MPA', (0, 15))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('anti-apoptotic', 'CPA', (94, 108))	('IL13Ralpha2', 'Var', (56, 67))
9422	29304038	Cell line #215 was established by culturing the cells from a MPNST excised from an NF-1 patient at Penn State Hershey Medical center and pathologically identified as NF-1 tumor (IRB # 30750NHR approved on 3-26-09 and IRB # 21561EP approved on 8-8-13).	('NF-1 tumor', 'Disease', (166, 176))	('patient', 'Species', '9606', (88, 95))	('NF-1 tumor', 'Disease', 'MESH:C537392', (166, 176))	('IRB # 30750NHR', 'Var', (178, 192))	('IRB # 21561EP', 'Var', (217, 230))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))
9439	29304038	To determine the tumorigenic potential of the IL13Ralpha2 expressing ST88-14 cells, we injected 1x105 ST88-14 cells in the sciatic nerve of NIHIII nude mice (Crl: NIH-Lystbg-JFOXn1nuBtkxid).	('tumor', 'Disease', (17, 22))	('ST88-14', 'Var', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('nude mice', 'Species', '10090', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
9500	29304038	Based on the endogenous fluorescent property of doxorubicin, the binding and transport of the IL13LIPDXR in the ST88-14 tumor spheroids was monitored by confocal microscopy and the fluorescent image indicates that IL13LIPDXR infiltrated the tumor spheroids.	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('IL13LIPDXR', 'Var', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('doxorubicin', 'Chemical', 'MESH:D004317', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
9504	29304038	Delivery of doxorubicin through IP injection of IL13LIPDXR resulted in slower tumor progression when compared to control (saline injected) and unconjugated liposomal doxorubicin (LIPDXR) injected groups (Fig 8).	('doxorubicin', 'Chemical', 'MESH:D004317', (166, 177))	('slower', 'NegReg', (71, 77))	('IL13LIPDXR', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('doxorubicin', 'Chemical', 'MESH:D004317', (12, 23))	('tumor', 'Disease', (78, 83))	('saline', 'Chemical', 'MESH:D012965', (122, 128))
9505	29304038	In the IL13LIPDXR group, the tumor progression was slower for 4 weeks beyond which the tumors started growing rapidly.	('IL13LIPDXR', 'Var', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
9521	29304038	Therapeutic strategies with bacterial toxins like IL13PE38QQR (Pseudomonas Exotoxin), IL13DT (Diphtheria toxin) and IL13 linked nanovesicles were demonstrated to selectively target and eliminate GBM tumors leading to increased survival of the tumor bearing mice.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (243, 248))	('mice', 'Species', '10090', (257, 261))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('eliminate', 'NegReg', (185, 194))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('IL13DT', 'Var', (86, 92))	('survival', 'CPA', (227, 235))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('GBM tumors', 'Disease', (195, 205))	('GBM tumors', 'Disease', 'MESH:D005910', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('IL13PE38QQR', 'Var', (50, 61))	('increased', 'PosReg', (217, 226))
9522	29304038	In our earlier studies, we showed improved efficacy of the IL13 conjugated liposomal doxorubicin (IL13LIPDXR) in GBM tumors expressing IL13Ralpha2.	('improved', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('efficacy', 'MPA', (43, 51))	('GBM tumors', 'Disease', (113, 123))	('GBM tumors', 'Disease', 'MESH:D005910', (113, 123))	('IL13Ralpha2', 'Var', (135, 146))
9528	29304038	Based on our earlier investigation, we attribute this property to the ability of IL13LIPDXR to overcome the multidrug resistance imparted by the cancer cells.	('cancer', 'Disease', (145, 151))	('multidrug resistance imparted', 'MPA', (108, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('IL13LIPDXR', 'Var', (81, 91))	('overcome', 'PosReg', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('drug resistance', 'Phenotype', 'HP:0020174', (113, 128))
9532	29304038	An in-depth investigation of the mechanism of interaction of the IL13 conjugated nanoliposomes with glioma tumors expressing IL13Ralpha2 and their ability to overcome the known drug resistance properties was described in our earlier study.	('glioma tumors', 'Disease', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('glioma tumors', 'Disease', 'MESH:D005910', (100, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (177, 192))	('interaction', 'Interaction', (46, 57))	('IL13Ralpha2', 'Var', (125, 136))
9534	29304038	Based on our in vivo therapeutic efficacy study in the sciatic nerve tumor model, it is evident that tumor progression is attenuated in the mice treated with IL13LIPDXR at 7 mg/kg body weight, when compared to the non-targeted group.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (140, 144))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('nerve tumor', 'Phenotype', 'HP:0030430', (63, 74))	('sciatic nerve tumor', 'Disease', (55, 74))	('sciatic nerve tumor', 'Disease', 'MESH:D020426', (55, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('attenuated', 'NegReg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('IL13LIPDXR', 'Var', (158, 168))
9545	28483980	The aberrant expression of AJAP1 is associated with alterations in cell migration, invasion, increased tumor growth, and tumor vascularization, suggesting AJAP1 as a putative tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (175, 180))	('AJAP1', 'Gene', (27, 32))	('alterations', 'Reg', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('expression', 'MPA', (13, 23))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', (103, 108))	('aberrant', 'Var', (4, 12))	('tumor', 'Disease', (121, 126))	('invasion', 'CPA', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cell migration', 'CPA', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
9556	28483980	Deletion or epigenetic silencing, caused by hyper-methylation of the proximal promoter as shown in glioblastoma tumors, leads to loss of AJAP1 and is associated with cancer development.	('cancer', 'Disease', (166, 172))	('glioblastoma tumors', 'Disease', (99, 118))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('AJAP1', 'Protein', (137, 142))	('loss', 'NegReg', (129, 133))	('associated with', 'Reg', (150, 165))	('hyper-methylation', 'Var', (44, 61))	('epigenetic silencing', 'Var', (12, 32))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (99, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('Deletion', 'Var', (0, 8))
9570	28483980	However, in highly invasive oligodendroglioma cells, AJAP1 is epigenetically down-regulated.	('oligodendroglioma', 'Disease', 'MESH:D009837', (28, 45))	('epigenetically', 'Var', (62, 76))	('AJAP1', 'Gene', (53, 58))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('oligodendroglioma', 'Disease', (28, 45))
9571	28483980	Increased tumor vascularization and invasion inversely correlate with the mRNA levels of AJAP1, indicating that AJAP1 is important for cell and tissue integrity and that loss of AJAP1 promotes tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('invasion', 'CPA', (36, 44))	('AJAP1', 'Gene', (178, 183))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('loss', 'Var', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mRNA levels', 'MPA', (74, 85))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('promotes', 'PosReg', (184, 192))
9572	28483980	We investigated the role of AJAP1 in endothelial cells, in particular during angiogenic sprouting, by examining the effect of siRNA-mediated AJAP1 knockdown on the sprouting activity in a spheroid-based angiogenesis assay in human umbilical vein endothelial cells (HUVECs).	('AJAP1', 'Gene', (141, 146))	('human', 'Species', '9606', (225, 230))	('knockdown', 'Var', (147, 156))
9573	28483980	Supported by the scratched wound healing assay, these results showed that the knockdown of AJAP1 had a positive influence on cell migration in human endothelial cells, which was not caused by increased cell viability, suggesting that AJAP1 influences the migration process itself.	('human', 'Species', '9606', (143, 148))	('knockdown', 'Var', (78, 87))	('influence', 'Reg', (112, 121))	('cell migration in human endothelial cells', 'CPA', (125, 166))	('influences', 'Reg', (240, 250))	('migration process', 'CPA', (255, 272))	('AJAP1', 'Gene', (91, 96))
9595	28483980	However, in the glioblastoma context, it has been observed that upon restoration of AJAP1 expression, the cytoskeleton is altered.	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('cytoskeleton', 'MPA', (106, 118))	('restoration', 'Var', (69, 80))	('expression', 'MPA', (90, 100))	('AJAP1', 'Gene', (84, 89))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))	('altered', 'Reg', (122, 129))
9617	28483980	Primary antibodies against GAPDH (AM4300, Ambion), and AJAP1 (ab121361, Abcam, Cambridge, UK) were incubated over night at 4 C. Secondary horseradish peroxidase-conjugated antibodies (115-035-003, 111-035-003, Jackson Immuno Research, Newmarket, UK) were incubated for 1.5 h at room temperature.	('GAPDH', 'Gene', '2597', (27, 32))	('GAPDH', 'Gene', (27, 32))	('115-035-003', 'Var', (184, 195))	('horseradish', 'Species', '3704', (138, 149))
9620	28483980	The primary antibodies were incubated over night at 4 C. Primary antibodies were alpha-tubulin [ab52866 (Abcam), A11126 (Life Technologies)] and five different antibodies to detect AJAP1 [ab121361 (Abcam), custom made antibody (Nanotools, Teningen, Germany), clone F (Genovac Aldevron, Freiburg, Germany), AAS47449C, AAS46449C (Antibody verify, Las Vegas, NV, USA)].	('AAS47449C', 'Var', (306, 315))	('alpha-tubulin', 'Gene', (81, 94))	('alpha-tubulin', 'Gene', '10376', (81, 94))	('AAS46449C', 'Var', (317, 326))
9639	27199435	Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival.	('prolonged', 'PosReg', (91, 100))	('PI3K', 'Var', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('overall', 'MPA', (101, 108))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
9641	27199435	This appeal arises in part from the decreased likelihood of acquired resistance through mutations in target TME cells, as is frequently observed with cancer cell-targeted therapies.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (88, 97))	('acquired resistance', 'MPA', (60, 79))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
9646	27199435	In many cancers, including glioma, elevated TAM numbers are associated with high grade and poor patient prognosis.	('glioma', 'Disease', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('elevated', 'Var', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('TAM numbers', 'MPA', (44, 55))	('glioma', 'Disease', 'MESH:D005910', (27, 33))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('patient', 'Species', '9606', (96, 103))	('TAM', 'Chemical', 'MESH:D013629', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))
9650	27199435	We have shown that BLZ945 blocks early gliomagenesis, while short-term treatment of advanced, high-grade glioma causes robust tumor debulking after just 7 days.	('blocks', 'NegReg', (26, 32))	('glioma', 'Disease', (39, 45))	('glioma', 'Disease', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('BLZ945', 'Chemical', 'MESH:C568289', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('BLZ945', 'Var', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('tumor', 'Disease', (126, 131))
9663	27199435	Histological analysis showed that after 7d of BLZ945, tumor grade was significantly reduced.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('reduced', 'NegReg', (84, 91))	('BLZ945', 'Chemical', 'MESH:C568289', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('BLZ945', 'Var', (46, 52))	('tumor', 'Disease', (54, 59))
9677	27199435	We treated PDG mice bearing high-grade gliomas with BLZ945 until they showed tumor rebound by MRI, at which point we intervened with BKM120 treatment (Fig.	('PDG', 'Gene', (11, 14))	('BLZ945', 'Var', (52, 58))	('BKM120', 'Chemical', 'MESH:C571178', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('gliomas', 'Disease', (39, 46))	('PDG', 'Gene', '26227', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mice', 'Species', '10090', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('tumor', 'Disease', (77, 82))	('BLZ945', 'Chemical', 'MESH:C568289', (52, 58))
9681	27199435	By contrast, BKM120 monotherapy in rebound tumors (i.e.	('BKM120', 'Chemical', 'MESH:C571178', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('BKM120', 'Var', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
9683	27199435	Moreover, BKM120 was only modestly effective in treatment-naive tumors (fig.	('BKM120', 'Var', (10, 16))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('BKM120', 'Chemical', 'MESH:C571178', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
9686	27199435	With this early intervention, the percentage of animals that survived to endpoint increased substantially (91% BLZ945+BKM120) compared to single-agent treatments (44% BLZ945 alone and 0% BKM120 alone; Fig.	('BLZ945', 'Chemical', 'MESH:C568289', (111, 117))	('BLZ945+BKM120', 'Var', (111, 124))	('BLZ945', 'Chemical', 'MESH:C568289', (167, 173))	('increased', 'PosReg', (82, 91))	('BKM120', 'Chemical', 'MESH:C571178', (118, 124))	('BKM120', 'Chemical', 'MESH:C571178', (187, 193))
9688	27199435	Our finding that PI3K activation underlies resistance to CSF-1R inhibition was intriguing in light of the high frequency of mutations in the PI3K pathway in glioma patients.	('mutations', 'Var', (124, 133))	('PI3K pathway', 'Pathway', (141, 153))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioma', 'Disease', (157, 163))	('patients', 'Species', '9606', (164, 172))
9690	27199435	To address this question, we compared BLZ945 efficacy in two additional RCAS-hPDGF-B/Nestin-Tv-a GBM models harboring distinct clinically-relevant oncogenic alterations besides Ink4a/Arf loss, including Pten deletion (Pten KO model) or p53 knockdown (p53 KD model; see methods).	('deletion', 'Var', (208, 216))	('loss', 'NegReg', (187, 191))	('p53', 'Gene', (236, 239))	('Pten', 'Gene', (218, 222))	('PDG', 'Gene', '26227', (78, 81))	('Pten', 'Gene', '19211', (218, 222))	('Pten', 'Gene', '19211', (203, 207))	('Pten', 'Gene', (203, 207))	('RCAS', 'Chemical', '-', (72, 76))	('Ink4a/Arf', 'Gene', '12578', (177, 186))	('knockdown', 'Var', (240, 249))	('PDG', 'Gene', (78, 81))	('BLZ945', 'Chemical', 'MESH:C568289', (38, 44))	('Ink4a/Arf', 'Gene', (177, 186))
9691	27199435	After 2 weeks of treatment, we found that BLZ945 efficacy in the p53 KD model (56% reduction of tumor volume) was comparable to that of the PDG model (62% reduction).	('BLZ945', 'Chemical', 'MESH:C568289', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('BLZ945', 'Gene', (42, 48))	('p53', 'Var', (65, 68))	('PDG', 'Gene', '26227', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('reduction', 'NegReg', (83, 92))	('PDG', 'Gene', (140, 143))
9694	27199435	These results suggest that treatment efficacy of CSF-1R inhibitors may be blunted in patients with existing genetic alterations in the PTEN/PI3K pathway.	('patients', 'Species', '9606', (85, 93))	('genetic alterations', 'Var', (108, 127))	('PTEN/PI3K pathway', 'Pathway', (135, 152))	('blunted', 'NegReg', (74, 81))
9725	27199435	Corroborating these findings, we confirmed increased expression of Il4 in rebound tumors by qRT-PCR (Fig.	('Il4', 'Gene', '16189', (67, 70))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('Il4', 'Gene', (67, 70))	('qRT-PCR', 'Var', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('increased', 'PosReg', (43, 52))	('expression', 'MPA', (53, 63))
9730	27199435	S7, A to G), there was a significant increase in the proportion of CD3+ T cells in rebound tumors, driven by the CD8+ fraction (Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CD8+', 'Var', (113, 117))	('increase', 'PosReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CD3', 'Gene', (67, 70))	('CD3', 'Gene', '28134', (67, 70))
9741	27199435	5C, and Table S1), elevated p-IGF-1R was found in rebound tumors by immunostaining and western blotting (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('elevated', 'PosReg', (19, 27))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('p-IGF-1R', 'Var', (28, 36))
9750	27199435	After this treatment, we collected CM from the GMEC-stimulated BMDMs (Stim CM) and applied it to either rebound or naive tumor cell lines in an MTT assay, +/- a neutralizing antibody against IGF-1 (see fig.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('IGF-1', 'Gene', (191, 196))	('neutralizing', 'Var', (161, 173))	('tumor', 'Disease', (121, 126))	('MTT', 'Chemical', 'MESH:C070243', (144, 147))	('GMEC', 'Chemical', '-', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
9756	27199435	Together these data support our hypothesis that high IGF-1 levels translate to elevated PI3K signaling in patients, and that this axis is associated with M2-like gene expression.	('high IGF-', 'Phenotype', 'HP:0030269', (48, 57))	('IGF-1', 'Gene', (53, 58))	('PI3K signaling', 'Pathway', (88, 102))	('patients', 'Species', '9606', (106, 114))	('elevated', 'PosReg', (79, 87))	('high', 'Var', (48, 52))
9777	27199435	To validate the significance of these pathways in vivo, PDG mice with high-grade GBMs were treated continuously with BLZ945 alone until 28d, at which point FK506 (a NFAT-calcineurin inhibitor) or AS15171499 (a Stat6 inhibitor) was added until the trial endpoint.	('BLZ945', 'Chemical', 'MESH:C568289', (117, 123))	('PDG', 'Gene', '26227', (56, 59))	('FK506', 'Var', (156, 161))	('FK506', 'Chemical', 'MESH:D016559', (156, 161))	('BLZ945', 'Var', (117, 123))	('PDG', 'Gene', (56, 59))	('Stat6', 'Gene', '20852', (210, 215))	('Stat6', 'Gene', (210, 215))	('AS15171499', 'Chemical', '-', (196, 206))	('mice', 'Species', '10090', (60, 64))	('AS15171499', 'Var', (196, 206))
9778	27199435	With addition of either of these inhibitors, the percentage of animals that survived to endpoint was significantly increased (22% BLZ945+Veh, 50% BLZ945+AS1517499, and 82% BLZ945+FK506; Fig.	('BLZ945+FK506', 'Var', (172, 184))	('BLZ945+Veh', 'Var', (130, 140))	('increased', 'PosReg', (115, 124))	('BLZ945+AS1517499', 'Var', (146, 162))	('FK506', 'Chemical', 'MESH:D016559', (179, 184))	('BLZ945', 'Chemical', 'MESH:C568289', (146, 152))	('BLZ945', 'Chemical', 'MESH:C568289', (130, 136))	('AS1517499', 'Chemical', 'MESH:C544923', (153, 162))	('BLZ945', 'Chemical', 'MESH:C568289', (172, 178))
9779	27199435	In accordance with these results, when we treated animals with AS1517499 in combination with continued BLZ945 treatment at a later time point, during the rebound phase, we were able to extend survival (Fig.	('BLZ945', 'Chemical', 'MESH:C568289', (103, 109))	('AS1517499', 'Chemical', 'MESH:C544923', (63, 72))	('survival', 'CPA', (192, 200))	('extend', 'PosReg', (185, 191))	('AS1517499', 'Var', (63, 72))
9786	27199435	OSI906 was chosen because it is currently being clinically evaluated for multiple cancer types, its effect on BMDM viability in vitro was minimal compared to other IGF-1R inhibitors tested (fig.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('OSI906', 'Chemical', 'MESH:C551528', (0, 6))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('OSI906', 'Var', (0, 6))
9787	27199435	S11A), and we confirmed it is brain-penetrant in rebound tumors by showing reduced p-IGF-1R immunostaining (fig.	('p-IGF-1R immunostaining', 'MPA', (83, 106))	('S11A', 'Var', (0, 4))	('S11A', 'SUBSTITUTION', 'None', (0, 4))	('reduced', 'NegReg', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
9796	27199435	Similar combination treatment efficacy and mechanistic commonalities (including immunofluorescence quantification of Ki67: CC3 ratios, CD206, and p-IGF-1R) were observed in orthotopic xenograft trials performed with patient-derived proneural tumorspheres, and with established human glioma cell lines (Fig.	('CD206', 'Var', (135, 140))	('Ki67', 'Gene', '17345', (117, 121))	('glioma', 'Disease', (283, 289))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('patient', 'Species', '9606', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('glioma', 'Phenotype', 'HP:0009733', (283, 289))	('glioma', 'Disease', 'MESH:D005910', (283, 289))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))	('human', 'Species', '9606', (277, 282))	('Ki67', 'Gene', (117, 121))
9798	27199435	With early combination treatment, we indeed extended overall survival and increased the percentage of animals that survived to endpoint (89% BLZ945+OSI906 versus 44% BLZ945 alone or 0% OSI906 alone; Fig.	('BLZ945', 'Chemical', 'MESH:C568289', (141, 147))	('extended', 'PosReg', (44, 52))	('BLZ945+OSI906', 'Var', (141, 154))	('OSI906', 'Chemical', 'MESH:C551528', (185, 191))	('increased', 'PosReg', (74, 83))	('BLZ945', 'Chemical', 'MESH:C568289', (166, 172))	('OSI906', 'Chemical', 'MESH:C551528', (148, 154))
9799	27199435	Given that pharmacological inhibition of IGF-1R using OSI906 cannot confirm whether tumor cell-specific blockade is sufficient to reduce recurrent disease, we utilized a genetic approach to target this receptor in glioma cells.	('OSI906', 'Chemical', 'MESH:C551528', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('OSI906', 'Var', (54, 60))	('glioma', 'Disease', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('glioma', 'Disease', 'MESH:D005910', (214, 220))	('IGF-1R', 'Gene', (41, 47))
9808	27199435	While classical mechanisms of tumor cell-intrinsic resistance to cytotoxic and targeted agents have been well-defined, including aberrant drug metabolism and transport, drug target mutation, and activation of alternative survival pathways, it still remains unclear whether resistance to TME-directed therapies will follow similar principles.	('drug metabolism', 'MPA', (138, 153))	('transport', 'MPA', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutation', 'Var', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('aberrant', 'Var', (129, 137))
9810	27199435	In light of this problem, we have now identified a mechanism of drug resistance that can circumvent therapeutic response to a TME-targeted therapy, and promote disease progression in the absence of tumor cell-intrinsic alterations.	('drug resistance', 'Var', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('disease progression', 'CPA', (160, 179))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('promote', 'PosReg', (152, 159))	('circumvent', 'NegReg', (89, 99))	('drug resistance', 'Phenotype', 'HP:0020174', (64, 79))
9813	27199435	Multiple nodes in this signaling loop can be targeted therapeutically by agents that are currently used clinically, including OSI906, BKM120, or FK506, resulting in a substantial improvement in survival in the preclinical setting when combined with CSF-1R inhibition.	('OSI906', 'Chemical', 'MESH:C551528', (126, 132))	('BKM120', 'Chemical', 'MESH:C571178', (134, 140))	('OSI906', 'Var', (126, 132))	('survival', 'MPA', (194, 202))	('BKM120', 'Var', (134, 140))	('FK506', 'Var', (145, 150))	('improvement', 'PosReg', (179, 190))	('FK506', 'Chemical', 'MESH:D016559', (145, 150))
9828	27199435	BKM120 (Buparlisib; 1 muM unless indicated otherwise), AEW541, ADW742, BMS754807 and OSI906 (Linsitinib; 10 muM unless indicated otherwise) were purchased from Selleckchem for in vitro use, and were used up to 100 muM for dose response assays versus an equal percent DMSO as a vehicle control.	('OSI906', 'Chemical', 'MESH:C551528', (85, 91))	('DMSO', 'Chemical', 'MESH:D004121', (267, 271))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('AEW541', 'Var', (55, 61))	('Buparlisib', 'Chemical', 'MESH:C571178', (8, 18))	('Linsitinib', 'Chemical', 'MESH:C551528', (93, 103))	('BMS754807', 'Var', (71, 80))
9840	27199435	For in vivo inhibition of NFAT signaling, FK506 was used to inhibit the activating interaction between calcineurin and NFAT, at a dose of 10 mg/kg (administered i.p.	('FK506', 'Var', (42, 47))	('FK506', 'Chemical', 'MESH:D016559', (42, 47))	('activating interaction', 'MPA', (72, 94))	('inhibit', 'NegReg', (60, 67))
9855	27199435	In this model, injection into the SVZ induces tumors with low latency (4-5 weeks), 100% penetrance, and histological features characteristic of patient GBM including microvascular proliferation and pseudopalisading necrosis.	('microvascular proliferation', 'CPA', (166, 193))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('injection', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('necrosis', 'Disease', (215, 223))	('induces', 'Reg', (38, 45))	('patient', 'Species', '9606', (144, 151))	('tumors', 'Disease', (46, 52))	('necrosis', 'Disease', 'MESH:D009336', (215, 223))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
9882	27199435	Nanostring analysis confirmed PDGFRA overexpression, and sequenom analyses were negative for IDH1/2 mutations.	('mutations', 'Var', (100, 109))	('IDH1/2', 'Gene', (93, 99))	('overexpression', 'PosReg', (37, 51))	('PDGFRA', 'Gene', '18595', (30, 36))	('IDH1/2', 'Gene', '15926;269951', (93, 99))	('PDGFRA', 'Gene', (30, 36))
9896	27199435	Once BLZ945-treated tumors reached 3x the volume of their lowest BLI measurement, tumors were considered 'resistant', and mice were randomly assigned to combination treatment with BLZ945 + OSI906, or BLZ945 + vehicle.	('mice', 'Species', '10090', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('BLZ945 +', 'Var', (180, 188))	('BLZ945', 'Chemical', 'MESH:C568289', (180, 186))	('BLZ945', 'Chemical', 'MESH:C568289', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('OSI906', 'Chemical', 'MESH:C551528', (189, 195))	('BLZ945', 'Chemical', 'MESH:C568289', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
9929	27199435	Mouse taqman probes (Applied Biosystems) were used for quantifying expression of Igf1 (Mm00439560_m1), Chil3 (Mm00657889_mH), Ccl17 (Mm01244826_g1), Retnla (Mm00445109_m1), Il4 (Mm00445260_m1), Arg1 (Mm00475988_m1), Cd36 (Mm00432403_m1), Mrc1 (Mm01329362_m1), Ubc (Mm02525934_g1; housekeeping), and Hprt (Mm01545339_m1; housekeeping).	('Mm01545339_m1', 'Var', (305, 318))	('Arg1', 'Gene', (194, 198))	('Retnla', 'Gene', (149, 155))	('Mm00432403_m1', 'Var', (222, 235))	('Mm00445260_m1', 'Var', (178, 191))	('Mm00439560_m1', 'Var', (87, 100))	('Igf1', 'Gene', (81, 85))	('Mm00657889_mH', 'Var', (110, 123))	('Ccl17', 'Gene', '20295', (126, 131))	('Cd36', 'Species', '42374', (216, 220))	('Mm02525934_g1', 'Var', (265, 278))	('Mm01329362_m1', 'Var', (244, 257))	('Mm00475988_m1', 'Var', (200, 213))	('Retnla', 'Gene', '57262', (149, 155))	('Il4', 'Gene', (173, 176))	('Mm01244826_g1', 'Var', (133, 146))	('Igf1', 'Gene', '16000', (81, 85))	('Chil3', 'Gene', (103, 108))	('Arg1', 'Gene', '11846', (194, 198))	('Il4', 'Gene', '16189', (173, 176))	('Mm00445109_m1', 'Var', (157, 170))	('Ccl17', 'Gene', (126, 131))	('Chil3', 'Gene', '12655', (103, 108))	('Mrc1', 'Gene', '17533', (238, 242))	('Mrc1', 'Gene', (238, 242))	('Mouse', 'Species', '10090', (0, 5))
9930	27199435	Human taqman probes (Applied Biosystems) were used for quantifying expression of IL4 (Hs00174122_m1), IL13 (Hs00174379_m1), IGF1 (Hs01547656_m1) and HPRT1 (Hs02800695_m1; housekeeping).	('IL13', 'Gene', (102, 106))	('IL13', 'Gene', '3596', (102, 106))	('Human', 'Species', '9606', (0, 5))	('Hs02800695_m1', 'Var', (156, 169))	('Hs00174379_m1', 'Var', (108, 121))	('Hs01547656_m1', 'Var', (130, 143))	('IGF1', 'Gene', (124, 128))	('Hs00174122_m1', 'Var', (86, 99))	('IL4', 'Gene', (81, 84))	('HPRT1', 'Gene', '3251', (149, 154))	('HPRT1', 'Gene', (149, 154))
9973	27788487	Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique.	('Prolactin receptor', 'Gene', (14, 32))	('patients', 'Species', '9606', (191, 199))	('brain tumor', 'Phenotype', 'HP:0030692', (159, 170))	('U373', 'CellLine', 'CVCL:2219', (129, 133))	('U251-MG', 'CellLine', 'CVCL:0021', (71, 78))	('U87-MG', 'CellLine', 'CVCL:0022', (97, 103))	('PrlR', 'Gene', (34, 38))	('brain tumor', 'Disease', 'MESH:D001932', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('brain tumor', 'Disease', (159, 170))	('Prolactin receptor', 'Gene', '5618', (14, 32))	('U251-MG', 'Var', (71, 78))
9976	27788487	We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('blocking', 'Var', (102, 110))	('PrlR', 'Gene', (114, 118))	('cellular invasion', 'CPA', (157, 174))	('reduce', 'NegReg', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('U251-MG', 'CellLine', 'CVCL:0021', (122, 129))	('GBM tumors', 'Disease', (82, 92))	('GBM tumors', 'Disease', 'MESH:D005910', (82, 92))
9989	27788487	Of note, loss of TSC1 accelerates malignant glioma genesis when it is combined with oncogenic signals.	('accelerates', 'PosReg', (22, 33))	('malignant glioma genesis', 'Disease', 'MESH:D005910', (34, 58))	('malignant glioma genesis', 'Disease', (34, 58))	('TSC1', 'Gene', '7248', (17, 21))	('TSC1', 'Gene', (17, 21))	('loss', 'Var', (9, 13))	('rat', 'Species', '10116', (28, 31))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
9990	27788487	Patients with tuberous sclerosis have a bi-allelic loss of TSC1/TSC2 and a few clinical cases have been reported on the occurrence of GBM in such patients, but further investigations related to this association are needed.	('TSC1/TSC2', 'Disease', 'MESH:C565346', (59, 68))	('tuberous sclerosis', 'Disease', (14, 32))	('TSC1/TSC2', 'Disease', (59, 68))	('bi-allelic', 'Var', (40, 50))	('Patients', 'Species', '9606', (0, 8))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (14, 32))	('loss', 'NegReg', (51, 55))	('patients', 'Species', '9606', (146, 154))
10010	27788487	We could not detect any STAT3 phosphorylation in U251-MG and U87-MG but it was found constitutively active in U373 cells (Data not shown).	('U251-MG', 'CellLine', 'CVCL:0021', (49, 56))	('U251-MG', 'Var', (49, 56))	('U373', 'CellLine', 'CVCL:2219', (110, 114))	('STAT3', 'Gene', '6774', (24, 29))	('U87-MG', 'CellLine', 'CVCL:0022', (61, 67))	('STAT3', 'Gene', (24, 29))
10018	27788487	Moreover, we found significantly increased levels of phosphorylated STAT5 in Prl treated U251-MG and U87-MG cells but not in U373 cells.	('U87-MG', 'Var', (101, 107))	('STAT5', 'Gene', (68, 73))	('Prl', 'Gene', (77, 80))	('increased', 'PosReg', (33, 42))	('STAT5', 'Gene', '6776', (68, 73))	('U87-MG', 'CellLine', 'CVCL:0022', (101, 107))	('U251-MG', 'CellLine', 'CVCL:0021', (89, 96))	('U251-MG', 'Var', (89, 96))	('U373', 'CellLine', 'CVCL:2219', (125, 129))
10019	27788487	Enhanced activity and invasiveness in response to Prl treatment was found only in U251-MG cells but not in U87-MG and U373 cells.	('U251-MG', 'Var', (82, 89))	('U373', 'CellLine', 'CVCL:2219', (118, 122))	('U87-MG', 'CellLine', 'CVCL:0022', (107, 113))	('activity', 'MPA', (9, 17))	('invasiveness', 'CPA', (22, 34))	('U251-MG', 'CellLine', 'CVCL:0021', (82, 89))	('Enhanced', 'PosReg', (0, 8))
10020	27788487	Interestingly, high expression of PrlR was detected in U251-MG cells compared to U87-MG and U373 cells and consequently significant or no invasion capacity of GBM cells in response to Prl may reflect the impact of different levels of PrlR expression on GBM cells.	('U373', 'CellLine', 'CVCL:2219', (92, 96))	('expression', 'MPA', (20, 30))	('invasion capacity', 'CPA', (138, 155))	('U251-MG', 'CellLine', 'CVCL:0021', (55, 62))	('U251-MG', 'Var', (55, 62))	('PrlR', 'Gene', (34, 38))	('U87-MG', 'CellLine', 'CVCL:0022', (81, 87))
10021	27788487	Furthermore, the invasiveness of U251-MG cells could be significantly reduced to that of control cells by using a novel high affinity PrlRA.	('invasiveness', 'CPA', (17, 29))	('reduced', 'NegReg', (70, 77))	('U251-MG', 'Var', (33, 40))	('U251-MG', 'CellLine', 'CVCL:0021', (33, 40))
10024	27788487	A number of different alterations of cell signaling molecules have been found to promote angiogenesis/growth in GBM, including increased signaling from Vascular Endothelial Growth Factor receptor (VEGFR), Epidermal Growth Factor receptor (EGFR) and Platelet-derived Growth Factor (PDGF).	('Vascular Endothelial Growth Factor receptor', 'Gene', (152, 195))	('signaling', 'MPA', (137, 146))	('promote', 'PosReg', (81, 88))	('VEGFR', 'Gene', (197, 202))	('Epidermal Growth Factor receptor', 'Gene', '1956', (205, 237))	('rat', 'Species', '10116', (26, 29))	('angiogenesis/growth', 'CPA', (89, 108))	('Vascular Endothelial Growth Factor receptor', 'Gene', '3791', (152, 195))	('EGFR', 'Gene', '1956', (198, 202))	('alterations', 'Var', (22, 33))	('EGFR', 'Gene', '1956', (239, 243))	('EGFR', 'Gene', (198, 202))	('VEGFR', 'Gene', '3791', (197, 202))	('increased', 'PosReg', (127, 136))	('EGFR', 'Gene', (239, 243))	('Epidermal Growth Factor receptor', 'Gene', (205, 237))
10025	27788487	In our study, we could show that PrlR, which belongs to the cytokine receptor family, is highly expressed on U251-MG cells compared to U87-MG and U373 cells.	('PrlR', 'Gene', (33, 37))	('U87-MG', 'CellLine', 'CVCL:0022', (135, 141))	('U251-MG', 'CellLine', 'CVCL:0021', (109, 116))	('highly', 'PosReg', (89, 95))	('U373', 'CellLine', 'CVCL:2219', (146, 150))	('U251-MG', 'Var', (109, 116))
10043	27788487	STAT5 is a transcription factor that is activated by Prl and phosphorylation of this protein has an anti-apoptotic role in cells.	('STAT5', 'Gene', (0, 5))	('anti-apoptotic', 'CPA', (100, 114))	('phosphorylation', 'Var', (61, 76))	('STAT5', 'Gene', '6776', (0, 5))
10078	27788487	A changed amino acid in human Prl at position 129, where Gly is substituted for Arg, generates a protein (hPrl-G129R) that blocks the Prl receptor.	('G129R', 'Mutation', 'p.G129R', (111, 116))	('human', 'Species', '9606', (24, 29))	('blocks', 'NegReg', (123, 129))	('hPrl', 'Gene', '5617', (106, 110))	('hPrl', 'Gene', (106, 110))	('Gly', 'Chemical', 'MESH:D005998', (57, 60))	('Prl receptor', 'Protein', (134, 146))	('Arg', 'Chemical', 'MESH:D001120', (80, 83))	('changed', 'Var', (2, 9))	('rat', 'Species', '10116', (89, 92))
10079	27788487	Studies have shown that Prl G129R competes with exogenous Prl when added in >10-fold molar excess to compensate for its lower affinity for the PrlR.	('Prl G129R', 'Var', (24, 33))	('-fold molar', 'Phenotype', 'HP:0011093', (79, 90))	('G129R', 'Mutation', 'p.G129R', (28, 33))	('G129R', 'Var', (28, 33))
10080	27788487	In the present study we used a protein with increased affinity to block the receptor, Prl S33A, Q73L, G129R, K190R.	('S33A', 'Mutation', 'p.S33A', (90, 94))	('Q73L', 'Var', (96, 100))	('K190R', 'Mutation', 'p.K190R', (109, 114))	('G129R', 'Var', (102, 107))	('G129R', 'Mutation', 'p.G129R', (102, 107))	('K190R', 'Var', (109, 114))	('Q73L', 'Mutation', 'p.Q73L', (96, 100))
10189	27777605	Therefore, the question was whether a substitution of glucose by pyruvate contributes to gluconeogenesis sufficient for their supply.	('contributes', 'Reg', (74, 85))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('pyruvate', 'Chemical', 'MESH:D019289', (65, 73))	('gluconeogenesis', 'MPA', (89, 104))	('substitution', 'Var', (38, 50))	('gluconeogenesis sufficient', 'Phenotype', 'HP:0005959', (89, 115))
10236	27240162	Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs.	('rats', 'Species', '10116', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('human', 'Species', '9606', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('survival', 'CPA', (142, 150))	('improved', 'PosReg', (133, 141))	('BMP4/NP-hAMSCs', 'Var', (97, 111))	('tumors', 'Disease', (60, 66))
10332	27240162	The risks of insertional mutagenesis, excessive inflammation and immune response, and toxicity associated with viruses are significant hurdles for the clinical application of therapies based on genetically engineered cells.	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('inflammation', 'Disease', (48, 60))	('insertional mutagenesis', 'Var', (13, 36))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))
10352	27240162	Three days after injection, high fluorescence signal above background autofluorescence was observed in the brains of rats treated with GFP/NP-hAMSCs either IN or IV (Fig.	('rats', 'Species', '10116', (117, 121))	('GFP/NP-hAMSCs', 'Var', (135, 148))	('fluorescence signal', 'MPA', (33, 52))
10353	27240162	Specifically, the fluorescence signal of the left hemisphere, where the tumor had been implanted, was approximately 5-fold higher in the animals injected with GFP/NP-hAMSCs compared to the left hemisphere of the control rats injected with non-transfected hAMSCs (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('rats', 'Species', '10116', (220, 224))	('tumor', 'Disease', (72, 77))	('higher', 'PosReg', (123, 129))	('fluorescence signal', 'MPA', (18, 37))	('GFP/NP-hAMSCs', 'Var', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
10437	26110080	This demonstrates that the mTBI group performed significantly worse than the OIC group on psychomotor speed and reaction time tasks, despite having a Glasgow coma scale score of 15 and normal neuroimaging findings.	('mTBI', 'Var', (27, 31))	('psychomotor speed', 'Disease', (90, 107))	('worse', 'NegReg', (62, 67))	('reaction time tasks', 'CPA', (112, 131))	('coma', 'Disease', 'MESH:D003128', (158, 162))	('coma', 'Phenotype', 'HP:0001259', (158, 162))	('coma', 'Disease', (158, 162))	('psychomotor speed', 'Phenotype', 'HP:0025356', (90, 107))	('psychomotor speed', 'Disease', 'MESH:D011596', (90, 107))
10492	26110080	However, only 7% of patients of the hemicraniectomy group had a mRS 3 (moderate disability) or better versus 3% in the control.	('mRS', 'Disease', (64, 67))	('hemicraniectomy', 'Var', (36, 51))	('patients', 'Species', '9606', (20, 28))
10493	26110080	Only 6% of patients in the hemicraniectomy and 5% in the control group had mRS of 3 or better at 12 months.	('patients', 'Species', '9606', (11, 19))	('hemicraniectomy', 'Var', (27, 42))	('mRS', 'CPA', (75, 78))
10531	25558448	O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG).	('glioblastoma', 'Disease', (332, 344))	('glioblastoma', 'Phenotype', 'HP:0012174', (332, 344))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (200, 238))	('glioma', 'Disease', (170, 176))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 38))	('GBM', 'Phenotype', 'HP:0012174', (346, 349))	('MGMT', 'Gene', (113, 117))	('glioma', 'Disease', (366, 372))	('methylation', 'Var', (181, 192))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('anaplastic glioma', 'Disease', 'MESH:D005910', (159, 176))	('MGMT', 'Gene', (240, 244))	('glioma', 'Disease', 'MESH:D005910', (366, 372))	('O6-methylguanine-DNA methyltransferase', 'Gene', (200, 238))	('anaplastic glioma', 'Disease', (159, 176))	('anaplastic glioma', 'Disease', 'MESH:D005910', (355, 372))	('glioblastoma', 'Disease', 'MESH:D005909', (142, 154))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('O6-methylguanine-DNA methyltransferase', 'Gene', (0, 38))	('glioma', 'Phenotype', 'HP:0009733', (366, 372))	('anaplastic glioma', 'Disease', (355, 372))	('glioblastoma', 'Disease', 'MESH:D005909', (332, 344))	('MGMT', 'Gene', '4255', (113, 117))	('glioblastoma', 'Disease', (142, 154))	('MGMT', 'Gene', '4255', (240, 244))	('glioblastoma', 'Phenotype', 'HP:0012174', (142, 154))
10535	25558448	Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P <= 0.005) and longer PFS (P <= 0.036) compared to unmethylated tumors, despite overlapping activities.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Disease', (194, 200))	('lower', 'NegReg', (113, 118))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('MGMT', 'Gene', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('MGMT', 'Gene', '4255', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('activity', 'MPA', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('PFS', 'MPA', (152, 155))	('methylated', 'Var', (77, 87))
10536	25558448	PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P <= 0.005), and among unmethylated tumors with less than median activity (P <= 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('promote', 'PosReg', (232, 239))	('MGMT', 'Gene', (227, 231))	('greater', 'PosReg', (27, 34))	('tumors', 'Disease', (133, 139))	('PFS', 'MPA', (0, 3))	('MGMT', 'Gene', '4255', (227, 231))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('methylated', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('alkylator resistance', 'MPA', (240, 260))
10543	25558448	Better response in methylated tumors is unlikely due to lower MGMT activity alone.	('methylated', 'Var', (19, 29))	('MGMT', 'Gene', (62, 66))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('MGMT', 'Gene', '4255', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
10561	25558448	Hypermethylation of the MGMT promoter has also been observed in an appreciable fraction of GBMs and other gliomas.	('observed', 'Reg', (52, 60))	('MGMT', 'Gene', '4255', (24, 28))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('GBMs', 'Disease', (91, 95))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('Hypermethylation', 'Var', (0, 16))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('MGMT', 'Gene', (24, 28))
10564	25558448	The association of promoter methylation status with clinical response strongly suggests that absence or low expression of MGMT promotes alkylator sensitivity in vivo.	('alkylator sensitivity', 'MPA', (136, 157))	('promotes', 'PosReg', (127, 135))	('expression', 'MPA', (108, 118))	('MGMT', 'Gene', (122, 126))	('low', 'NegReg', (104, 107))	('MGMT', 'Gene', '4255', (122, 126))	('absence', 'Var', (93, 100))
10573	25558448	In all groups examined, less than median MGMT activity was associated with longer PFS following alkylators therapy.	('less', 'Var', (24, 28))	('MGMT', 'Gene', '4255', (41, 45))	('PFS', 'MPA', (82, 85))	('MGMT', 'Gene', (41, 45))
10579	25558448	GBMs harboring mutant IDH1/2 or with histological evidence of progression from a lower grade glioma (so-called secondary GBM) were excluded from this study.	('glioma', 'Disease', (93, 99))	('IDH1/2', 'Gene', (22, 28))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('mutant', 'Var', (15, 21))	('IDH1/2', 'Gene', '3417;3418', (22, 28))
10665	25558448	This observation suggests that the association of outcome with MGMT in all 84 AGs does not merely reflect the contribution of treatment-responsive oligodendroglial tumors harboring deletions on chromosomes 1p and 19q.	('deletions on', 'Var', (181, 193))	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('AGs', 'Chemical', '-', (78, 81))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (147, 170))	('oligodendroglial tumors', 'Disease', (147, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
10671	25558448	Finally, analysis of groups by alkylator regimen revealed significant inverse associations in dichotomous and continuous models between MGMT activity and PFS for the 42 tumors receiving PCV, the most frequent treatment regimen, as well as significant associations for the 42 tumors treated with other alkylating agents (Table 5).	('PCV', 'Var', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('PFS', 'Gene', (154, 157))	('tumors', 'Disease', (275, 281))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('inverse', 'NegReg', (70, 77))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('MGMT', 'Gene', '4255', (136, 140))	('MGMT', 'Gene', (136, 140))	('tumors', 'Disease', (169, 175))
10675	25558448	As noted earlier, CpG methylation of the MGMT promoter is associated with better outcome following alkylator therapy in GBMs, and methylation has been associated in some, but not all, studies, with low or absent MGMT activity .	('better', 'PosReg', (74, 80))	('methylation', 'Var', (130, 141))	('CpG methylation', 'Var', (18, 33))	('GBM', 'Phenotype', 'HP:0012174', (120, 123))	('MGMT', 'Gene', '4255', (212, 216))	('MGMT', 'Gene', (212, 216))	('MGMT', 'Gene', '4255', (41, 45))	('MGMT', 'Gene', (41, 45))
10682	25558448	3A, PFS for these unmethylated tumors with low MGMT activity remained significantly shorter than that for methylated tumors (5 vs. 7.5 months; P <= 0.005).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (31, 37))	('low', 'Var', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('MGMT', 'Gene', (47, 51))	('shorter', 'NegReg', (84, 91))	('MGMT', 'Gene', '4255', (47, 51))
10689	25558448	Promoter methylation was displayed by 59% (20/34) of AGs and was accompanied by significantly lower risk for progression (HR = 0.113; P <= 0.001) and longer PFS (56 vs. 8 months; P <= 0.001).	('AGs', 'Chemical', '-', (53, 56))	('Promoter methylation', 'Var', (0, 20))	('lower', 'NegReg', (94, 99))	('PFS', 'MPA', (157, 160))
10690	25558448	2, mean MGMT activity was 2.3-fold lower in methylated tumors (3.7 +- 2.7 vs. 11 +- 8.6 fmol/106 cells; P <= 0.0001).	('methylated', 'Var', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MGMT', 'Gene', '4255', (8, 12))	('MGMT', 'Gene', (8, 12))	('lower', 'NegReg', (35, 40))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))
10698	25558448	Here we present evidence that low MGMT activity is associated with better response to alkylating agent therapy and with promoter methylation in high-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('response', 'MPA', (74, 82))	('low', 'Var', (30, 33))	('promoter', 'MPA', (120, 128))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('MGMT', 'Gene', (34, 38))	('gliomas', 'Disease', (155, 162))	('better', 'PosReg', (67, 73))	('MGMT', 'Gene', '4255', (34, 38))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
10705	25558448	We used PFS after initiating alkylator therapy as an endpoint in our analyses to provide evidence that the association between activity and clinical outcome is a reflection of MGMT-mediated removal of potentially lethal O6-alkylguanine lesions.	('O6-alkylguanine', 'Chemical', '-', (220, 235))	('MGMT', 'Gene', '4255', (176, 180))	('O6-alkylguanine', 'Var', (220, 235))	('MGMT', 'Gene', (176, 180))
10716	25558448	We also found that the reduced risk of progression in GBMs and AGs displaying MGMT promoter methylation was accompanied by lower MGMT activity (Fig.	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('methylation', 'Var', (92, 103))	('lower', 'NegReg', (123, 128))	('MGMT', 'Gene', (129, 133))	('MGMT', 'Gene', '4255', (78, 82))	('MGMT', 'Gene', '4255', (129, 133))	('MGMT', 'Gene', (78, 82))	('reduced', 'NegReg', (23, 30))	('AGs', 'Chemical', '-', (63, 66))
10717	25558448	Our findings are in accord with those of others as well as the recent report that the fraction of cells immunopositive for MGMT is significantly lower in methylated GBMs.	('methylated', 'Var', (154, 164))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('MGMT', 'Gene', (123, 127))	('lower', 'NegReg', (145, 150))	('MGMT', 'Gene', '4255', (123, 127))
10718	25558448	These results support the hypothesis that the better treatment outcome associated with promoter methylation is due, at least in part, to decreased removal of O6-alkylguanine adducts.	('O6-alkylguanine', 'Chemical', '-', (158, 173))	('promoter methylation', 'Var', (87, 107))	('O6-alkylguanine adducts', 'MPA', (158, 181))	('removal', 'MPA', (147, 154))	('decreased', 'NegReg', (137, 146))
10719	25558448	However, we found that the range of MGMT activities overlapped appreciably between methylated and unmethylated GBMs and AGs.	('MGMT', 'Gene', (36, 40))	('MGMT', 'Gene', '4255', (36, 40))	('methylated', 'Var', (83, 93))	('AGs', 'Chemical', '-', (120, 123))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
10725	25558448	found that PFS was reduced for elderly patients with promoter methylated GBMs following concomitant treatment with corticosteroids and alkylators compared to treatment with alkylators alone.	('GBMs', 'Gene', (73, 77))	('patients', 'Species', '9606', (39, 47))	('PFS', 'MPA', (11, 14))	('promoter methylated', 'Var', (53, 72))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('reduced', 'NegReg', (19, 26))
10726	25558448	Nevertheless, we found that the prolonged PFS that accompanies low MGMT activity in methylated gliomas was not observed in unmethylated tumors with comparable activity (Fig.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('PFS', 'MPA', (42, 45))	('MGMT', 'Gene', '4255', (67, 71))	('gliomas', 'Disease', (95, 102))	('MGMT', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('methylated', 'Var', (84, 94))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('low', 'Var', (63, 66))
10727	25558448	This novel finding suggests that MGMT promoter methylation is associated with an alkylation sensitive phenotype that is absent in unmethylated gliomas with low MGMT activity.	('MGMT', 'Gene', (160, 164))	('associated', 'Reg', (62, 72))	('methylation', 'Var', (47, 58))	('MGMT', 'Gene', (33, 37))	('MGMT', 'Gene', '4255', (160, 164))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('MGMT', 'Gene', '4255', (33, 37))	('alkylation sensitive phenotype', 'MPA', (81, 111))	('gliomas', 'Disease', (143, 150))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))
10728	25558448	While the identity of the genes critical for clinical response remains to be completely elucidated, promoter CpG island methylation appears to silence the expression of a number of DNA repair activities in addition to MGMT, suggesting possible candidate genes that influence sensitivity to alkylating agent-based treatment.	('silence', 'NegReg', (143, 150))	('methylation', 'Var', (120, 131))	('expression', 'MPA', (155, 165))	('MGMT', 'Gene', (218, 222))	('DNA', 'MPA', (181, 184))	('MGMT', 'Gene', '4255', (218, 222))
10744	24390738	In this setting, the tumors acquired remarkably consistent genetic deletions at late stages of progression, similar to those deleted in human proneural Glioblastoma.	('human', 'Species', '9606', (136, 141))	('Glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Glioblastoma', 'Disease', (152, 164))	('Glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('genetic deletions', 'Var', (59, 76))
10745	24390738	Remarkably, deletion of p53 at the time of tumor initiation obviated the acquisition of later deletions, establishing a link between the proneural transcriptional network and the subtype-specific deletions selected during glioma progression.	('deletion', 'Var', (12, 20))	('p53', 'Gene', (24, 27))	('tumor initiation obviated', 'Disease', (43, 68))	('glioma', 'Disease', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('glioma', 'Disease', 'MESH:D005910', (222, 228))	('tumor initiation obviated', 'Disease', 'MESH:D009369', (43, 68))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
10747	24390738	Significant new evidence suggests that the acquisition of genetic alterations during tumor progression may be a deterministic rather than random process, influenced by multiple genetic and epigenetic factors.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('genetic alterations', 'Var', (58, 77))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
10751	24390738	Proneural gliomas bear characteristic genetic alterations, such as TP53 and IDH1 mutations, as well as PDGFRA amplification.	('IDH1', 'Gene', (76, 80))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('PDGFRA', 'Gene', (103, 109))	('PDGFRA', 'Gene', '5156', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('IDH1', 'Gene', '3417', (76, 80))	('TP53', 'Gene', '7157', (67, 71))	('mutations', 'Var', (81, 90))	('TP53', 'Gene', (67, 71))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
10754	24390738	To address this question, we used a murine model of proneural glioma induced by overexpression of the PDGF oncogene, and inactivation of the Pten tumor suppressor.	('overexpression', 'PosReg', (80, 94))	('Pten', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('murine', 'Species', '10090', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('tumor', 'Disease', (146, 151))	('inactivation', 'Var', (121, 133))	('induced by', 'Reg', (69, 79))	('PDGF', 'Gene', (102, 106))	('glioma', 'Disease', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
10761	24390738	Our analysis showed remarkable consistency in the pattern of spontaneously occurring copy number alterations, including a subset of genes commonly deleted in both human and murine proneural tumors, thus establishing a temporal relationship between tumor phenotype and genotype.	('murine', 'Species', '10090', (173, 179))	('copy number alterations', 'Var', (85, 108))	('tumor', 'Disease', (248, 253))	('proneural tumors', 'Disease', 'MESH:D009369', (180, 196))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('proneural tumors', 'Disease', (180, 196))	('human', 'Species', '9606', (163, 168))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
10763	24390738	Notably, upfront deletion of p53 facilitates glioma progression, without requiring accumulation of additional proneural specific deletions.	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('p53', 'Gene', (29, 32))	('deletion', 'Var', (17, 25))	('facilitates', 'PosReg', (33, 44))	('glioma', 'Disease', (45, 51))
10764	24390738	The *PTEN-/-, *PTEN-/-p53-/- and *p53 tumors were generated by injecting PIC virus into the subcortical white matter of adult mice harboring floxed Pten or floxed p53, as previously described.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mice', 'Species', '10090', (126, 130))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('floxed Pten', 'Var', (141, 152))	('floxed', 'Var', (156, 162))
10774	24390738	The log2 ratio signal for tumor/non-tumor gene copy number for a probe that hybridizes the Cre/lox-mediated Pten deletion showed significantly lower Log2 ratio for *PTEN 35 dpi tumors than either *PTEN or *PTEN/p53 end-stage tumors, suggesting a smaller fraction of tumor DNA on the former than the later groups, biasing against finding deletions in *PTEN 35 dpi tumors but not on *PTEN/p53 end-stage tumors (Supplementary Figure 1).	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('deletions', 'Var', (337, 346))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', (266, 271))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (401, 407))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('end-stage tumors', 'Disease', 'MESH:D007676', (391, 407))	('tumors', 'Phenotype', 'HP:0002664', (363, 369))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('end-stage tumors', 'Disease', 'MESH:D007676', (215, 231))	('end-stage tumors', 'Disease', (391, 407))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (177, 182))	('dpi', 'Chemical', '-', (359, 362))	('tumors', 'Disease', (401, 407))	('tumors', 'Disease', (363, 369))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('end-stage tumors', 'Disease', (215, 231))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (363, 368))	('dpi', 'Chemical', '-', (173, 176))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('Log2 ratio', 'MPA', (149, 159))	('tumors', 'Disease', 'MESH:D009369', (401, 407))	('tumors', 'Disease', 'MESH:D009369', (363, 369))	('deletion', 'Var', (113, 121))	('lower', 'NegReg', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('*PTEN 35 dpi', 'Var', (350, 362))	('tumors', 'Disease', (177, 183))	('tumors', 'Disease', (225, 231))	('tumor', 'Disease', (401, 406))
10792	24390738	This analysis revealed a collection of copy number alterations, mostly deletions that increased in number over time, and were consistently seen at specific loci during later time points of *PTEN tumor progression (Figure 1B and C).	('deletions', 'Var', (71, 80))	('tumor', 'Disease', (195, 200))	('*PTEN', 'Gene', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
10793	24390738	*PTEN tumors acquired recurrent deletions with remarkable consistency, including 541 genes deleted in 75 to 100% of end-stage tumors (statistically significant by random permutation test, p <= 0.05) (Supplementary Table 1).	('PTEN tumors', 'Disease', 'MESH:D006223', (1, 12))	('deletions', 'Var', (32, 41))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('end-stage tumors', 'Disease', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('PTEN tumors', 'Disease', (1, 12))	('end-stage tumors', 'Disease', 'MESH:D007676', (116, 132))
10795	24390738	However, by 35 dpi, gene deletions were detected with similar frequency to end-stage *PTEN tumors (Figure 1C).	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('dpi', 'Chemical', '-', (15, 18))	('PTEN tumors', 'Disease', (86, 97))	('PTEN tumors', 'Disease', 'MESH:D006223', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gene deletions', 'Var', (20, 34))
10796	24390738	Notably, CGH was able to detect the Cre-mediated deletion of Pten as early as 21 dpi (Supplementary Figure 1), arguing against the possibility that the differences in spontaneous deletions seen in early versus late stage tumors are merely due to changes in the fraction of retrovirus-infected tumor cells (harbouring Cre-mediated Pten deletion).	('dpi', 'Chemical', '-', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('Pten', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('deletion', 'Var', (49, 57))	('tumors', 'Disease', (221, 227))	('retrovirus-infected tumor', 'Disease', (273, 298))	('retrovirus-infected tumor', 'Disease', 'MESH:D012192', (273, 298))
10797	24390738	Rather, these results support the conclusion that the spontaneous deletions are acquired in a subset of tumor cells and then selected for during tumor progression.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (145, 150))	('deletions', 'Var', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
10800	24390738	Of these gene deletions, 75 were significantly and selectively enriched in the proneural subtype of human GBM (p <= 0.05, FDR <= 0.1)(Figure 2A, Supplementary Table 4).	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('human', 'Species', '9606', (100, 105))	('proneural subtype of human GBM', 'Disease', (79, 109))	('deletions', 'Var', (14, 23))	('enriched', 'Reg', (63, 71))
10803	24390738	Interestingly the putative tumor suppressor gene CIC was deleted in 6/8 *PTEN 35 dpi and 5/8 *PTEN end-stage mouse tumors.	('CIC', 'Gene', (49, 52))	('deleted', 'Var', (57, 64))	('dpi', 'Chemical', '-', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('mouse', 'Species', '10090', (109, 114))
10804	24390738	Situated in the 19q locus in the human genome, CIC is often deleted or mutated in human oligodendrogliomas, as well as in 13.6% of proneural GBM from TCGA dataset.	('oligodendrogliomas', 'Disease', (88, 106))	('mutated', 'Var', (71, 78))	('human', 'Species', '9606', (33, 38))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('GBM', 'Phenotype', 'HP:0012174', (141, 144))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (88, 106))	('CIC', 'Gene', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('human', 'Species', '9606', (82, 87))
10805	24390738	We also compared the distribution of the proneural-specific deletions with other genetic alterations characteristic of proneural glioma, including PDGFRA amplification, TP53 mutations and IDH1 mutations, which coincide with a CpG island hypermethylation phenotype.	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('PDGFRA', 'Gene', (147, 153))	('deletions', 'Var', (60, 69))	('PDGFRA', 'Gene', '5156', (147, 153))	('TP53', 'Gene', '7157', (169, 173))	('IDH1', 'Gene', (188, 192))	('mutations', 'Var', (193, 202))	('TP53', 'Gene', (169, 173))	('IDH1', 'Gene', '3417', (188, 192))	('glioma', 'Disease', (129, 135))	('mutations', 'Var', (174, 183))
10806	24390738	Deletion of 11q and 17p were overrepresented within proneural GBM patients bearing PDGFRA amplification (p <= 0.05) and deletion of 11p and 19q were overrepresented within proneural GBM patients bearing IDH1 mutations (p <= 0.01) (Supplementary Table 5), which in the case of 19q, resembles the scenario described in oligodendrogliomas.	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('patients', 'Species', '9606', (186, 194))	('PDGFRA', 'Gene', (83, 89))	('GBM', 'Phenotype', 'HP:0012174', (182, 185))	('mutations', 'Var', (208, 217))	('PDGFRA', 'Gene', '5156', (83, 89))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (317, 335))	('IDH1', 'Gene', '3417', (203, 207))	('overrepresented', 'PosReg', (149, 164))	('patients', 'Species', '9606', (66, 74))	('deletion', 'Var', (120, 128))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('gliomas', 'Phenotype', 'HP:0009733', (328, 335))	('IDH1', 'Gene', (203, 207))	('overrepresented', 'PosReg', (29, 44))	('oligodendrogliomas', 'Disease', (317, 335))	('Deletion', 'Var', (0, 8))
10808	24390738	This allowed for direct investigation of the temporal relationship between genetic alterations and proneural phenotype during tumor progression.	('genetic alterations', 'Var', (75, 94))	('proneural', 'MPA', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
10809	24390738	To evaluate whether the proneural phenotype precedes deletion of these genes, we performed RNA-Seq analysis of early and late stage tumors and used this data to classify tumor phenotype according to the Verhaak et al., gene set.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('deletion', 'Var', (53, 61))	('tumor', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
10810	24390738	We found that at 21 dpi, a time point that precedes the presence of highly recurrent gene deletions, murine gliomas already had higher resemblance to proneural glioma than to any other subgroup (Figure 3A).	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('glioma', 'Disease', (108, 114))	('murine', 'Species', '10090', (101, 107))	('glioma', 'Disease', (160, 166))	('dpi', 'Chemical', '-', (20, 23))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('deletions', 'Var', (90, 99))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
10812	24390738	Furthermore, differential gene expression analysis showed that OPC genes that are part of the proneural gene set are significantly higher in both *PTEN 21 dpi and *PTEN end-stage in comparison to expression in NB specimens (Figure 3B).	('OPC genes', 'Gene', (63, 72))	('*PTEN', 'Var', (163, 168))	('dpi', 'Chemical', '-', (155, 158))	('higher', 'PosReg', (131, 137))	('*PTEN 21 dpi', 'Var', (146, 158))
10817	24390738	Notably, p53 was identified as a proneural MR of both early and late stage tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p53', 'Var', (9, 12))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
10825	24390738	Moreover, TP53 mutations are enriched within the proneural subtype of human GBM.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('human', 'Species', '9606', (70, 75))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('TP53', 'Gene', '7157', (10, 14))
10827	24390738	Furthermore, inactivation of p53, via direct mutations and deletions of the TP53 gene or via genetic alterations of other genes that are part of the p53 transcriptional network, will likely provide a powerful selective advantage to proneural glioma cells.	('mutations', 'Var', (45, 54))	('inactivation', 'Var', (13, 25))	('TP53', 'Gene', '7157', (76, 80))	('deletions', 'Var', (59, 68))	('glioma', 'Disease', (242, 248))	('TP53', 'Gene', (76, 80))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))
10829	24390738	To investigate this hypothesis, we analyzed the genome of a cohort of PDGF+PTEN-/-p53-/- (*PTEN/p53) mouse tumors.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mouse', 'Species', '10090', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('PDGF+PTEN-/-p53-/-', 'Var', (70, 88))
10831	24390738	The *PTEN/p53 tumors have a proneural expression pattern similar to that of *PTEN tumors, however the *PTEN/p53 tumors more rapidly progress to GBM.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('PTEN tumors', 'Disease', 'MESH:D006223', (77, 88))	('tumors', 'Disease', (82, 88))	('proneural expression pattern', 'MPA', (28, 56))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('GBM', 'Phenotype', 'HP:0012174', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('progress', 'PosReg', (132, 140))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('*PTEN/p53', 'Var', (102, 111))	('PTEN tumors', 'Disease', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (112, 118))
10835	24390738	Gene copy number analysis revealed that *PTEN/p53 tumors accumulated gene deletions with a significantly lower frequency than *PTEN end-stage tumors (Figure 5) whereas gene amplifications occurred with a low frequency in both models (Figure 5 and Supplementary Table 2).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('end-stage tumors', 'Disease', (132, 148))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('gene deletions', 'MPA', (69, 83))	('end-stage tumors', 'Disease', 'MESH:D007676', (132, 148))	('tumors', 'Disease', (142, 148))	('*PTEN/p53', 'Var', (40, 49))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
10838	24390738	*PTEN/p53 tumors had a significantly shorter survival than *PTEN lesions (Log-rank p <= 0.01) (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('*PTEN/p53', 'Var', (0, 9))	('survival', 'MPA', (45, 53))	('shorter', 'NegReg', (37, 44))
10842	24390738	These findings, and the similar Ki-67 labelling, suggest that *PTEN tumor cells evolve over time into a more aggressive and proliferative phenotype, which, in the end-stage tumors, is comparable to that seen in *PTEN/p53 tumors.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('end-stage tumors', 'Disease', 'MESH:D007676', (163, 179))	('*PTEN', 'Var', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', (221, 227))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('end-stage tumors', 'Disease', (163, 179))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
10846	24390738	This down-regulations coincided with the accumulation of deletions seen in *PTEN tumors, suggesting a possible functional relationship between the deleted genes and the expression of p53 and its targets.	('deletions', 'Var', (57, 66))	('PTEN tumors', 'Disease', (76, 87))	('down-regulations', 'NegReg', (5, 21))	('PTEN tumors', 'Disease', 'MESH:D006223', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
10847	24390738	In support of this idea, Ingenuity-based analysis identified numerous previously described functional interactions between the gene deletions encountered in 75-100% of *PTEN tumors with p53 and/or its transcriptional targets that are established tumor suppressors (Figure 6C).	('tumor', 'Disease', (174, 179))	('interactions', 'Interaction', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('PTEN tumors', 'Disease', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('PTEN tumors', 'Disease', 'MESH:D006223', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (246, 251))	('deletions', 'Var', (132, 141))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
10848	24390738	*PTEN tumors also acquired non-synonymous mutations in Trp53.	('non-synonymous mutations', 'Var', (27, 51))	('PTEN tumors', 'Disease', 'MESH:D006223', (1, 12))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Trp53', 'Gene', (55, 60))	('PTEN tumors', 'Disease', (1, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
10849	24390738	Sanger sequencing analysis of Trp53 (exons 5 through 9) revealed that one third of the end-stage *PTEN tumors (n=5/15) had acquired missense mutations leading to a single amino acid substitutions within the DNA-binding domain of p53.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('DNA-binding', 'Interaction', (207, 218))	('PTEN tumors', 'Disease', 'MESH:D006223', (98, 109))	('p53', 'Gene', (229, 232))	('missense mutations', 'Var', (132, 150))	('PTEN tumors', 'Disease', (98, 109))
10850	24390738	Of note, all of these mutations were located in mutational "hotspots" in the p53 gene, which correspond to the most common mutations seen in human GBM (Figure 6D and Supplementary Figure 5).	('p53', 'Gene', (77, 80))	('human', 'Species', '9606', (141, 146))	('GBM', 'Phenotype', 'HP:0012174', (147, 150))	('mutations', 'Var', (22, 31))
10851	24390738	Previous studies have shown that these mutated alleles are expressed, but have abnormal transcriptional activity and loss of p53 tumor suppressor function.	('transcriptional activity', 'MPA', (88, 112))	('loss', 'NegReg', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('p53', 'Gene', (125, 128))	('mutated', 'Var', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
10852	24390738	Examination of the RNA-Seq data of *PTEN end-stage tumors confirmed the transcription of the mutated allele in two cases that had paired RNA/DNA sequencing data.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('end-stage tumors', 'Disease', 'MESH:D007676', (41, 57))	('mutated', 'Var', (93, 100))	('transcription', 'MPA', (72, 85))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('end-stage tumors', 'Disease', (41, 57))
10853	24390738	Sanger sequencing of 2 cell lines derived from *PTEN tumors also showed Trp53 mutations, with the presence of a single peak, indicative of LOH with loss of the wild-type allele.	('PTEN tumors', 'Disease', (48, 59))	('Trp53', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('PTEN tumors', 'Disease', 'MESH:D006223', (48, 59))
10854	24390738	Immunohistochemical analysis of one of these cells lines, which harbors a single mutant allele (R175H), showed nuclear staining for p53 (Supplementary Figure 5).	('p53', 'Protein', (132, 135))	('R175H', 'Mutation', 'rs28934578', (96, 101))	('R175H', 'Var', (96, 101))
10855	24390738	A key question within the field of cancer biology is the cause-effect and temporal relationship that exists between tumor phenotype and genotype, especially in cases in which a particular genetic alteration is associated with a specific phenotype.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('associated', 'Reg', (210, 220))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('alteration', 'Var', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (116, 121))	('cancer', 'Disease', (35, 41))
10859	24390738	Our results also suggest that the selection of specific genetic alterations was influenced by initial conditions of gliomagenesis, which include the initiating genetic alteration and the cellular context in which these occur.	('glioma', 'Disease', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))	('alteration', 'Var', (168, 178))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('genetic alteration', 'Var', (160, 178))
10860	24390738	Nevertheless, this regulatory network had a strong influence on the selective pressure for these deletions during tumor progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('deletions', 'Var', (97, 106))	('influence', 'Reg', (51, 60))
10861	24390738	This point was illustrated by the fact that upfront deletion of Trp53, a highly interconnected MR transcription factor identified in the proneural regulatory network, accelerated tumor progression while obviating the selection of the highly recurrent deletions seen on the *PTEN tumor model.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Disease', (279, 284))	('accelerated', 'PosReg', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))	('deletion', 'Var', (52, 60))	('Trp53', 'Gene', (64, 69))
10865	24390738	Several previous studies have shown that deleting p53, in combination with other genetic alterations, will facilitate the formation of brain tumors.	('facilitate', 'PosReg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('brain tumors', 'Disease', (135, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('deleting', 'Var', (41, 49))	('p53', 'Gene', (50, 53))	('brain tumors', 'Phenotype', 'HP:0030692', (135, 147))	('brain tumors', 'Disease', 'MESH:D001932', (135, 147))
10867	24390738	The survival curve for the PDGF+/p53-/- (*p53) model is significantly longer than that seen on *PTEN/p53 tumors, and significantly shorter than that seen on *PTEN tumors (Supplementary Figure 6).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('PTEN tumors', 'Disease', 'MESH:D006223', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('longer', 'PosReg', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('shorter', 'NegReg', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('PTEN tumors', 'Disease', (158, 169))	('PDGF+/p53-/-', 'Var', (27, 39))
10868	24390738	Similar to the *PTEN and *PTEN/p53 tumors, the *p53 tumors express high levels of glial progenitor markers and have a proneural phenotype (Supplementary Figure 6, Supplementary Table 6).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('*p53', 'Var', (47, 51))	('glial progenitor markers', 'MPA', (82, 106))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (35, 41))	('proneural phenotype', 'MPA', (118, 137))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
10875	24390738	Chow et al., reported the genetic alterations in murine brain tumors, some of which had a proneural phenotype, induced by deleting various combinations of 3 tumor suppressors; Pten, Trp53 and Rb.	('tumor', 'Disease', (157, 162))	('brain tumors', 'Disease', (56, 68))	('induced', 'Reg', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (62, 67))	('brain tumors', 'Disease', 'MESH:D001932', (56, 68))	('deleting', 'Var', (122, 130))	('Trp53', 'Protein', (182, 187))	('brain tumors', 'Phenotype', 'HP:0030692', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Pten', 'Gene', (176, 180))	('murine', 'Species', '10090', (49, 55))
10879	24390738	This approach takes advantage of the phenotypic and genetic similarities between the mouse tumor models and human cancer, as well as the species-specific differences in genomic architecture and size of the copy number alterations.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('copy', 'Var', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('cancer', 'Disease', (114, 120))
10881	24390738	Furthermore, some genes contained within a single deletion in human gliomas were distributed into multiple deletions on separate chromosomes in mouse gliomas, suggesting independent selection pressure for their loss (Supplementary Figure 2).	('mouse', 'Species', '10090', (144, 149))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('deletion', 'Var', (50, 58))	('human', 'Species', '9606', (62, 67))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
10882	24390738	These relationships included correlations of some of these deletions with established proneural-specific oncogenic genetic alterations, such as in the case of 11q and 17p with PDGFR amplification, or 11p and 19q with IDH1R132 mutation, as well as correlations among the deletions that we encountered.	('PDGFR', 'Gene', (176, 181))	('PDGFR', 'Gene', '5159', (176, 181))	('mutation', 'Var', (226, 234))	('IDH1', 'Gene', (217, 221))	('amplification', 'Var', (182, 195))	('IDH1', 'Gene', '3417', (217, 221))
10956	33611709	Ablation of > 90% of BMRS was associated with a higher likelihood of improved KPS.	('BMRS', 'Chemical', '-', (21, 25))	('KPS', 'Disease', (78, 81))	('Ablation', 'Var', (0, 8))	('improved', 'PosReg', (69, 77))
11213	32366879	Engelman and co-workers suggested in 2008 that combining PI3K and MEK inhibitors can have a synergistic therapeutic effect in a lung cancer model.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('MEK', 'Gene', (66, 69))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('PI3K', 'Var', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
11216	32366879	Trametinib is the first FDA-approved MEK1/2 inhibitor currently in use for unresectable and metastatic melanoma with BRAF V600E or V600K mutation in combination with Dabrafenib.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('V600K', 'Var', (131, 136))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('Dabrafenib', 'Chemical', 'MESH:C561627', (166, 176))	('unresectable', 'Disease', (75, 87))	('MEK1/2', 'Gene', '5604;5605', (37, 43))	('BRAF', 'Var', (117, 121))	('MEK1/2', 'Gene', (37, 43))	('V600E', 'Mutation', 'rs113488022', (122, 127))	('V600K', 'Mutation', 'rs121913227', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
11220	32366879	First, we evaluated the effect of the highly specific MEK1/2 inhibitor Trametinib on the metabolic activity of two established GB cell lines, A172 and U87MG (Fig.	('U87MG', 'Var', (151, 156))	('metabolic activity', 'MPA', (89, 107))	('GB', 'Phenotype', 'HP:0012174', (127, 129))	('Trametinib', 'Gene', (71, 81))	('Trametinib', 'Chemical', 'MESH:C560077', (71, 81))	('MEK1/2', 'Gene', '5604;5605', (54, 60))	('MEK1/2', 'Gene', (54, 60))	('U87MG', 'CellLine', 'CVCL:0022', (151, 156))
11234	32366879	As our data so far indicate that Trametinib treatment has a predominantly antiproliferative effect affecting the cell cycle distribution which, in turn, mediates sensitivity to radiotherapy, we devised three different sequence combinations of inhibitor treatment followed by three doses of 2 Gray, mimicking the clinical situation during the radiotherapy phase of GB therapy.	('antiproliferative', 'MPA', (74, 91))	('GB', 'Phenotype', 'HP:0012174', (364, 366))	('affecting', 'Reg', (99, 108))	('Trametinib', 'Chemical', 'MESH:C560077', (33, 43))	('inhibitor', 'Var', (243, 252))	('cell', 'MPA', (113, 117))
11248	32366879	Importantly, the presence of Pictilisib appears to prevent the sprouting of Trametinib-treated cell clusters (Fig.	('Trametinib', 'Chemical', 'MESH:C560077', (76, 86))	('Pictilisib', 'Gene', (29, 39))	('Pictilisib', 'Chemical', 'MESH:C532162', (29, 39))	('prevent', 'NegReg', (51, 58))	('presence', 'Var', (17, 25))	('sprouting', 'CPA', (63, 72))
11267	32366879	Alterations in the v-raf murine sarcoma viral oncogene homolog B (BRAF) protein, the upstream activator of the MEK-ERK signalling cascade, are frequently found in both, paediatric and adult brain tumours, but extremely rare in GB, present in only 1-2% of these tumours.	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('Alterations', 'Var', (0, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('found', 'Reg', (154, 159))	('brain tumours', 'Phenotype', 'HP:0030692', (190, 203))	('tumours', 'Disease', (261, 268))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (19, 64))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', (19, 64))	('adult brain tumours', 'Disease', 'MESH:D001932', (184, 203))	('tumours', 'Phenotype', 'HP:0002664', (261, 268))	('adult brain tumours', 'Disease', (184, 203))	('tumours', 'Disease', (196, 203))	('tumours', 'Disease', 'MESH:D009369', (261, 268))	('brain tumour', 'Phenotype', 'HP:0030692', (190, 202))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('GB', 'Phenotype', 'HP:0012174', (227, 229))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('BRAF', 'Gene', (66, 70))
11269	32366879	Enhanced EGFR activity by gene amplification or mutation is found in more than 57% of all GBs, reducing the potential need for additional activating mutations further downstream of the signalling cascade.	('activity', 'MPA', (14, 22))	('GB', 'Phenotype', 'HP:0012174', (90, 92))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutation', 'Var', (48, 56))	('gene amplification', 'Var', (26, 44))	('Enhanced', 'PosReg', (0, 8))
11290	32366879	Trametinib (GSK1120212) - Selleckchem, Housten, Texas, USA Temozolomide (TMZ) - Sigma-Aldrich, Steinheim, Germany Pictilisib (GDC-0941) - Selleckchem The irradiation device used (HWM D400) was manufactured by Walischmiller Engineering GmbH (Markdorf, Germany).	('Temozolomide', 'Chemical', 'MESH:D000077204', (59, 71))	('GSK1120212', 'Var', (12, 22))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('GSK1120212', 'Chemical', 'MESH:C560077', (12, 22))	('TMZ', 'Chemical', 'MESH:D000077204', (73, 76))	('Pictilisib', 'Chemical', 'MESH:C532162', (114, 124))	('Aldrich', 'Disease', (86, 93))	('Aldrich', 'Disease', 'MESH:D014923', (86, 93))	('GDC-0941', 'Chemical', 'MESH:C532162', (126, 134))
11312	31963507	High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression.	('expression', 'MPA', (19, 29))	('High', 'Var', (0, 4))	('AIF1', 'Gene', (14, 18))	('TSPO', 'Gene', (5, 9))	('decrease', 'NegReg', (65, 73))	('patient', 'Species', '9606', (77, 84))	('patient survival', 'CPA', (77, 93))
11337	31963507	Mouse transgenic GSCs used to model genetic GBM subtypes were derived from transgenic neural precursor cells that were additionally transduced to carry typical driver mutations for proneural (p53KOPDGFB) or classical (cdkn2aKOEGFRvIII) GBM subtypes and were kept under stem cell-like conditions until orthotopic implantation into immunocompetent mice.	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('p53', 'Gene', '22060', (192, 195))	('GBM', 'Phenotype', 'HP:0012174', (236, 239))	('mutations', 'Var', (167, 176))	('Mouse', 'Species', '10090', (0, 5))	('p53', 'Gene', (192, 195))	('mice', 'Species', '10090', (346, 350))
11348	31963507	By immunofluorescent staining against TSPO, the distinction between tumor-free brain and tumor samples became obvious when using murine Gl261, as well as the classical cdkn2aKOEGFRvIII or proneural 53KOPDGFB GSCs (Figure 2B).	('tumor', 'Disease', (68, 73))	('murine', 'Var', (129, 135))	('murine', 'Species', '10090', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
11371	31963507	Looking at patient survival, we found that high TSPO or AIF1 expression was associated with significantly shorter survival, while high SLC7A5 (=LAT1) levels were correlated with an increased survival (Figure 6B).	('survival', 'MPA', (114, 122))	('shorter', 'NegReg', (106, 113))	('high', 'Var', (43, 47))	('SLC7A5', 'Gene', (135, 141))	('AIF1', 'Gene', (56, 60))	('patient', 'Species', '9606', (11, 18))	('increased', 'PosReg', (181, 190))	('TSPO', 'Gene', (48, 52))	('SLC7A5', 'Gene', '8140', (135, 141))
11380	31963507	Additionally, in almost all types of CNS pathologies, TSPO levels are increased, and in some psychiatric disorders, such as schizophrenia, the TSPO signal in PET is decreased.	('decreased', 'NegReg', (165, 174))	('pathologies', 'Var', (41, 52))	('TSPO signal in PET', 'MPA', (143, 161))	('increased', 'PosReg', (70, 79))	('schizophrenia', 'Phenotype', 'HP:0100753', (124, 137))	('TSPO levels', 'MPA', (54, 65))	('psychiatric disorders', 'Disease', 'MESH:D001523', (93, 114))	('CNS', 'Disease', (37, 40))	('psychiatric disorders', 'Phenotype', 'HP:0000708', (93, 114))	('psychiatric disorders', 'Disease', (93, 114))	('schizophrenia', 'Disease', 'MESH:D012559', (124, 137))	('schizophrenia', 'Disease', (124, 137))
11397	31963507	High TSPO expression in astrocytoma has been shown to correlate with shorter survival and higher proliferation.	('astrocytoma', 'Disease', 'MESH:D001254', (24, 35))	('High', 'Var', (0, 4))	('astrocytoma', 'Disease', (24, 35))	('astrocytoma', 'Phenotype', 'HP:0009592', (24, 35))	('TSPO', 'Gene', (5, 9))	('shorter', 'NegReg', (69, 76))	('expression', 'MPA', (10, 20))	('higher', 'PosReg', (90, 96))	('rat', 'Species', '10116', (104, 107))
11411	31963507	For that group of patients, our results would propose that a high expression of TSPO could be a marker for decreased survival.	('TSPO', 'Gene', (80, 84))	('high', 'Var', (61, 65))	('decreased', 'NegReg', (107, 116))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (117, 125))
11508	32002519	Mechanistically, we observed that MCT4 depletion induces anaplerotic glutaminolysis and abrogates de novo pyrimidine biosynthesis.	('depletion', 'Var', (39, 48))	('de novo pyrimidine biosynthesis', 'MPA', (98, 129))	('abrogates', 'NegReg', (88, 97))	('anaplerotic glutaminolysis', 'Disease', 'None', (57, 83))	('induces', 'Reg', (49, 56))	('anaplerotic glutaminolysis', 'Disease', (57, 83))	('pyrimidine', 'Chemical', 'MESH:C030986', (106, 116))	('MCT4', 'Gene', (34, 38))
11513	32002519	Using a combined metabolomics and transcriptomics approach, we show that MCT4 depletion significantly reduces tumorigenicity by inhibition of de novo pyrimidine biosynthesis and promotes accumulation of DNA damage.	('reduces', 'NegReg', (102, 109))	('depletion', 'Var', (78, 87))	('inhibition', 'NegReg', (128, 138))	('promotes', 'PosReg', (178, 186))	('pyrimidine', 'Chemical', 'MESH:C030986', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('DNA damage', 'MPA', (203, 213))	('MCT4', 'Gene', (73, 77))	('accumulation', 'MPA', (187, 199))	('de novo pyrimidine biosynthesis', 'MPA', (142, 173))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
11514	32002519	The combination of MCT4 depletion and adjuvant radiation in vivo is more effective than either treatment alone thus highlighting the potential for a novel GBM treatment strategy.	('GBM', 'Disease', (155, 158))	('MCT4', 'Protein', (19, 23))	('depletion', 'Var', (24, 33))	('GBM', 'Disease', 'MESH:D005909', (155, 158))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))
11515	32002519	MCT4 Depletion in Brain Cancer-Associated Hypoxia Inhibits de novo pyrimidine biosynthesis:leading to the accumulation of DNA damage and reduced cell survival.	('Depletion', 'Var', (5, 14))	('Depletion in Brain', 'Phenotype', 'HP:0012444', (5, 23))	('Brain Cancer', 'Phenotype', 'HP:0030692', (18, 30))	('Inhibits', 'NegReg', (50, 58))	('accumulation', 'PosReg', (106, 118))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cell survival', 'CPA', (145, 158))	('DNA damage', 'MPA', (122, 132))	('MCT4', 'Gene', (0, 4))	('Brain Cancer-Associated Hypoxia', 'Disease', 'MESH:D002534', (18, 49))	('de novo pyrimidine biosynthesis', 'MPA', (59, 90))	('pyrimidine', 'Chemical', 'MESH:C030986', (67, 77))	('reduced', 'NegReg', (137, 144))	('Brain Cancer-Associated Hypoxia', 'Disease', (18, 49))
11524	32002519	HSR-GBM1 and HSR040821 were a kind gift from Dr. Angelo Vescovi and were established from freshly resected GBM tumors and passaged as previously described.	('HSR-GBM1', 'Gene', '114564', (0, 8))	('HSR040821', 'Chemical', 'MESH:C103510', (13, 22))	('GBM', 'Disease', (4, 7))	('HSR-GBM1', 'Gene', (0, 8))	('GBM', 'Disease', 'MESH:D005909', (4, 7))	('GBM', 'Disease', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('HSR040821', 'Var', (13, 22))	('GBM', 'Disease', 'MESH:D005909', (107, 110))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))
11527	32002519	HSR-GBM1 and HSR040821 are EGFRWT, IDH1WT.HSR-GBM1 is P53WT while HSR040821 carries an S278P point mutation in the P53 gene.	('HSR-GBM1', 'Gene', '114564', (0, 8))	('P53', 'Gene', (54, 57))	('HSR040821', 'Chemical', 'MESH:C103510', (13, 22))	('HSR-GBM1', 'Gene', (0, 8))	('HSR-GBM1', 'Gene', '114564', (42, 50))	('HSR040821', 'Chemical', 'MESH:C103510', (66, 75))	('HSR-GBM1', 'Gene', (42, 50))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('S278P point', 'Var', (87, 98))	('P53', 'Gene', '22060', (115, 118))	('P53', 'Gene', '22060', (54, 57))	('S278P', 'Mutation', 'rs17849781', (87, 92))	('P53', 'Gene', (115, 118))	('HSR040821', 'Var', (66, 75))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))
11541	32002519	MCT4 depletion significantly impaired growth by at least 40% in both HSR-GBM1 and HSR040821 (Figure 1A and B).	('depletion', 'Var', (5, 14))	('HSR-GBM1', 'Gene', '114564', (69, 77))	('impaired', 'NegReg', (29, 37))	('MCT4', 'MPA', (0, 4))	('HSR-GBM1', 'Gene', (69, 77))	('HSR040821', 'Var', (82, 91))	('growth', 'MPA', (38, 44))	('HSR040821', 'Chemical', 'MESH:C103510', (82, 91))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))
11543	32002519	MCT4 depletion resulted in a 60-90% (****P < .0001, one-way ANOVA) and 80-83% reduction (****P < .0001, ***P < .001, one-way ANOVA) in the number of clonogenic neurospheres (sphere diameter >100 mum), in HSR-GBM1 and HSR040821, respectively (Figure 1C and D).	('depletion', 'Var', (5, 14))	('HSR040821', 'Chemical', 'MESH:C103510', (217, 226))	('reduction', 'NegReg', (78, 87))	('HSR-GBM1', 'Gene', '114564', (204, 212))	('HSR-GBM1', 'Gene', (204, 212))	('MCT4', 'Protein', (0, 4))	('GBM', 'Phenotype', 'HP:0012174', (208, 211))
11564	32002519	To directly visualize and quantify DNA damage, we performed immunostaining against gammaH2AX, a common marker used to label double-strand breaks (DSBs) in DNA, in hypoxic neurospheres where MCT4 expression was inhibited either conditionally or constitutively.	('gammaH2AX', 'Gene', (83, 92))	('hypoxic neurospheres', 'Disease', (163, 183))	('hypoxic neurospheres', 'Disease', 'MESH:D000860', (163, 183))	('double-strand breaks', 'Var', (124, 144))	('gammaH2AX', 'Gene', '15270', (83, 92))
11565	32002519	qPCR analysis confirmed MCT4 knockdown and Western blot analyses showed a large increase in the amount of phosphorylated H2AX (gammaH2AX) (Supplementary Figure S3A and B).	('gammaH2AX', 'Gene', (127, 136))	('knockdown', 'Var', (29, 38))	('H2AX', 'Gene', (121, 125))	('H2AX', 'Gene', (132, 136))	('increase', 'PosReg', (80, 88))	('S3A and B', 'Gene', '252903;11778', (160, 169))	('H2AX', 'Gene', '15270', (121, 125))	('H2AX', 'Gene', '15270', (132, 136))	('gammaH2AX', 'Gene', '15270', (127, 136))
11567	32002519	Quantification of 2 independent experiments is shown in Figure 4D, with HSR-GBM1 showing an averaged increase from 24% to 54.7% and 45.5% (constitutive sh1 and sh2, respectively; ***P < .001, *P < .05 one-way ANOVA), HSR040821 showing an averaged increase from 9.8% to 31% and 67% (sh1 and sh2, respectively; ***P < .001, ****P < .0001 one-way ANOVA), and HSR-GBM1 shMCT4 Tet-ON showing an averaged increase from 18% to 46% (****P < .0001 student t test).	('HSR-GBM1', 'Gene', (356, 364))	('HSR-GBM1 shMCT4', 'Gene', '80879', (356, 371))	('sh2', 'Gene', '100125854', (290, 293))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('sh1', 'Gene', (282, 285))	('sh2', 'Gene', (290, 293))	('HSR040821', 'Chemical', 'MESH:C103510', (217, 226))	('sh1', 'Gene', '100125848', (282, 285))	('****P', 'Var', (322, 327))	('GBM', 'Phenotype', 'HP:0012174', (360, 363))	('HSR040821', 'Var', (217, 226))	('sh1', 'Gene', (152, 155))	('sh1', 'Gene', '100125848', (152, 155))	('HSR-GBM1 shMCT4', 'Gene', (356, 371))	('increase', 'PosReg', (399, 407))	('sh2', 'Gene', '100125854', (160, 163))	('HSR-GBM1', 'Gene', '114564', (72, 80))	('HSR-GBM1', 'Gene', (72, 80))	('sh2', 'Gene', (160, 163))	('HSR-GBM1', 'Gene', '114564', (356, 364))
11572	32002519	Tail length increased in HSR-GBM1 26.6-fold and 13.8-fold (constitutive sh1 and sh2, respectively; ***P < .001 one-way ANOVA) and 16.8-fold and 17.6-fold in HSR040821 expressing sh1 and sh2 constitutively (one-way ANOVA ****P < .0001).	('HSR-GBM1', 'Gene', '114564', (25, 33))	('GBM', 'Phenotype', 'HP:0012174', (29, 32))	('HSR-GBM1', 'Gene', (25, 33))	('sh1', 'Gene', '100125848', (72, 75))	('Tail length', 'CPA', (0, 11))	('HSR040821', 'Var', (157, 166))	('sh1', 'Gene', (178, 181))	('increased', 'PosReg', (12, 21))	('sh2', 'Gene', '100125854', (186, 189))	('sh2', 'Gene', '100125854', (80, 83))	('sh2', 'Gene', (80, 83))	('sh1', 'Gene', '100125848', (178, 181))	('sh1', 'Gene', (72, 75))	('HSR040821', 'Chemical', 'MESH:C103510', (157, 166))	('sh2', 'Gene', (186, 189))
11577	32002519	Similarly, in HSR040821, sh1 and sh2 reduced the viable cell fraction by 56% and 48% (one-way ANOVA ***P < .001) (Figure 5B).	('viable cell fraction', 'CPA', (49, 69))	('HSR040821', 'Chemical', 'MESH:C103510', (14, 23))	('sh1', 'Gene', (25, 28))	('sh2', 'Gene', '100125854', (33, 36))	('HSR040821', 'Var', (14, 23))	('reduced', 'NegReg', (37, 44))	('sh2', 'Gene', (33, 36))	('sh1', 'Gene', '100125848', (25, 28))
11584	32002519	In HSR-GBM1, MCT4 depletion increased gammaH2AX-positive nuclei from 24% to 54.8% and 45.5% (sh1 and sh2, respectively; *P < .05, ***P < .001, ****P < .0001, one-way ANOVA; Figure 5D).	('increased', 'PosReg', (28, 37))	('gammaH2AX', 'Gene', (38, 47))	('HSR-GBM1', 'Gene', '114564', (3, 11))	('HSR-GBM1', 'Gene', (3, 11))	('sh1', 'Gene', '100125848', (93, 96))	('sh2', 'Gene', '100125854', (101, 104))	('GBM', 'Phenotype', 'HP:0012174', (7, 10))	('gammaH2AX', 'Gene', '15270', (38, 47))	('sh1', 'Gene', (93, 96))	('sh2', 'Gene', (101, 104))	('***P', 'Var', (130, 134))
11585	32002519	In HSR040821 MCT4 depletion increased gammaH2AX-positive nuclei from 18.8% to 36.5% and 59.1% (sh1 and sh2, respectively; *P < .05, ***P < .001, ****P < .0001, one-way ANOVA; Figure 5E).	('increased', 'PosReg', (28, 37))	('sh1', 'Gene', (95, 98))	('gammaH2AX', 'Gene', (38, 47))	('sh2', 'Gene', '100125854', (103, 106))	('HSR040821', 'Chemical', 'MESH:C103510', (3, 12))	('sh2', 'Gene', (103, 106))	('sh1', 'Gene', '100125848', (95, 98))	('gammaH2AX', 'Gene', '15270', (38, 47))	('HSR040821', 'Var', (3, 12))
11586	32002519	Finally, similar results were obtained with conditional MCT4 depletion in HSR-GBM1 shMCT4 Tet-ON, increasing gammaH2AX-positive nuclei from 15.8% to 35.7% (****P < .0001, one-way ANOVA), and supplementation with either cytidine or uridine pyrimidine nucleosides completely blocked the accumulation of nuclear gammaH2AX foci following MCT4 depletion (Figure 5F).	('HSR-GBM1 shMCT4', 'Gene', (74, 89))	('depletion', 'Var', (61, 70))	('gammaH2AX', 'Gene', (309, 318))	('HSR-GBM1 shMCT4', 'Gene', '80879', (74, 89))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('increasing', 'PosReg', (98, 108))	('cytidine', 'Chemical', 'MESH:D003562', (219, 227))	('gammaH2AX', 'Gene', '15270', (109, 118))	('blocked', 'NegReg', (273, 280))	('gammaH2AX', 'Gene', '15270', (309, 318))	('uridine pyrimidine nucleosides', 'Chemical', 'MESH:D011741', (231, 261))	('gammaH2AX', 'Gene', (109, 118))
11587	32002519	If the antitumor effect of MCT4 depletion is strictly dependent on shutting down pyrimidine synthesis, then these effects should be comparable to pharmacological inhibition of this pathway by the FDA-approved DHODH inhibitor Leflunomide.	('Leflunomide', 'Chemical', 'MESH:C045463', (225, 236))	('DHODH', 'Gene', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('pyrimidine', 'Chemical', 'MESH:C030986', (81, 91))	('pyrimidine synthesis', 'MPA', (81, 101))	('MCT4', 'Var', (27, 31))	('shutting down', 'NegReg', (67, 80))	('tumor', 'Disease', (11, 16))	('DHODH', 'Gene', '56749', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
11590	32002519	Leflunomide treatment reduced the fraction of viable cells by approximately 90% and 30%, in HSR-GBM1 and HSR040821, respectively (Figure 5G).	('fraction of', 'MPA', (34, 45))	('HSR040821', 'Var', (105, 114))	('Leflunomide', 'Chemical', 'MESH:C045463', (0, 11))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('reduced', 'NegReg', (22, 29))	('HSR-GBM1', 'Gene', '114564', (92, 100))	('HSR040821', 'Chemical', 'MESH:C103510', (105, 114))	('HSR-GBM1', 'Gene', (92, 100))
11591	32002519	These effects are likely due to an increase in DNA damage as we documented a 21-fold and 18-fold increase in gammaH2AX-positive nuclei in HSR-GBM1 and HSR040821, respectively (Figure 5H).	('HSR-GBM1', 'Gene', '114564', (138, 146))	('increase', 'PosReg', (97, 105))	('HSR040821', 'Chemical', 'MESH:C103510', (151, 160))	('gammaH2AX', 'Gene', '15270', (109, 118))	('HSR-GBM1', 'Gene', (138, 146))	('HSR040821', 'Var', (151, 160))	('GBM', 'Phenotype', 'HP:0012174', (142, 145))	('gammaH2AX', 'Gene', (109, 118))
11592	32002519	Taken together, these results strongly suggest that MCT4 and Leflunomide inhibit a common pathway, namely, de novo pyrimidine synthesis.	('Leflunomide', 'Chemical', 'MESH:C045463', (61, 72))	('MCT4', 'Var', (52, 56))	('de novo pyrimidine synthesis', 'MPA', (107, 135))	('pyrimidine', 'Chemical', 'MESH:C030986', (115, 125))	('inhibit', 'NegReg', (73, 80))
11594	32002519	Fourteen days after tumor implantation the mice were segregated into the following 4 treatment groups: standard chow (control), radiation (12 Gy), doxycycline (dox), and the combination of MCT4 depletion and radiation (dox+12 Gy).	('mice', 'Species', '10090', (43, 47))	('doxycycline', 'Chemical', 'MESH:D004318', (147, 158))	('dox', 'Chemical', 'MESH:D004318', (160, 163))	('MCT4', 'Var', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('dox', 'Chemical', 'MESH:D004318', (147, 150))	('dox', 'Chemical', 'MESH:D004318', (219, 222))	('tumor', 'Disease', (20, 25))
11600	32002519	MCT4 depletion alone increased median survival from 47 to 54 days (log-rank ****P < .0001, Figure 6D, purple triangles), and the median survival of mice receiving doxycycline and radiation increased to 67 days (log-rank ****P < .0001, Figure 6D, green triangles), underscoring the benefit of a combinatorial approach based on MCT4 depletion and IR.	('increased', 'PosReg', (21, 30))	('depletion', 'Var', (5, 14))	('doxycycline', 'Chemical', 'MESH:D004318', (163, 174))	('median survival', 'CPA', (31, 46))	('mice', 'Species', '10090', (148, 152))	('increased', 'PosReg', (189, 198))
11616	32002519	We documented a significant reduction in the levels of several pyrimidine nucleotides and an increase in DNA damage following MCT4 depletion.	('increase', 'PosReg', (93, 101))	('pyrimidine nucleotides', 'Chemical', 'MESH:D011742', (63, 85))	('DNA damage', 'MPA', (105, 115))	('MCT4 depletion', 'Var', (126, 140))	('reduction', 'NegReg', (28, 37))	('levels of several pyrimidine nucleotides', 'MPA', (45, 85))
11618	32002519	The question remains, how does MCT4 depletion result in decreased pyrimidine levels?	('MCT4', 'Var', (31, 35))	('pyrimidine', 'Chemical', 'MESH:C030986', (66, 76))	('pyrimidine levels', 'MPA', (66, 83))	('decreased', 'NegReg', (56, 65))
11703	31320671	It has been reported that SDT can produce BBB disruption and brain tissue damage in the absence of microbubbles if the applied intensity is high (~100 W/cm2).	('SDT', 'Chemical', '-', (26, 29))	('SDT', 'Var', (26, 29))	('BBB disruption', 'CPA', (42, 56))	('brain tissue damage', 'CPA', (61, 80))	('produce', 'Reg', (34, 41))
11708	31320671	Previous reports have demonstrated ALA-SDT produces antitumor effects on pancreatic cancer, melanoma, osteosarcoma, tongue squamous carcinoma, and glioma.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('osteosarcoma', 'Disease', 'MESH:D012516', (102, 114))	('ALA-SDT', 'Chemical', '-', (35, 42))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('glioma', 'Disease', (147, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (123, 141))	('tongue squamous carcinoma', 'Phenotype', 'HP:0030413', (116, 141))	('osteosarcoma', 'Phenotype', 'HP:0002669', (102, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('tumor', 'Disease', (56, 61))	('rat', 'Species', '10116', (29, 32))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ALA-SDT', 'Var', (35, 42))	('pancreatic cancer', 'Disease', (73, 90))	('tongue squamous carcinoma', 'Disease', 'MESH:D002294', (116, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tongue squamous carcinoma', 'Disease', (116, 141))	('osteosarcoma', 'Disease', (102, 114))
11709	31320671	It has been shown that SDT could generate intracellular reactive oxygen species (ROS) and subsequently produce direct cytotoxicity in malignant cells.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (56, 79))	('produce', 'Reg', (103, 110))	('SDT', 'Chemical', '-', (23, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('rat', 'Species', '10116', (37, 40))	('SDT', 'Var', (23, 26))	('intracellular reactive oxygen species', 'MPA', (42, 79))	('cytotoxicity', 'Disease', (118, 130))
11780	29679017	Activation of TLR4 in tumor cells promotes the synthesis of NFkappaB target genes, including IL-6 and IL1beta, which results in resistance of tumor cells against cytotoxic lymphocytes.	('IL-6', 'Gene', (93, 97))	('NFkappaB', 'Gene', (60, 68))	('TLR4', 'Gene', '7099', (14, 18))	('TLR4', 'Gene', (14, 18))	('IL-6', 'Gene', '3569', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('promotes', 'PosReg', (34, 42))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('resistance', 'CPA', (128, 138))	('IL1beta', 'Gene', '3553', (102, 109))	('Activation', 'Var', (0, 10))	('tumor', 'Disease', (22, 27))	('results in', 'Reg', (117, 127))	('synthesis', 'MPA', (47, 56))	('IL1beta', 'Gene', (102, 109))
11783	29679017	This cell behaviour is reversed following downregulation or inactivation of TLR4.	('TLR4', 'Gene', '7099', (76, 80))	('downregulation', 'NegReg', (42, 56))	('TLR4', 'Gene', (76, 80))	('inactivation', 'Var', (60, 72))
11789	29679017	GSCs were derived from patients with primary glioblastoma with wild-type IDH1 and EGFR amplification.	('EGFR', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (73, 77))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', '1956', (82, 86))	('IDH1', 'Gene', (73, 77))	('primary glioblastoma', 'Disease', 'MESH:D005909', (37, 57))	('wild-type', 'Var', (63, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('primary glioblastoma', 'Disease', (37, 57))	('amplification', 'Var', (87, 100))
11792	29679017	Then, cells were incubated with rabbit anti-GFAP (DAKO, Glostrup, Denmark) and anti-Ki67 (SP6, Thermo Scientific, Waltham, MA) or mouse anti-phospho histone H2AX (05-636, Millipore, Billerica, MA) antibodies.	('SP6', 'Gene', (90, 93))	('SP6', 'Gene', '80320', (90, 93))	('histone H2AX', 'Gene', '3014', (149, 161))	('anti-Ki67', 'Var', (79, 88))	('GFAP', 'Gene', (44, 48))	('rabbit', 'Species', '9986', (32, 38))	('histone H2AX', 'Gene', (149, 161))	('GFAP', 'Gene', '2670', (44, 48))	('mouse', 'Species', '10090', (130, 135))
11819	29679017	In order to assess whether downregulation of TLR4 modified the differentiation pattern of GSCs, we first analyzed the expression of GFAP, an astrocytic differentiation marker, and found that low levels of TLR4 correlated with increased expression of GFAP (about 3-fold higher intensity with shRNA-1 relative to control) as determined by immunofluorescence (Fig.	('low', 'Var', (191, 194))	('TLR4', 'Gene', (45, 49))	('GFAP', 'Gene', (250, 254))	('TLR4', 'Gene', '7099', (205, 209))	('GFAP', 'Gene', '2670', (132, 136))	('TLR4', 'Gene', (205, 209))	('TLR4', 'Gene', '7099', (45, 49))	('GFAP', 'Gene', '2670', (250, 254))	('GFAP', 'Gene', (132, 136))	('increased', 'PosReg', (226, 235))	('higher', 'PosReg', (269, 275))	('expression', 'MPA', (236, 246))
11823	29679017	In line with these results, the mRNA levels of MAP2 were also upregulated in differentiating cells following treatment with neutralizing anti-TL4 antibodies (Fig.	('mRNA levels', 'MPA', (32, 43))	('upregulated', 'PosReg', (62, 73))	('neutralizing', 'Var', (124, 136))	('MAP2', 'Gene', (47, 51))	('MAP2', 'Gene', '4133', (47, 51))
11837	29679017	Consistently, 4-MU reduced the proliferation capacity (Fig.	('4-MU', 'Chemical', 'MESH:D006923', (14, 18))	('4-MU', 'Var', (14, 18))	('proliferation capacity', 'CPA', (31, 53))	('reduced', 'NegReg', (19, 26))
11854	29679017	We showed that blockade of TLR4-NFkappaB signaling by using genetic strategies or blocking antibodies accelerates maturation of differentiating GSCs.	('blockade', 'Var', (15, 23))	('TLR4', 'Gene', (27, 31))	('accelerates', 'PosReg', (102, 113))	('maturation of differentiating GSCs', 'CPA', (114, 148))	('TLR4', 'Gene', '7099', (27, 31))
11861	29679017	Blockade of HA synthesis abrogated the TLR4-NFkappaB pathway indicating that GSCs develop their own mechanism to assure activation of NFkappaB during the differentiation process.	('abrogated', 'NegReg', (25, 34))	('NFkappaB', 'Protein', (134, 142))	('Blockade', 'Var', (0, 8))	('activation', 'PosReg', (120, 130))	('TLR4', 'Gene', '7099', (39, 43))	('HA', 'Chemical', 'MESH:D006820', (12, 14))	('TLR4', 'Gene', (39, 43))
11875	29147648	ncRNAs are associated to higher eukaryotes complexity; accordingly, their dysfunction results in pathological phenotypes, including cancer.	('dysfunction', 'Var', (74, 85))	('cancer', 'Disease', (132, 138))	('ncRNA', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ncRNA', 'Gene', '220202', (0, 5))	('results in', 'Reg', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
11891	29147648	These observations strongly suggest that ncRNAs are closely related to the complexity of higher eukaryotes and that their dysfunction may result in pathological phenotypes.	('dysfunction', 'Var', (122, 133))	('result in', 'Reg', (138, 147))	('ncRNA', 'Gene', '220202', (41, 46))	('ncRNA', 'Gene', (41, 46))
11906	29147648	In the last two decades, their mutations and altered expression were reported to be causally related to the neoplastic features of the cells, thus providing new perspectives for the understanding of the complex regulatory networks that rule tumor biology.	('mutations', 'Var', (31, 40))	('expression', 'MPA', (53, 63))	('related', 'Reg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('rule tumor', 'Disease', 'MESH:D009369', (236, 246))	('rule tumor', 'Disease', (236, 246))	('neoplastic features of the cells', 'CPA', (108, 140))
11907	29147648	miRNA dysfunctions exert a pleiotropic effect on the expression of their mRNA targets impairing the functioning of biological networks.	('impairing', 'NegReg', (86, 95))	('dysfunctions', 'Var', (6, 18))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('functioning', 'MPA', (100, 111))	('expression', 'MPA', (53, 63))
11912	29147648	They include transcripts that may be classified as (a) intergenic lncRNAs, (b) intronic lncRNAs, (c) sense or antisense transcripts, (d) pseudogenes, and (e) retrotransposons.	('pseudogenes', 'Var', (137, 148))	('ncRNA', 'Gene', (67, 72))	('ncRNA', 'Gene', (89, 94))	('ncRNA', 'Gene', '220202', (67, 72))	('ncRNA', 'Gene', '220202', (89, 94))
11920	29147648	Dysregulation of lncRNA activity has been frequently reported in association to diseases, including several types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Dysregulation', 'Var', (0, 13))	('reported', 'Reg', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('ncRNA', 'Gene', (18, 23))	('cancer', 'Disease', (117, 123))	('ncRNA', 'Gene', '220202', (18, 23))
11927	29147648	circRNAs are a circularized isoform of linear protein-coding genes generated through backsplicing, a molecular process that is different from the canonical splicing of linear RNAs.	('cir', 'Gene', (15, 18))	('cir', 'Gene', '9541', (15, 18))	('cir', 'Gene', (0, 3))	('cir', 'Gene', '9541', (0, 3))	('backsplicing', 'Var', (85, 97))
11937	29147648	Just few of these studies attempted to functionally explain how abnormal expression of circRNAs could impair physiological cell homeostasis and thus promote cancer phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('abnormal expression', 'Var', (64, 83))	('promote', 'PosReg', (149, 156))	('cir', 'Gene', '9541', (87, 90))	('impair', 'NegReg', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('physiological cell homeostasis', 'MPA', (109, 139))	('cir', 'Gene', (87, 90))
11968	29147648	Interestingly, HuR and let-7b/AGO2 complex also decreased the stability of lincRNA-p21, an oncogenic lncRNA that reduced translation of beta-catenin and JUNB (JunB proto-oncogene, subunit of transcription factor AP-1) mRNAs in human cervical carcinoma HeLa cells; even if in other experiments HuR was not able to transfer let-7b to AGO2.	('let-7b', 'Gene', (322, 328))	('ncRNA', 'Gene', (77, 82))	('lincRNA-p21', 'Gene', (75, 86))	('let-7b', 'Gene', (23, 29))	('AGO2', 'Gene', (30, 34))	('ncRNA', 'Gene', '220202', (77, 82))	('translation', 'MPA', (121, 132))	('JUNB', 'Gene', '3726', (153, 157))	('reduced', 'NegReg', (113, 120))	('beta-catenin', 'Gene', (136, 148))	('beta-catenin', 'Gene', '1499', (136, 148))	('decreased', 'NegReg', (48, 57))	('AGO2', 'Gene', '27161', (332, 336))	('carcinoma HeLa', 'Disease', (242, 256))	('JUNB', 'Gene', (153, 157))	('carcinoma HeLa', 'Disease', 'MESH:D002277', (242, 256))	('HuR', 'Gene', (293, 296))	('HuR', 'Gene', (15, 18))	('complex', 'Var', (35, 42))	('AGO2', 'Gene', '27161', (30, 34))	('let-7b', 'Gene', '406884', (322, 328))	('let-7b', 'Gene', '406884', (23, 29))	('stability', 'MPA', (62, 71))	('AGO2', 'Gene', (332, 336))	('HuR', 'Gene', '1994', (293, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('ncRNA', 'Gene', (102, 107))	('JunB', 'Gene', (159, 163))	('human', 'Species', '9606', (227, 232))	('HuR', 'Gene', '1994', (15, 18))	('lincRNA-p21', 'Gene', '102800311', (75, 86))	('ncRNA', 'Gene', '220202', (102, 107))	('JunB', 'Gene', '3726', (159, 163))
12002	29147648	Dysregulation of FER1L4-miR-106a-5p-PTEN axis increased cell proliferation by promoting the G0/G1 to S phase transition.	('Dysregulation', 'Var', (0, 13))	('increased', 'PosReg', (46, 55))	('FER1L4', 'Gene', '80307', (17, 23))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('promoting', 'PosReg', (78, 87))	('miR-106a', 'Gene', '406899', (24, 32))	('cell proliferation', 'CPA', (56, 74))	('miR-106a', 'Gene', (24, 32))	('FER1L4', 'Gene', (17, 23))	('G0/G1 to S phase transition', 'CPA', (92, 119))
12015	29147648	Upregulation of lncRNA CCAT1 (colon cancer associated transcript 1) in HCC tissues was associated with increased cell proliferation and migration; these oncogenic activities were mediated by its molecular sponge function for let-7: inhibition of let-7 caused upregulated expression of let-7 targets: HMGA2 (high mobility group AT-hook 2) and MYC (MYC proto-oncogene, bHLH transcription factor).	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('MYC', 'Gene', '4609', (347, 350))	('HMGA2', 'Gene', (300, 305))	('upregulated', 'PosReg', (259, 270))	('inhibition', 'Var', (232, 242))	('CCAT1', 'Gene', '100507056', (23, 28))	('expression', 'MPA', (271, 281))	('CCAT1', 'Gene', (23, 28))	('MYC', 'Gene', (342, 345))	('colon cancer associated transcript 1', 'Gene', '100507056', (30, 66))	('colon cancer associated transcript 1', 'Gene', (30, 66))	('let-7', 'Gene', (246, 251))	('high mobility group AT-hook 2', 'Gene', (307, 336))	('ncRNA', 'Gene', (17, 22))	('HMGA2', 'Gene', '8091', (300, 305))	('ncRNA', 'Gene', '220202', (17, 22))	('MYC', 'Gene', (347, 350))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('MYC', 'Gene', '4609', (342, 345))	('high mobility group AT-hook 2', 'Gene', '8091', (307, 336))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
12046	29147648	Overexpression of TUG1 was involved in glioblastoma angiogenesis by modulation of endothelial cell proliferation, migration, and tube formation.	('glioblastoma', 'Disease', (39, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('TUG1', 'Gene', (18, 22))	('modulation', 'Reg', (68, 78))	('involved', 'Reg', (27, 35))	('migration', 'CPA', (114, 123))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('endothelial cell proliferation', 'CPA', (82, 112))	('Overexpression', 'Var', (0, 14))	('tube formation', 'CPA', (129, 143))	('TUG1', 'Gene', '55000', (18, 22))
12048	29147648	In fact, knockdown of TUG1-induced upregulation of miR-299 and concomitant decrease of VEGFA (vascular endothelial growth factor A), target of miR-299.	('miR-299', 'Gene', '407023', (51, 58))	('vascular endothelial growth factor A', 'Gene', '7422', (94, 130))	('decrease', 'NegReg', (75, 83))	('knockdown', 'Var', (9, 18))	('VEGFA', 'Gene', (87, 92))	('vascular endothelial growth factor A', 'Gene', (94, 130))	('miR-299', 'Gene', (143, 150))	('TUG1', 'Gene', '55000', (22, 26))	('VEGFA', 'Gene', '7422', (87, 92))	('miR-299', 'Gene', (51, 58))	('upregulation', 'PosReg', (35, 47))	('miR-299', 'Gene', '407023', (143, 150))	('TUG1', 'Gene', (22, 26))
12053	29147648	Because POU2F1 is a target of miR-9-5p, silencing of TUG1-inhibited cell proliferation and colony formation, while inducing G0/G1 cell cycle arrest and apoptosis.	('miR-9-5p', 'Gene', (30, 38))	('miR-9-5p', 'Gene', '407052', (30, 38))	('colony formation', 'CPA', (91, 107))	('inducing', 'NegReg', (115, 123))	('TUG1', 'Gene', '55000', (53, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('POU2F1', 'Gene', (8, 14))	('silencing', 'Var', (40, 49))	('POU2F1', 'Gene', '5451', (8, 14))	('TUG1', 'Gene', (53, 57))	('apoptosis', 'CPA', (152, 161))	('G0/G1 cell cycle arrest', 'CPA', (124, 147))
12058	29147648	They found that ectopic expression of TUSC7 inhibited cell metastasis, invasion, and EMT, by functioning as a competitive sponge for miR-10a.	('TUSC7', 'Gene', (38, 43))	('TUSC7', 'Gene', '285194', (38, 43))	('inhibited', 'NegReg', (44, 53))	('ectopic expression', 'Var', (16, 34))	('invasion', 'CPA', (71, 79))	('miR-10a', 'Gene', (133, 140))	('cell metastasis', 'CPA', (54, 69))	('EMT', 'CPA', (85, 88))	('miR-10a', 'Gene', '406902', (133, 140))
12063	29147648	TUSC7, downregulated in gastric cancer, was an independent prognostic marker of disease-free survival in patients, and its ectopic expression suppressed cancer cell growth both in in vitro and in vivo models, in part by negatively regulating the expression of miR-23.	('miR', 'Gene', (260, 263))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('negatively regulating', 'NegReg', (220, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('TUSC7', 'Gene', (0, 5))	('TUSC7', 'Gene', '285194', (0, 5))	('cancer', 'Disease', (32, 38))	('ectopic expression', 'Var', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('expression', 'MPA', (246, 256))	('suppressed', 'NegReg', (142, 152))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('patients', 'Species', '9606', (105, 113))	('downregulated', 'NegReg', (7, 20))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('miR', 'Gene', '220972', (260, 263))	('gastric cancer', 'Disease', (24, 38))
12067	29147648	Silencing of UCA1 decreased ROS production and promoted mitochondrial glutaminolysis in bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('decreased', 'NegReg', (18, 27))	('promoted', 'PosReg', (47, 55))	('ROS production', 'MPA', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('mitochondrial glutaminolysis', 'MPA', (56, 84))	('UCA1', 'Gene', '652995', (13, 17))	('UCA1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))
12092	29147648	Circ-TTBK2 harbors MREs for miR-217, which has a tumor-suppressive role in glioma cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('miR-217', 'Gene', '406999', (28, 35))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('miR-217', 'Gene', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TTBK2', 'Gene', (5, 10))	('TTBK2', 'Gene', '146057', (5, 10))	('tumor', 'Disease', (49, 54))	('glioma', 'Disease', (75, 81))	('Cir', 'Gene', '9541', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('Cir', 'Gene', (0, 3))	('MREs', 'Var', (19, 23))
12096	29147648	Moreover, restoration of miR-217 expression reversed the circ-TTBK2-induced promotion of cancer progression, suggesting a reciprocal negative feedback between circ-TTBK2 and miR-217.	('TTBK2', 'Gene', '146057', (164, 169))	('miR-217', 'Gene', '406999', (25, 32))	('TTBK2', 'Gene', '146057', (62, 67))	('restoration', 'Var', (10, 21))	('cir', 'Gene', (57, 60))	('promotion', 'PosReg', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('TTBK2', 'Gene', (164, 169))	('cir', 'Gene', '9541', (57, 60))	('TTBK2', 'Gene', (62, 67))	('miR-217', 'Gene', '406999', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('miR-217', 'Gene', (174, 181))	('cir', 'Gene', (159, 162))	('miR-217', 'Gene', (25, 32))	('cir', 'Gene', '9541', (159, 162))
12102	29147648	Cir-ITCH was downregulated in CRC tissues and its ectopic expression led to decreased cell proliferation.	('ITCH', 'Phenotype', 'HP:0000989', (4, 8))	('ITCH', 'Gene', '83737', (4, 8))	('-ITCH', 'Phenotype', 'HP:0000989', (3, 8))	('downregulated', 'NegReg', (13, 26))	('ectopic expression', 'Var', (50, 68))	('decreased', 'NegReg', (76, 85))	('Cir', 'Gene', '9541', (0, 3))	('ITCH', 'Gene', (4, 8))	('cell proliferation', 'CPA', (86, 104))	('Cir', 'Gene', (0, 3))
12115	29147648	Initially, Sry circRNA was considered an artifact of aberrant RNA splicing and no specific function was attributed to it.	('Sry', 'Gene', '6736', (11, 14))	('cir', 'Gene', (15, 18))	('Sry', 'Gene', (11, 14))	('cir', 'Gene', '9541', (15, 18))	('aberrant', 'Var', (53, 61))
12140	29147648	In spite of unclear stoichiometric relationships among ncRNAs in cancer, multiple experimental evidence shows that in vitro and in vivo modulation of ncRNAs strongly impair aggressive properties of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('ncRNA', 'Gene', '220202', (55, 60))	('cancer', 'Disease', (198, 204))	('ncRNA', 'Gene', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ncRNA', 'Gene', '220202', (150, 155))	('ncRNA', 'Gene', (55, 60))	('cancer', 'Disease', (65, 71))	('impair', 'NegReg', (166, 172))	('modulation', 'Var', (136, 146))
12168	28864225	Such DNA adducts induce nicks in the DNA leading to cell cycle arrest and apoptosis.	('induce', 'Reg', (17, 23))	('apoptosis', 'CPA', (74, 83))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('arrest', 'Disease', (63, 69))	('nicks', 'Var', (24, 29))
12169	28864225	Over-activation of the DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT) can lead to resistance to TMZ in GBM patients.	('O6-methylguanine-DNA methyltransferase', 'Gene', (42, 80))	('TMZ', 'Chemical', 'MESH:D000077204', (114, 117))	('lead to', 'Reg', (92, 99))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (42, 80))	('MGMT', 'Gene', '4255', (82, 86))	('MGMT', 'Gene', (82, 86))	('resistance to TMZ', 'MPA', (100, 117))	('Over-activation', 'Var', (0, 15))	('patients', 'Species', '9606', (125, 133))
12171	28864225	Reports have shown that TMZ increases overall survival of GBM patients only by 2.5 months.	('TMZ', 'Chemical', 'MESH:D000077204', (24, 27))	('increases', 'PosReg', (28, 37))	('TMZ', 'Var', (24, 27))	('overall survival', 'MPA', (38, 54))	('patients', 'Species', '9606', (62, 70))
12183	28864225	Working with the nematode Caenorhabditis elegans (C. elegans), Craig Mello and Andrew Fire discovered that double-stranded RNA is more effective than single-stranded RNA at interfering endogenous mRNA in cells.	('C. elegans', 'Species', '6239', (50, 60))	('Caenorhabditis elegans', 'Species', '6239', (26, 48))	('double-stranded RNA', 'Var', (107, 126))	('interfering endogenous mRNA in', 'MPA', (173, 203))
12186	28864225	On the other hand, the combined work of Ambros and Ruvkun laboratories, both working also in C. elegans, discovered the mechanism by which naturally occurring small non-coding RNAs (miRNA) inactivate gene expression through imperfect base-pair complementarity with its cognate mRNAs.	('base-pair complementarity', 'MPA', (234, 259))	('miR', 'Gene', '735281', (182, 185))	('miR', 'Gene', (182, 185))	('C. elegans', 'Species', '6239', (93, 103))	('imperfect', 'Var', (224, 233))	('rat', 'Species', '10116', (62, 65))	('inactivate', 'NegReg', (189, 199))	('gene expression', 'MPA', (200, 215))
12189	28864225	Multiple studies involving various types of human cancers have demonstrated that aberrantly expressed miRNAs can contribute to cancer cell growth, proliferation, and tumor maintenance.	('human', 'Species', '9606', (44, 49))	('cancer', 'Disease', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('miR', 'Gene', (102, 105))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR', 'Gene', '735281', (102, 105))	('cancer', 'Disease', (127, 133))	('proliferation', 'CPA', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('contribute', 'Reg', (113, 123))	('rat', 'Species', '10116', (154, 157))	('tumor', 'Disease', (166, 171))	('aberrantly expressed', 'Var', (81, 101))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (127, 133))
12202	28864225	The use of specific inhibitors have been effective; for instance, the use of a miR-27a inhibitor reduced cell proliferation and induced apoptosis in CRL-1690 GBM cells, miR-21 inhibition led to a decreased migration and invasion of A172 GBM cells, and miR-10b inhibition reduced tumor growth, invasion, and angiogenesis of U87-MG GBM cells.	('miR-27a', 'Gene', (79, 86))	('miR-10b', 'Gene', (252, 259))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('inhibition', 'Var', (176, 186))	('cell proliferation', 'CPA', (105, 123))	('CRL', 'Gene', '133396', (149, 152))	('migration', 'CPA', (206, 215))	('reduced', 'NegReg', (97, 104))	('rat', 'Species', '10116', (117, 120))	('tumor', 'Disease', (279, 284))	('rat', 'Species', '10116', (209, 212))	('inhibition reduced', 'NegReg', (260, 278))	('miR-21', 'Gene', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('invasion', 'CPA', (293, 301))	('angiogenesis', 'CPA', (307, 319))	('decreased', 'NegReg', (196, 205))	('apoptosis', 'CPA', (136, 145))	('CRL', 'Gene', (149, 152))	('invasion', 'CPA', (220, 228))
12203	28864225	Dysregulation of other miRNAs has been associated with drug resistance of GBM cells.	('miR', 'Gene', '735281', (23, 26))	('miR', 'Gene', (23, 26))	('Dysregulation', 'Var', (0, 13))	('drug resistance', 'Phenotype', 'HP:0020174', (55, 70))	('drug resistance', 'Disease', (55, 70))	('associated', 'Reg', (39, 49))
12208	28864225	Taken together, targeting dysregulated miRNAs could reduce cell growth and proliferation, induce apoptosis, reduce cell invasion and migration, sensitize GBM cells to chemotherapeutic agents; and destroy GBM stem cell populations.	('GBM stem cell populations', 'CPA', (204, 229))	('destroy', 'NegReg', (196, 203))	('miR', 'Gene', '735281', (39, 42))	('miR', 'Gene', (39, 42))	('cell growth', 'CPA', (59, 70))	('induce', 'Reg', (90, 96))	('reduce', 'NegReg', (52, 58))	('rat', 'Species', '10116', (82, 85))	('rat', 'Species', '10116', (136, 139))	('reduce', 'NegReg', (108, 114))	('dysregulated', 'Var', (26, 38))	('apoptosis', 'CPA', (97, 106))
12258	28864225	When these mice were treated continuously with miR-10b ASO or control ASO via osmotic pumps for two weeks, a reduction in tumor growth in the treatment group was observed compared to the control group.	('ASO', 'Chemical', 'MESH:D016376', (55, 58))	('ASO', 'Chemical', 'MESH:D016376', (70, 73))	('reduction', 'NegReg', (109, 118))	('miR-10b ASO', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
12259	28864225	used a syngeneic model to evaluate how STAT3 expression affects GBM tumor growth in vivo.	('GBM tumor', 'Disease', (64, 73))	('STAT3', 'Gene', '20848', (39, 44))	('STAT3', 'Gene', (39, 44))	('affects', 'Reg', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('expression', 'Var', (45, 55))	('GBM tumor', 'Disease', 'MESH:D005910', (64, 73))
12265	28864225	bred a spontaneous tumor mouse model of non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice heterozygous for a mutation in the Sonic hedgehog receptor patched 1 (Ptc) with NOD/SCID mice heterozygous for the P53 gene (Ptc +/-, p53 +/-).	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (59, 91))	('mouse', 'Species', '10090', (25, 30))	('Ptc', 'Gene', '19206', (178, 181))	('tumor', 'Disease', (19, 24))	('Ptc', 'Gene', '19206', (233, 236))	('P53', 'Gene', (223, 226))	('obese diabetic', 'Disease', 'MESH:D009765', (44, 58))	('mice', 'Species', '10090', (197, 201))	('immunodeficiency', 'Disease', (75, 91))	('SCID', 'Disease', 'MESH:D053632', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('immunodeficiency', 'Disease', 'MESH:D007153', (75, 91))	('SCID', 'Disease', 'MESH:D053632', (97, 101))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (66, 91))	('mutation', 'Var', (127, 135))	('SCID', 'Disease', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('immunodeficiency', 'Phenotype', 'HP:0002721', (75, 91))	('SCID', 'Disease', (97, 101))	('patched 1', 'Gene', (167, 176))	('mice', 'Species', '10090', (103, 107))	('patched 1', 'Gene', '19206', (167, 176))	('P53', 'Gene', '22060', (223, 226))	('p53', 'Gene', (242, 245))	('obese diabetic', 'Disease', (44, 58))	('Ptc', 'Gene', (178, 181))	('p53', 'Gene', '22060', (242, 245))	('Ptc', 'Gene', (233, 236))
12282	28864225	Chemical modifications in the siRNA/miRNA strands are basically the same performed to antisense oligonucleotides (ASOs) (recently revised by Khvorova and Watts).	('antisense', 'Var', (86, 95))	('ASOs', 'Chemical', 'MESH:D016376', (114, 118))	('oligonucleotides', 'Chemical', 'MESH:D009841', (96, 112))	('miR', 'Gene', '735281', (36, 39))	('miR', 'Gene', (36, 39))
12283	28864225	The most common modification in siRNA strands is the substitution of one or two oxygen to sulfur in the non-bridge phosphate groups to produce phosphorothioates (PS) and phophodithionate (PS2), respectively.	('PS2', 'Gene', (188, 191))	('phosphate', 'Chemical', 'MESH:D010710', (115, 124))	('phophodithionate', 'Chemical', '-', (170, 186))	('PS', 'Chemical', 'MESH:D010278', (162, 164))	('substitution', 'Var', (53, 65))	('produce', 'Reg', (135, 142))	('oxygen', 'Chemical', 'MESH:D010100', (80, 86))	('PS', 'Chemical', 'MESH:D010278', (188, 190))	('sulfur', 'Chemical', 'MESH:D013455', (90, 96))	('PS2', 'Gene', '21784', (188, 191))	('phosphorothioates', 'Chemical', 'MESH:D010278', (143, 160))
12286	28864225	Similarly, substitution of one oxygen in the phosphate group by BH3 (boranophosphate) increased siRNA serum stability and silencing effects.	('phosphate', 'Chemical', 'MESH:D010710', (45, 54))	('increased', 'PosReg', (86, 95))	('BH3', 'Chemical', 'MESH:C006008', (64, 67))	('silencing effects', 'CPA', (122, 139))	('oxygen', 'Chemical', 'MESH:D010100', (31, 37))	('phosphate', 'Chemical', 'MESH:D010710', (75, 84))	('substitution', 'Var', (11, 23))	('siRNA serum stability', 'CPA', (96, 117))	('boranophosphate', 'Chemical', 'MESH:C510710', (69, 84))
12289	28864225	Additionally, the substitution of 2'-OH by 2'-F in both antisense and sense siRNA strands increased serum stability and the siRNA binding affinity to the mRNAs.	("2'-OH", 'Chemical', '-', (34, 39))	('increased', 'PosReg', (90, 99))	('serum', 'MPA', (100, 105))	('substitution', 'Var', (18, 30))	("2'-F", 'Chemical', '-', (43, 47))
12290	28864225	By contrast, full modification of the 2'-OH with 2'-OMe in the sense, antisense, or both siRNA strands reduced and/or abolished the silencing effect.	("2'-OH", 'Chemical', '-', (38, 43))	('reduced', 'NegReg', (103, 110))	("2'-OMe", 'Chemical', '-', (49, 55))	('modification', 'Var', (18, 30))	('abolished', 'NegReg', (118, 127))	('silencing effect', 'MPA', (132, 148))
12306	28864225	For example, AS1411, a Nucleolin specific aptamer, was the first oligodeoxynucleotide to reach phase I and II clinical trials for the treatment of cancers, including acute myeloid leukemia (NCT01034410) and renal cell carcinoma (NCT00740441).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Nucleolin', 'Gene', '17975', (23, 32))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (207, 227))	('NCT00740441', 'Var', (229, 240))	('AS1411', 'Chemical', 'MESH:C513936', (13, 19))	('NCT01034410', 'Var', (190, 201))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (166, 188))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (166, 188))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('renal cell carcinoma', 'Disease', (207, 227))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (207, 227))	('Nucleolin', 'Gene', (23, 32))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (172, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (65, 85))	('cancers', 'Disease', (147, 154))	('acute myeloid leukemia', 'Disease', (166, 188))
12308	28864225	Their results showed that treating U87-MG, U251, and SHG44 GBM cells with AS1411 reduced cell migration.	('AS1411', 'Var', (74, 80))	('rat', 'Species', '10116', (97, 100))	('AS1411', 'Chemical', 'MESH:C513936', (74, 80))	('reduced', 'NegReg', (81, 88))	('U251', 'CellLine', 'CVCL:0021', (43, 47))	('cell migration', 'CPA', (89, 103))
12314	28864225	showed that antimir-21/R8 treatment of U251 human GBM cells led to the downregulation of the well-known miR-21-regulated genes, PDCD4 and SERPINB5; as well as inhibition of cell migration by 25% in comparison to the antimir/R8 negative control group.	('human', 'Species', '9606', (44, 49))	('downregulation', 'NegReg', (71, 85))	('antimir-21/R8', 'Var', (12, 25))	('PDCD4', 'Gene', '27250', (128, 133))	('SERPINB5', 'Gene', '5268', (138, 146))	('R8', 'Chemical', '-', (23, 25))	('cell migration', 'CPA', (173, 187))	('SERPINB5', 'Gene', (138, 146))	('R8', 'Chemical', '-', (224, 226))	('rat', 'Species', '10116', (181, 184))	('U251', 'CellLine', 'CVCL:0021', (39, 43))	('PDCD4', 'Gene', (128, 133))	('miR-21-regulated genes', 'Gene', (104, 126))	('inhibition', 'NegReg', (159, 169))
12343	28864225	Their results showed that systemic administration of T7-LPC/siEGFR accumulated preferably in the brain tumor tissue, increased downregulation of EGFR, and extended the overall survival of mice compared to the non-targeted formulation.	('mice', 'Species', '10090', (188, 192))	('T7-LPC/siEGFR', 'Var', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increased', 'PosReg', (117, 126))	('brain tumor', 'Phenotype', 'HP:0030692', (97, 108))	('accumulated', 'PosReg', (67, 78))	('rat', 'Species', '10116', (43, 46))	('downregulation', 'NegReg', (127, 141))	('EGFR', 'Gene', (145, 149))	('brain tumor', 'Disease', 'MESH:D001932', (97, 108))	('extended', 'PosReg', (155, 163))	('brain tumor', 'Disease', (97, 108))
12346	28864225	This treatment led to anti-miR-21 accumulation in brain tumor tissue, effective silencing of miR-21, and upregulation of RhoB (miR-21 target mRNA) in a syngeneic GL261 mouse model.	('silencing', 'NegReg', (80, 89))	('brain tumor', 'Disease', 'MESH:D001932', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mouse', 'Species', '10090', (168, 173))	('upregulation', 'PosReg', (105, 117))	('brain tumor', 'Phenotype', 'HP:0030692', (50, 61))	('RhoB', 'Gene', (121, 125))	('anti-miR-21', 'Var', (22, 33))	('accumulation', 'PosReg', (34, 46))	('RhoB', 'Gene', '11852', (121, 125))	('miR-21', 'Gene', (93, 99))	('GL261', 'CellLine', 'CVCL:Y003', (162, 167))	('brain tumor', 'Disease', (50, 61))
12349	28864225	In fact, thiolated nucleic acids can be covalently attached to the AuNPs and therefore facilitate their delivery to brain tumors.	('facilitate', 'PosReg', (87, 97))	('brain tumors', 'Disease', 'MESH:D001932', (116, 128))	('brain tumors', 'Phenotype', 'HP:0030692', (116, 128))	('brain tumor', 'Phenotype', 'HP:0030692', (116, 127))	('thiolated nucleic acids', 'Chemical', '-', (9, 32))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('brain tumors', 'Disease', (116, 128))	('delivery', 'MPA', (104, 112))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('thiolated', 'Var', (9, 18))
12350	28864225	Nucleic acids attached to AuNPs are known as spherical nucleic acids (SNAs), and they have shown to cross the BBB and the brain tumor barrier (BTB) through targeting class A scavenger receptors.	('brain tumor', 'Disease', (122, 133))	('brain tumor', 'Disease', 'MESH:D001932', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('brain tumor', 'Phenotype', 'HP:0030692', (122, 133))	('Nucleic acids', 'Var', (0, 13))	('class', 'Protein', (166, 171))	('targeting', 'Reg', (156, 165))
12353	28864225	BCl2L12 specific SNAs, currently known as UN-0129, are undergoing a clinical trial (NCT03020017) where UN-0129 is intravenously injected into GBM and gliosarcoma patients prior to surgery.	('patients', 'Species', '9606', (162, 170))	('BCl2L12', 'Gene', '83596', (0, 7))	('gliosarcoma', 'Disease', (150, 161))	('UN-0129', 'Var', (103, 110))	('gliosarcoma', 'Disease', 'MESH:D018316', (150, 161))	('BCl2L12', 'Gene', (0, 7))
12365	28864225	Results showed that BMMSCs were able to deliver Cy3-labeled miR-124 mimics to orthotopic U87-MG xenograft tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('miR', 'Gene', (60, 63))	('U87-MG xenograft tumors', 'Disease', 'MESH:D000080343', (89, 112))	('U87-MG xenograft tumors', 'Disease', (89, 112))	('Cy3', 'Chemical', '-', (48, 51))	('Cy3-labeled', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miR', 'Gene', '735281', (60, 63))
12383	27811375	In addition, pyruvate attenuates the anti-neoplastic effect of carnosine, even when ATP production via tricarboxylic acid cycle and oxidative phosphorylation is blocked.	('pyruvate', 'Chemical', 'MESH:D019289', (13, 21))	('pyruvate', 'Var', (13, 21))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (103, 121))	('anti-neoplastic effect', 'CPA', (37, 59))	('attenuates', 'NegReg', (22, 32))	('ATP', 'Chemical', 'MESH:D000255', (84, 87))
12393	27811375	More recent data point towards variants of glycolytic enzymes that may specifically be expressed in tumors such as pyruvate kinase M2.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('variants', 'Var', (31, 39))	('expressed', 'Reg', (87, 96))	('pyruvate kinase M2', 'Disease', (115, 133))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('glycolytic', 'Chemical', '-', (43, 53))	('pyruvate', 'Chemical', 'MESH:D019289', (115, 123))
12398	27811375	As carnosine inhibits glycolytic ATP production the most straight interpretation of the observation of Holiday and McFarland would be a tumor cell switch to OxPhos when glycolysis is inhibited and pyruvate is supplied.	('ATP', 'Chemical', 'MESH:D000255', (33, 36))	('carnosine', 'Var', (3, 12))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('glycolytic ATP production', 'MPA', (22, 47))	('glycolytic', 'Chemical', '-', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('pyruvate', 'Chemical', 'MESH:D019289', (197, 205))	('tumor', 'Disease', (136, 141))	('inhibits', 'NegReg', (13, 21))
12415	27811375	As can be seen in Figure 1, only the absence of FBS from the culture medium prominently decreased viability as revealed by reduced dehydrogenase activity and ATP in cell lysates.	('ATP', 'Chemical', 'MESH:D000255', (158, 161))	('absence', 'Var', (37, 44))	('FBS', 'Gene', (48, 51))	('dehydrogenase', 'Enzyme', (131, 144))	('decreased', 'NegReg', (88, 97))	('FBS', 'Gene', '26269', (48, 51))	('reduced', 'NegReg', (123, 130))	('viability', 'CPA', (98, 107))
12436	27811375	However, as the production of NAD(P)H is higher in medium containing pyruvate than in the medium without any supplement there is an obvious production of NAD(P)H via pyruvate.	('pyruvate', 'Chemical', 'MESH:D019289', (69, 77))	('NAD(P)H', 'Gene', '1666', (30, 37))	('NAD(P)H', 'Gene', '1666', (154, 161))	('NAD(P)H', 'Gene', (30, 37))	('higher', 'PosReg', (41, 47))	('pyruvate', 'Chemical', 'MESH:D019289', (166, 174))	('pyruvate', 'Var', (69, 77))	('NAD(P)H', 'Gene', (154, 161))	('production', 'MPA', (16, 26))	('NAD(P)H via pyruvate', 'Disease', 'MESH:C000656865', (154, 174))
12442	27811375	CPI-613 is a lipoic acid analog which activates the lipoate-responsive regulatory phosphorylation of the E1alpha pyruvate dehydrogenase subunit and was shown to be selective for tumor cells in culture.	('tumor', 'Disease', (178, 183))	('lipoate-responsive regulatory phosphorylation', 'MPA', (52, 97))	('E1alpha', 'Enzyme', (105, 112))	('CPI-613', 'Var', (0, 7))	('CPI-613', 'Chemical', 'MESH:C568850', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('activates', 'PosReg', (38, 47))	('pyruvate', 'Chemical', 'MESH:D019289', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('lipoic acid', 'Chemical', 'MESH:D008063', (13, 24))	('lipoate', 'Chemical', '-', (52, 59))
12448	27811375	Furthermore, cells from the lines U87 and LN405 did not show any significant change in the amount of ATP in the presence of glucose and CPI-613, whereas ATP of cells from the line T98G was strongly reduced.	('glucose', 'Chemical', 'MESH:D005947', (124, 131))	('LN405', 'Var', (42, 47))	('CPI-613', 'Chemical', 'MESH:C568850', (136, 143))	('U87', 'Gene', (34, 37))	('ATP', 'Chemical', 'MESH:D000255', (101, 104))	('U87', 'Gene', '641648', (34, 37))	('ATP', 'Chemical', 'MESH:D000255', (153, 156))
12458	27811375	At this point it also has to be noted that the amount of ATP in the presence of glucose and pyruvate compared to glucose alone was ~2-fold higher in LN405 and comparable in U87 cells (1.3-fold higher).	('U87', 'Gene', (173, 176))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('U87', 'Gene', '641648', (173, 176))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('glucose', 'Chemical', 'MESH:D005947', (113, 120))	('LN405', 'Var', (149, 154))	('higher', 'PosReg', (139, 145))	('pyruvate', 'Chemical', 'MESH:D019289', (92, 100))
12460	27811375	This underscores that ATP production from pyruvate via the TCA cycle significantly contributes to ATP production in cells from the line T98G, but also demonstrates that ATP can also be produced by OxPhos in the other cell lines.	('ATP', 'Chemical', 'MESH:D000255', (98, 101))	('ATP', 'MPA', (22, 25))	('pyruvate', 'Chemical', 'MESH:D019289', (42, 50))	('TCA', 'Chemical', 'MESH:D014233', (59, 62))	('contributes', 'Reg', (83, 94))	('ATP production', 'MPA', (98, 112))	('T98G', 'Var', (136, 140))	('ATP', 'Chemical', 'MESH:D000255', (169, 172))	('ATP', 'Chemical', 'MESH:D000255', (22, 25))
12468	27811375	When cells cultivated in pyruvate received CPI-613 alone, the amount of ATP was reduced from 126 +- 21% to 48 +- 10% and cell viability determined by Calcein AM/PI was reduced from 98.5 +- 0.3% to 27.4 +- 11.2% (p < 0.02; Figure 7; Table 1).	('pyruvate', 'Chemical', 'MESH:D019289', (25, 33))	('CPI-613', 'Var', (43, 50))	('cell viability', 'CPA', (121, 135))	('reduced', 'NegReg', (80, 87))	('CPI-613', 'Chemical', 'MESH:C568850', (43, 50))	('amount of ATP', 'MPA', (62, 75))	('Calcein AM', 'Chemical', 'MESH:C085925', (150, 160))	('ATP', 'Chemical', 'MESH:D000255', (72, 75))	('reduced', 'NegReg', (168, 175))
12470	27811375	Most importantly, although viability was strongly reduced when only glucose or only pyruvate were supplied in the presence of carnosine and CPI-613, viability in the presence of both, glucose and pyruvate, was completely restored (98.4 +- 0.8%).	('viability', 'MPA', (27, 36))	('pyruvate', 'Chemical', 'MESH:D019289', (196, 204))	('viability', 'MPA', (149, 158))	('glucose', 'Chemical', 'MESH:D005947', (184, 191))	('CPI-613', 'Var', (140, 147))	('glucose', 'Chemical', 'MESH:D005947', (68, 75))	('CPI-613', 'Chemical', 'MESH:C568850', (140, 147))	('reduced', 'NegReg', (50, 57))	('pyruvate', 'Chemical', 'MESH:D019289', (84, 92))
12475	27811375	DNP inhibits mitochondrial ATP production by uncoupling electron transport from phosphorylation.	('inhibits', 'NegReg', (4, 12))	('DNP', 'Chemical', 'MESH:D019297', (0, 3))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('DNP', 'Var', (0, 3))	('uncoupling electron transport', 'MPA', (45, 74))	('mitochondrial ATP production', 'MPA', (13, 41))
12479	27811375	Cells fed with pyruvate exhibited a strong reduction of ATP when incubated in the presence of DNP (0.5 +- 0.1% compared to cells in the absence of the inhibitor 138.5 +- 9%).	('pyruvate', 'Var', (15, 23))	('reduction', 'NegReg', (43, 52))	('pyruvate', 'Chemical', 'MESH:D019289', (15, 23))	('DNP', 'Chemical', 'MESH:D019297', (94, 97))	('ATP', 'Chemical', 'MESH:D000255', (56, 59))	('ATP', 'MPA', (56, 59))
12481	27811375	This demonstrates that DNP completely blocks ATP production from pyruvate, but also shows that a fraction of cells is able to survive at least after 24 hours of exposure to DNP.	('DNP', 'Chemical', 'MESH:D019297', (23, 26))	('blocks', 'NegReg', (38, 44))	('ATP', 'Chemical', 'MESH:D000255', (45, 48))	('DNP', 'Var', (23, 26))	('pyruvate', 'Chemical', 'MESH:D019289', (65, 73))	('DNP', 'Chemical', 'MESH:D019297', (173, 176))	('ATP production from pyruvate', 'MPA', (45, 73))
12485	27811375	As also seen in Figure 5 and Figure 2A, cells receiving pyruvate produced more ATP in the absence of inhibitors than cells cultivated in glucose (138.5 +- 9%).	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('pyruvate', 'Chemical', 'MESH:D019289', (56, 64))	('ATP', 'MPA', (79, 82))	('glucose', 'Chemical', 'MESH:D005947', (137, 144))	('pyruvate', 'Var', (56, 64))
12486	27811375	As the addition of carnosine always reduces ATP production in the presence of pyruvate alone, carnosine does obviously also inhibit mitochondrial ATP production, although to a lesser extent than it effects glycolytic ATP production.	('glycolytic', 'Chemical', '-', (206, 216))	('carnosine', 'Var', (94, 103))	('mitochondrial ATP production', 'MPA', (132, 160))	('ATP', 'Chemical', 'MESH:D000255', (217, 220))	('ATP', 'Chemical', 'MESH:D000255', (44, 47))	('reduces', 'NegReg', (36, 43))	('inhibit', 'NegReg', (124, 131))	('ATP', 'Chemical', 'MESH:D000255', (146, 149))	('ATP production', 'MPA', (44, 58))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))
12497	27811375	Neither CPI-613 (A3) nor DNP (A4) decrease viability in the presence of glucose.	('CPI-613', 'Chemical', 'MESH:C568850', (8, 15))	('DNP', 'Chemical', 'MESH:D019297', (25, 28))	('viability', 'MPA', (43, 52))	('DNP', 'Var', (25, 28))	('glucose', 'Chemical', 'MESH:D005947', (72, 79))	('CPI-613', 'Var', (8, 15))
12500	27811375	The slightly enhanced production of ATP in the presence of DNP (A4) demonstrates enhanced glycolytic production of ATP, when OxPhos is blocked by DNP.	('enhanced', 'PosReg', (13, 21))	('enhanced', 'PosReg', (81, 89))	('production of ATP', 'MPA', (22, 39))	('glycolytic', 'Chemical', '-', (90, 100))	('DNP', 'Chemical', 'MESH:D019297', (59, 62))	('glycolytic production of ATP', 'MPA', (90, 118))	('DNP', 'Var', (59, 62))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))	('DNP', 'Chemical', 'MESH:D019297', (146, 149))	('ATP', 'Chemical', 'MESH:D000255', (36, 39))
12502	27811375	The addition of CPI-613 (A5) or DNP (A6) to cells in the presence of glucose and carnosine results in the same loss of ATP and viability as in (A2).	('carnosine', 'MPA', (81, 90))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('CPI-613', 'Chemical', 'MESH:C568850', (16, 23))	('loss', 'NegReg', (111, 115))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('DNP', 'Var', (32, 35))	('viability', 'CPA', (127, 136))	('A2', 'Chemical', 'MESH:C021591', (144, 146))	('DNP', 'Chemical', 'MESH:D019297', (32, 35))	('CPI-613', 'Var', (16, 23))
12508	27811375	In addition, we have previously demonstrated that carnosine enhances the expression of pyruvate dehydrogenase kinase 4 (PDK4), although, in further experiments (which were done in the presence of FBS and GlutaMax) we did not detect a change of pyruvate dehydrogenase activity under the influence of carnosine (unpublished data).	('pyruvate dehydrogenase kinase 4', 'Gene', (87, 118))	('PDK4', 'Gene', (120, 124))	('FBS', 'Gene', (196, 199))	('enhances', 'PosReg', (60, 68))	('GlutaMax', 'Chemical', 'MESH:D005973', (204, 212))	('pyruvate', 'Chemical', 'MESH:D019289', (244, 252))	('carnosine', 'Var', (50, 59))	('expression', 'MPA', (73, 83))	('FBS', 'Gene', '26269', (196, 199))	('pyruvate', 'Chemical', 'MESH:D019289', (87, 95))	('pyruvate dehydrogenase kinase 4', 'Gene', '5166', (87, 118))	('PDK4', 'Gene', '5166', (120, 124))
12510	27811375	This observation of the experiments presented in Figure 5 (and repetitions of it) is in contrast to the data presented in Figure 3 in which a concentration of 50 muM CPI-613 severely diminished the amount of ATP.	('diminished', 'NegReg', (183, 193))	('amount of ATP', 'MPA', (198, 211))	('muM', 'Gene', '56925', (162, 165))	('muM', 'Gene', (162, 165))	('CPI-613', 'Chemical', 'MESH:C568850', (166, 173))	('CPI-613', 'Var', (166, 173))	('ATP', 'Chemical', 'MESH:D000255', (208, 211))
12511	27811375	It is tempting to speculate that this variation in the quantitative effect of CPI-613 on ATP is associated with the effect of CPI-613 on 2-oxoglutarate dehydrogenase.	('CPI-613', 'Gene', (78, 85))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('ATP', 'Disease', (89, 92))	('CPI-613', 'Chemical', 'MESH:C568850', (78, 85))	('CPI-613', 'Var', (126, 133))	('2-oxoglutarate dehydrogenase', 'MPA', (137, 165))	('CPI-613', 'Chemical', 'MESH:C568850', (126, 133))
12512	27811375	Moreover, the lipoate derivative CPI-613 could possibly also inhibit other mitochondrial enzyme complexes that require lipoate as coenzyme, e.g.	('mitochondrial enzyme complexes', 'Enzyme', (75, 105))	('CPI-613', 'Var', (33, 40))	('CPI-613', 'Chemical', 'MESH:C568850', (33, 40))	('lipoate', 'Chemical', '-', (119, 126))	('inhibit', 'NegReg', (61, 68))	('lipoate', 'Chemical', '-', (14, 21))
12513	27811375	However, these interpretations are speculative and CPI-613 at a concentration of 50 muM may simply not always completely block the pyruvate dehydrogenase activity.	('pyruvate dehydrogenase activity', 'MPA', (131, 162))	('block', 'NegReg', (121, 126))	('CPI-613', 'Var', (51, 58))	('CPI-613', 'Chemical', 'MESH:C568850', (51, 58))	('muM', 'Gene', '56925', (84, 87))	('pyruvate', 'Chemical', 'MESH:D019289', (131, 139))	('muM', 'Gene', (84, 87))
12521	27811375	This indicates that carnosine also inhibits other biochemical pathways required for survival even in the absence of ATP production.	('ATP', 'Chemical', 'MESH:D000255', (116, 119))	('inhibits', 'NegReg', (35, 43))	('carnosine', 'Var', (20, 29))
12522	27811375	The restoration of viability and ATP production in the experiments (C5) and (C6) whereby glucose and pyruvate are combined, demonstrates that exogenous pyruvate attenuates or even inhibits the effect of carnosine on glycolytic breakdown of glucose.	('attenuates', 'NegReg', (161, 171))	('effect', 'MPA', (193, 199))	('exogenous', 'Var', (142, 151))	('glycolytic', 'Chemical', '-', (216, 226))	('ATP', 'Chemical', 'MESH:D000255', (33, 36))	('inhibits', 'NegReg', (180, 188))	('glucose', 'Chemical', 'MESH:D005947', (89, 96))	('pyruvate', 'Chemical', 'MESH:D019289', (101, 109))	('pyruvate', 'Chemical', 'MESH:D019289', (152, 160))	('glycolytic breakdown of glucose', 'MPA', (216, 247))	('glucose', 'Chemical', 'MESH:D005947', (240, 247))
12524	27811375	Pyruvate could possibly restore NAD+ which is consumed in the glycolytic step from glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate.	('Pyruvate', 'Chemical', 'MESH:D019289', (0, 8))	('glycolytic', 'Chemical', '-', (62, 72))	('glyceraldehyde-3-phosphate', 'Chemical', 'MESH:D005986', (83, 109))	('Pyruvate', 'Var', (0, 8))	('1,3-bisphosphoglycerate', 'Chemical', 'MESH:C015891', (113, 136))	('NAD+', 'MPA', (32, 36))	('NAD+', 'Chemical', 'MESH:D009243', (32, 36))
12576	27863490	p38 also plays an important regulatory role in inducing cellular senescence, which can be triggered by Ras-Raf activation, oxidative stress, culture stress, or telomere shortening.	('activation', 'PosReg', (111, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (123, 139))	('telomere shortening', 'Phenotype', 'HP:0031413', (160, 179))	('ell', 'Gene', '8178', (57, 60))	('ell', 'Gene', (57, 60))	('p38', 'Gene', '1432', (0, 3))	('telomere', 'Var', (160, 168))	('Ras-Raf', 'Protein', (103, 110))	('p38', 'Gene', (0, 3))	('inducing', 'Reg', (47, 55))
12579	27863490	Therefore, eliciting cellular senescence or apoptosis could effectively repress immortality of GBM cancer cells and may be important for overcoming poor prognosis in GBM patients.	('patients', 'Species', '9606', (170, 178))	('ell', 'Gene', (22, 25))	('GBM cancer', 'Disease', 'MESH:D005910', (95, 105))	('repress', 'NegReg', (72, 79))	('apoptosis', 'CPA', (44, 53))	('eliciting', 'Var', (11, 20))	('immortality of', 'CPA', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ell', 'Gene', (107, 110))	('ell', 'Gene', '8178', (107, 110))	('GBM cancer', 'Disease', (95, 105))	('ell', 'Gene', '8178', (22, 25))
12591	27863490	SB203580, a specific p38 inhibitor, was purchased from Selleckchem (S1076) and dissolved in DMSO.	('DMSO', 'Chemical', 'MESH:D004121', (92, 96))	('SB203580', 'Var', (0, 8))	('p38', 'Gene', '1432', (21, 24))	('SB203580', 'Chemical', 'MESH:C093642', (0, 8))	('p38', 'Gene', (21, 24))	('ell', 'Gene', '8178', (56, 59))	('ell', 'Gene', (56, 59))
12592	27863490	The following commercial antibodies were used in Western blotting and Immunofluorescence: CD133 (Proteintech, 18470-1-AP), Bmi1 (GeneTex, GTX114008), Nanog (GeneTex, GTX100863), Oct3/4 (Santa Cruz, SC5279), Vimentin (GeneTex, GTX100619), Sox2 (GeneTex, GTX101507), tubulin (Proteintech, 66031-1-lg), PARP (Cell Signaling, 9542S), caspase-8 (GeneTex, GTX110723), caspase-9 (Cell Signaling, 9502S), caspase-3 (Cell Signaling, 9661S), cyclin B1 (Santa Cruz, SC245), CDK1 (Santa Cruz, SC8395), p21 (Cell Signaling, 2947S), PCNA (Cell Signaling, 2586S), Phospho-p38 (p-p38, T180/Y182) (Cell Signaling, 9211S), p38 (Cell Singling, 8690S), p53 (Cell Signaling, 2524S), Phospho-p53 (Ser15) (Cell Signaling, 9284S), Phospho-p53 (Ser33) (Cell Signaling, 2526S), and Alexa Fluor 594-conjugated goat anti-rabbit IgG polyclonal antibodies (Invitrogen, A-11037).	('ell', 'Gene', '8178', (496, 499))	('Bmi1', 'Gene', (123, 127))	('p53', 'Gene', (670, 673))	('p53', 'Gene', '7157', (715, 718))	('Vimentin', 'Gene', (207, 215))	('CD133', 'Gene', (90, 95))	('CD133', 'Gene', '8842', (90, 95))	('Nanog', 'Gene', '79923', (150, 155))	('caspase-8', 'Gene', (330, 339))	('ell', 'Gene', '8178', (639, 642))	('Sox2', 'Gene', (238, 242))	('ell', 'Gene', (374, 377))	('PARP', 'Gene', (300, 304))	('ell', 'Gene', (611, 614))	('Bmi1', 'Gene', '648', (123, 127))	('ell', 'Gene', '8178', (409, 412))	('ell', 'Gene', '8178', (526, 529))	('Nanog', 'Gene', (150, 155))	('caspase-3', 'Gene', '836', (397, 406))	('caspase-9', 'Gene', '842', (362, 371))	('ell', 'Gene', (729, 732))	('PCNA', 'Gene', '5111', (519, 523))	('ell', 'Gene', '8178', (582, 585))	('p38', 'Gene', (605, 608))	('Ser15', 'Chemical', '-', (675, 680))	('p53', 'Gene', (715, 718))	('caspase-3', 'Gene', (397, 406))	('p53', 'Gene', '7157', (633, 636))	('CDK1', 'Gene', (463, 467))	('CDK1', 'Gene', '983', (463, 467))	('p21', 'Gene', (490, 493))	('ell', 'Gene', '8178', (684, 687))	('p21', 'Gene', '644914', (490, 493))	('ell', 'Gene', (307, 310))	('p38', 'Gene', (564, 567))	('ell', 'Gene', (496, 499))	('cyclin B1', 'Gene', (432, 441))	('Ser33', 'Var', (720, 725))	('p53', 'Gene', (633, 636))	('Ser33', 'Chemical', '-', (720, 725))	('cyclin B1', 'Gene', '891', (432, 441))	('caspase-9', 'Gene', (362, 371))	('Sox2', 'Gene', '6657', (238, 242))	('p38', 'Gene', (557, 560))	('ell', 'Gene', '8178', (611, 614))	('rabbit', 'Species', '9986', (793, 799))	('caspase-8', 'Gene', '841', (330, 339))	('ell', 'Gene', (639, 642))	('p38', 'Gene', '1432', (605, 608))	('ell', 'Gene', (409, 412))	('ell', 'Gene', (526, 529))	('ell', 'Gene', '8178', (374, 377))	('ell', 'Gene', '8178', (729, 732))	('Oct3/4', 'Gene', '5460', (178, 184))	('ell', 'Gene', (582, 585))	('Oct3/4', 'Gene', (178, 184))	('p53', 'Gene', '7157', (670, 673))	('goat', 'Species', '9925', (783, 787))	('PARP', 'Gene', '1302', (300, 304))	('PCNA', 'Gene', (519, 523))	('Vimentin', 'Gene', '7431', (207, 215))	('ell', 'Gene', (684, 687))	('p38', 'Gene', '1432', (564, 567))	('p38', 'Gene', '1432', (557, 560))	('ell', 'Gene', '8178', (307, 310))
12613	27863490	To elucidate the effects of SAHA on GSCs, we used sphere cultures to induce spheroid bodies formation from U87MG (Fig.	('U87MG', 'Var', (107, 112))	('induce', 'PosReg', (69, 75))	('U87MG', 'CellLine', 'CVCL:0022', (107, 112))	('spheroid bodies formation', 'CPA', (76, 101))	('SAHA', 'Chemical', 'MESH:D000077337', (28, 32))
12614	27863490	1a) and U373MG (Additional file 1: Figure S1A) GBM cells, since a spheroid environment can be employed to enrich CSCs.	('U373MG', 'Var', (8, 14))	('U373MG', 'CellLine', 'CVCL:2219', (8, 14))	('ell', 'Gene', (52, 55))	('ell', 'Gene', '8178', (52, 55))
12621	27863490	Since stem cells are defined as being capable of both self-renewal and differentiation, we further studied generation of the secondary spheres from a single U87MG GSC, as well as induced cell differentiation after the spheroid body formation.	('ell', 'Gene', '8178', (188, 191))	('ell', 'Gene', (188, 191))	('U87MG', 'CellLine', 'CVCL:0022', (157, 162))	('ell', 'Gene', '8178', (172, 175))	('U87MG', 'Var', (157, 162))	('ell', 'Gene', (172, 175))	('ell', 'Gene', '8178', (12, 15))	('ell', 'Gene', (12, 15))
12624	27863490	We subsequently investigated the effects of SAHA on GBM adherent cells and GSCs, and results showed that SAHA treatment appeared to significantly inhibit cell viability in both adherent and GSCs (Fig.	('inhibit', 'NegReg', (146, 153))	('SAHA', 'Chemical', 'MESH:D000077337', (105, 109))	('SAHA', 'Chemical', 'MESH:D000077337', (44, 48))	('SAHA', 'Var', (105, 109))	('ell', 'Gene', '8178', (66, 69))	('ell', 'Gene', (155, 158))	('ell', 'Gene', (66, 69))	('ell', 'Gene', '8178', (155, 158))
12628	27863490	Furthermore, stemness-related markers such as CD133 and Bmi1 were also decreased by SAHA (Fig.	('Bmi1', 'Gene', '648', (56, 60))	('CD133', 'Gene', (46, 51))	('SAHA', 'Chemical', 'MESH:D000077337', (84, 88))	('CD133', 'Gene', '8842', (46, 51))	('SAHA', 'Var', (84, 88))	('Bmi1', 'Gene', (56, 60))	('stemness-related markers', 'CPA', (13, 37))	('decreased', 'NegReg', (71, 80))
12636	27863490	In summary, we confirmed that SAHA simultaneously inhibits cell viability and induces apoptosis at both early and late phases in GSCs.	('ell', 'Gene', '8178', (60, 63))	('induces', 'Reg', (78, 85))	('ell', 'Gene', (60, 63))	('SAHA', 'Chemical', 'MESH:D000077337', (30, 34))	('inhibits', 'NegReg', (50, 58))	('SAHA', 'Var', (30, 34))	('apoptosis', 'CPA', (86, 95))
12650	27863490	To investigate whether SAHA triggers cellular senescence via p38 activation, we used a p38-specific inhibitor, SB203580, and found that pre-treatment with SB203580 resulted in attenuation of SAHA-induced SA-beta-gal activity (Fig.	('attenuation', 'NegReg', (176, 187))	('p38', 'Gene', '1432', (61, 64))	('p38', 'Gene', (87, 90))	('SAHA', 'Chemical', 'MESH:D000077337', (23, 27))	('SA-beta', 'Gene', (204, 211))	('SB203580', 'Chemical', 'MESH:C093642', (155, 163))	('SB203580', 'Chemical', 'MESH:C093642', (111, 119))	('SA-beta', 'Gene', '9467', (204, 211))	('ell', 'Gene', (38, 41))	('SB203580', 'Var', (155, 163))	('beta-gal', 'Chemical', '-', (207, 215))	('ell', 'Gene', '8178', (38, 41))	('p38', 'Gene', '1432', (87, 90))	('p38', 'Gene', (61, 64))	('SAHA', 'Chemical', 'MESH:D000077337', (191, 195))
12651	27863490	Furthermore, low-dose SAHA-elicited phosphorylation of p38 at Thr180/Tyr182, phosphorylation of p53 at Ser33, and p53 protein levels were also significantly attenuated by SB203580 (Fig.	('attenuated', 'NegReg', (157, 167))	('phosphorylation', 'MPA', (77, 92))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('p53', 'Gene', (114, 117))	('SB203580', 'Var', (171, 179))	('p53', 'Gene', '7157', (114, 117))	('protein levels', 'MPA', (118, 132))	('SB203580', 'Chemical', 'MESH:C093642', (171, 179))	('Tyr182', 'Chemical', '-', (69, 75))	('SAHA', 'Chemical', 'MESH:D000077337', (22, 26))	('Ser33', 'Chemical', '-', (103, 108))	('p38', 'Gene', '1432', (55, 58))	('Thr180', 'Chemical', '-', (62, 68))	('phosphorylation', 'MPA', (36, 51))	('p38', 'Gene', (55, 58))
12676	27863490	Especially, these doses of SAHA triggered significant apoptosis in U87MG (p53wt) GBM cells (Fig.	('apoptosis', 'CPA', (54, 63))	('U87MG', 'CellLine', 'CVCL:0022', (67, 72))	('U87MG', 'Var', (67, 72))	('p53', 'Gene', (74, 77))	('ell', 'Gene', '8178', (86, 89))	('SAHA', 'Chemical', 'MESH:D000077337', (27, 31))	('ell', 'Gene', (86, 89))	('p53', 'Gene', '7157', (74, 77))
12677	27863490	When we further used another malignant GBM cell line, U373MG that expresses mutant p53 protein (R273H mutation, p53R273H), however, a high-dose SAHA (10 muM) inhibited cell viability in U373MG spheroids as well (Additional file 1: Figure S1).	('p53', 'Gene', (83, 86))	('R273H', 'Var', (96, 101))	('ell', 'Gene', '8178', (44, 47))	('U373MG', 'CellLine', 'CVCL:2219', (54, 60))	('U373MG', 'CellLine', 'CVCL:2219', (186, 192))	('p53', 'Gene', '7157', (112, 115))	('ell', 'Gene', '8178', (169, 172))	('R273H', 'Mutation', 'rs28934576', (115, 120))	('protein', 'Protein', (87, 94))	('muM', 'Gene', '56925', (153, 156))	('p53', 'Gene', (112, 115))	('muM', 'Gene', (153, 156))	('ell', 'Gene', '8178', (207, 210))	('ell', 'Gene', (44, 47))	('ell', 'Gene', (169, 172))	('R273H', 'Mutation', 'rs28934576', (96, 101))	('p53', 'Gene', '7157', (83, 86))	('inhibited', 'NegReg', (158, 167))	('SAHA', 'Chemical', 'MESH:D000077337', (144, 148))	('ell', 'Gene', (207, 210))
12685	27863490	Then these secondary modifications prevent the degradation of p53 and increase its apoptotic induction.	('modifications', 'Var', (21, 34))	('increase', 'PosReg', (70, 78))	('apoptotic induction', 'CPA', (83, 102))	('prevent', 'NegReg', (35, 42))	('degradation', 'MPA', (47, 58))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
12769	25832688	Two-year OS reached 26% in a subgroup of patients with a molecular profile characterized by methylation (and inactivation) of the promoter region of the MGMT (methylguanine methyl transferase) gene, responsible for expressing a DNA repair protein contributing, at least in part, to treatment resistance to alkylating agents.	('methylguanine methyl transferase', 'Gene', (159, 191))	('methylguanine methyl transferase', 'Gene', '4255', (159, 191))	('methylation', 'Var', (92, 103))	('MGMT', 'Gene', (153, 157))	('MGMT', 'Gene', '4255', (153, 157))	('OS', 'Chemical', '-', (9, 11))	('patients', 'Species', '9606', (41, 49))
12803	25821200	We surmise that NANOG potentiates the molecular circuitry of tumorigenesis, and thus may represent a novel therapeutic target or biomarker for the diagnosis, prognosis and treatment outcome of cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('potentiates', 'PosReg', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('molecular circuitry', 'MPA', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('NANOG', 'Var', (16, 21))	('tumor', 'Disease', (61, 66))
12811	25821200	Functional studies have provided compelling evidence that NANOG plays a vital role in malignant disease, correlating with cell proliferation and various malevolent properties such as clonogenic growth, tumorigenicity, invasiveness, and therapeutic resistance.	('NANOG', 'Var', (58, 63))	('tumor', 'Disease', (202, 207))	('as c', 'Gene', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('invasiveness', 'CPA', (218, 230))	('therapeutic resistance', 'CPA', (236, 258))	('malignant disease', 'Disease', 'MESH:D009369', (86, 103))	('malignant disease', 'Disease', (86, 103))	('as c', 'Gene', '29108', (180, 184))	('cell proliferation', 'CPA', (122, 140))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
12812	25821200	Among the earliest work, ectopic expression of mouse and human NANOG in NIH3T3 cells, respectively, promoted entry into S-phase and foci formation in soft agar.	('human', 'Species', '9606', (57, 62))	('NIH3T3', 'CellLine', 'CVCL:0594', (72, 78))	('entry', 'MPA', (109, 114))	('promoted', 'PosReg', (100, 108))	('NANOG', 'Gene', (63, 68))	('agar', 'Chemical', 'MESH:D000362', (155, 159))	('ectopic expression', 'Var', (25, 43))	('mouse', 'Species', '10090', (47, 52))	('foci formation in soft agar', 'CPA', (132, 159))
12814	25821200	Overexpression of NANOG in immortalized but benign HEK-293 cells promoted malignant transformation, accompanied by enhanced proliferation, anchorage-independent growth in soft agar and, importantly, tumor formation in athymic nude mice.	('tumor', 'Disease', (199, 204))	('HEK-293', 'CellLine', 'CVCL:0045', (51, 58))	('NANOG', 'Var', (18, 23))	('proliferation', 'CPA', (124, 137))	('nude mice', 'Species', '10090', (226, 235))	('malignant transformation', 'CPA', (74, 98))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('promoted', 'PosReg', (65, 73))	('anchorage-independent growth in soft agar', 'CPA', (139, 180))	('enhanced', 'PosReg', (115, 123))	('agar', 'Chemical', 'MESH:D000362', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
12816	25821200	For example, unlike transgenic mouse models in which Oct4 overexpression caused dysplastic and aggressive tumor-like growths in a remarkably short time frame in the skin and intestinal epithelia, Nanog overexpression in two similar doxycycline-inducible transgenic mouse models induced only modest hyperplastic outgrowths in the intestinal and colonic epithelium and stratified epithelium of the forestomach and esophagus.	('mouse', 'Species', '10090', (265, 270))	('mouse', 'Species', '10090', (31, 36))	('hyperplastic outgrowths in', 'CPA', (298, 324))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('intestinal epithelia', 'Disease', (174, 194))	('dysplastic', 'Disease', 'MESH:D004416', (80, 90))	('dysplastic', 'Disease', (80, 90))	('intestinal epithelia', 'Disease', 'MESH:D007410', (174, 194))	('Nanog', 'Var', (196, 201))	('doxycycline', 'Chemical', 'MESH:D004318', (232, 243))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('hyperplastic outgrowths', 'Phenotype', 'HP:0001548', (298, 321))	('tumor', 'Disease', (106, 111))
12819	25821200	However, when co-expressed with Wnt-1, Nanog enhanced mammary tumorigenesis and metastasis.	('Wnt-1', 'Gene', (32, 37))	('metastasis', 'CPA', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Nanog', 'Var', (39, 44))	('tumor', 'Disease', (62, 67))	('enhanced', 'PosReg', (45, 53))	('Wnt-1', 'Gene', '7471', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
12820	25821200	Consequently, NANOG seems to function as a cooperating or potentiating protumorigenic molecule in the appropriate context.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NANOG', 'Var', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('potentiating', 'PosReg', (58, 70))
12824	25821200	It is currently unknown to what degree the three full-length NANOG protein variants potentially encoded by NANOG1, NANOG2 and NANOGP8 loci possess unique biochemical activities or biological properties.	('NANOG1', 'Gene', (107, 113))	('NANOGP8', 'Gene', '388112', (126, 133))	('NANOG1', 'Gene', '79923', (107, 113))	('NANOG2', 'Gene', '404635', (115, 121))	('NANOG protein', 'Gene', (61, 74))	('NANOG2', 'Gene', (115, 121))	('variants', 'Var', (75, 83))	('NANOGP8', 'Gene', (126, 133))
12825	25821200	Although NANOG2 mRNA is quite distinct from that derived from either of the other 2 loci due to alternative 5' exon usage (encoding a shorter NANOG2 protein with an alternative N-terminus), NANOG1 and NANOGP8 only differ by a single conserved amino acid (aa), with both encoding proteins of 305 aa and NANOGP8 harboring a Q253H substitution in the C-terminal transactivation domain (Fig.	('NANOG1', 'Gene', (190, 196))	('NANOG1', 'Gene', '79923', (190, 196))	('NANOG2', 'Gene', '404635', (142, 148))	('NANOGP8', 'Gene', (201, 208))	('NANOG2', 'Gene', '404635', (9, 15))	('NANOGP8', 'Gene', '388112', (302, 309))	('Q253H', 'Mutation', 'rs4041291', (322, 327))	('NANOGP8', 'Gene', '388112', (201, 208))	('NANOG2', 'Gene', (9, 15))	('Q253H', 'Var', (322, 327))	('NANOG2', 'Gene', (142, 148))	('NANOGP8', 'Gene', (302, 309))
12826	25821200	One strategy relies on direct sequencing of the open reading frame to detect the 759G>C that results in the Q253H aa change in NANOGP8 (Fig.	('759G>C', 'Mutation', 'rs4041291', (81, 87))	('results in', 'Reg', (93, 103))	('NANOGP8', 'Gene', '388112', (127, 134))	('Q253H aa change', 'Var', (108, 123))	('Q253H', 'Mutation', 'rs4041291', (108, 113))	('NANOGP8', 'Gene', (127, 134))	('759G>C', 'Var', (81, 87))
12836	25821200	Thus, as a consequence of cis-element differences, trans factors regulating NANOG mRNA transcriptional activation or repression in cancer cells will vary depending on the locus-of-origin for NANOG expression and the cellular context.	('cancer', 'Disease', (131, 137))	('differences', 'Var', (38, 49))	('mRNA transcriptional', 'MPA', (82, 102))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('activation', 'PosReg', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('NANOG', 'Gene', (76, 81))
12845	25821200	Using fluorescent, ubiquitin-sensitive cell cycle reporters, human ESCs were recently shown to be particularly susceptible to differentiation in G1, such that altering the cell cycle of ESCs facilitates changes in cell specification.	('cell cycle', 'CPA', (172, 182))	('altering', 'Var', (159, 167))	('facilitates', 'PosReg', (191, 202))	('changes', 'Reg', (203, 210))	('human', 'Species', '9606', (61, 66))	('cell specification', 'CPA', (214, 232))
12848	25821200	pulled down with Nanog1 in murine ESCs, overexpression of Mbd3-the essential scaffold of the NuRD complex- has been found to augment Nanog-mediated reprogramming of murine MEFs.	('Nanog1', 'Gene', '79923', (17, 23))	('Mbd3', 'Gene', (58, 62))	('Nanog1', 'Gene', (17, 23))	('MEFs', 'CellLine', 'CVCL:9115', (172, 176))	('augment', 'PosReg', (125, 132))	('Nanog-mediated reprogramming of murine', 'CPA', (133, 171))	('murine', 'Species', '10090', (165, 171))	('overexpression', 'Var', (40, 54))	('murine', 'Species', '10090', (27, 33))	('Mbd3', 'Gene', '17192', (58, 62))
12855	25821200	Oncomine analysis reveals that NANOG mRNA is elevated in many types of cancer relative to matched benign tissues (Fig.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('NANOG', 'Var', (31, 36))	('types', 'Disease', (62, 67))	('elevated', 'PosReg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
12857	25821200	The presence of NANOG in neoplastic cells suggests a functional role for this molecule in tumor development or disease progression.	('disease progression', 'CPA', (111, 130))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('NANOG', 'Var', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
12859	25821200	Compelling evidence suggests that NANOG may foster CSC traits by imbuing subsets of cancer cells with self-renewal potential, thereby bolstering the immortality of the entire tumor population.	('CSC traits', 'Disease', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (175, 180))	('foster', 'PosReg', (44, 50))	('cancer', 'Disease', (84, 90))	('NANOG', 'Var', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('bolstering', 'NegReg', (134, 144))
12863	25821200	THIRD, in contrast, RNAi-mediated NANOG knockdown leads to attenuated CSC properties such as sphere formation and clonogenic efficiency in breast and prostate cancer cells.	('sphere formation', 'CPA', (93, 109))	('CSC properties', 'CPA', (70, 84))	('RNAi-mediated', 'Gene', (20, 33))	('knockdown', 'Var', (40, 49))	('attenuated', 'NegReg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('clonogenic efficiency', 'CPA', (114, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (139, 165))
12867	25821200	Similar scenarios have been reported in response to NANOG inhibition in a variety of other cell types, such as glioblastoma and breast and prostate carcinoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('glioblastoma', 'Disease', (111, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('NANOG', 'Var', (52, 57))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (139, 157))	('inhibition', 'NegReg', (58, 68))	('breast and prostate carcinoma', 'Disease', 'MESH:D011472', (128, 157))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))
12868	25821200	Interestingly, NANOG knockdown in breast cancer cells appeared to modulate cell cycle progression by inducing G0/G1 arrest correlating with decreased levels of the cell cycle regulatory protein cyclin D1.	('decreased', 'NegReg', (140, 149))	('cyclin D1', 'Gene', '595', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('cyclin D1', 'Gene', (194, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('inducing', 'Reg', (101, 109))	('NANOG', 'Var', (15, 20))	('cell cycle progression', 'CPA', (75, 97))	('levels of the', 'MPA', (150, 163))	('knockdown', 'Var', (21, 30))	('arrest', 'Disease', (116, 122))	('modulate', 'Reg', (66, 74))
12869	25821200	Unlike engineered reprogramming to generate iPS cells, deregulated and abnormal expression of NANOG (and/or other stem cell related factors) could foster 'oncogenic reprogramming' facilitating dynamic acquisition of states enhancing the adaptability of tumor cells to the gauntlet of challenges neoplastic cells face during tumor development and disease progression.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('enhancing', 'PosReg', (223, 232))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	("'oncogenic reprogramming'", 'CPA', (154, 179))	('foster', 'PosReg', (147, 153))	('tumor', 'Disease', (253, 258))	('deregulated', 'Var', (55, 66))	('NANOG', 'Gene', (94, 99))	('adaptability', 'MPA', (237, 249))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('abnormal expression', 'Var', (71, 90))
12871	25821200	Thus, NANOG-expressing cancer cells have been observed to mediate therapy resistance, tumor recurrence, and distant metastasis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('distant metastasis', 'CPA', (108, 126))	('therapy resistance', 'CPA', (66, 84))	('tumor', 'Disease', (86, 91))	('mediate', 'Reg', (58, 65))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('NANOG-expressing', 'Var', (6, 22))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
12876	25821200	NANOG expressing cancer cells purportedly possess enhanced capabilities to evade the immune system.	('NANOG', 'Var', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('evade', 'CPA', (75, 80))	('enhanced', 'PosReg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
12879	25821200	Mechanistically, NANOG induced CSC phenotypes and immune evasion through T cell leukemia/lymphoma 1A/Akt (Tcl1a/Akt) in human cervical cancer, a signaling axis potentially conserved in a variety of other cancer types.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('T cell leukemia', 'Phenotype', 'HP:0005517', (73, 88))	('Akt', 'Gene', '207', (112, 115))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('immune evasion', 'MPA', (50, 64))	('Tcl1a', 'Gene', (106, 111))	('cancer', 'Disease', (135, 141))	('human', 'Species', '9606', (120, 125))	('Akt', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cervical cancer', 'Disease', (126, 141))	('cervical cancer', 'Disease', 'MESH:D002583', (126, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('leukemia', 'Disease', (80, 88))	('leukemia', 'Disease', 'MESH:D007938', (80, 88))	('Akt', 'Gene', '207', (101, 104))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('CSC', 'Disease', (31, 34))	('Tcl1a', 'Gene', '8115', (106, 111))	('lymphoma', 'Disease', (89, 97))	('NANOG', 'Var', (17, 22))	('lymphoma', 'Disease', 'MESH:D008223', (89, 97))	('Akt', 'Gene', (112, 115))
12880	25821200	Furthermore, NANOG expression levels correlate with stage and prognosis of cervical cancer in patients, suggesting that NANOG may foster the development and progression of cervical cancer by facilitating immune evasion capabilities among CSCs.	('immune evasion capabilities', 'MPA', (204, 231))	('NANOG', 'Var', (120, 125))	('foster', 'PosReg', (130, 136))	('facilitating', 'PosReg', (191, 203))	('patients', 'Species', '9606', (94, 102))	('cervical cancer', 'Disease', 'MESH:D002583', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cervical cancer', 'Disease', (75, 90))	('progression', 'CPA', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('development', 'CPA', (141, 152))	('cervical cancer', 'Disease', (172, 187))	('cervical cancer', 'Disease', 'MESH:D002583', (172, 187))
12882	25821200	Although amplification of the short arm of chromosome 12 encoding NANOG is a 'hotspot' for oncogenic transformation and considered pathognomonic in male germ cell tumors (for a review, see), our focus here is on somatic human cancers.	('amplification', 'Var', (9, 22))	('human', 'Species', '9606', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('short arm', 'Phenotype', 'HP:0009824', (30, 39))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('tumors', 'Disease', (163, 169))	('cancers', 'Disease', (226, 233))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('NANOG', 'Gene', (66, 71))	('germ cell tumors', 'Phenotype', 'HP:0100728', (153, 169))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
12887	25821200	In contrast, knocking down NANOG in undifferentiated, PSA-/lo CSCs inhibited xenograft tumor regeneration.	('knocking down', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibited', 'NegReg', (67, 76))	('tumor', 'Disease', (87, 92))	('NANOG', 'Gene', (27, 32))	('PSA', 'Gene', '354', (54, 57))	('PSA', 'Gene', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
12888	25821200	In support of this suggestion and of potential interest, NANOG mRNA is elevated in some PCa metastases (Fig.	('elevated', 'PosReg', (71, 79))	('PCa metastases', 'Disease', (88, 102))	('PCa metastases', 'Disease', 'MESH:D009362', (88, 102))	('NANOG mRNA', 'Var', (57, 67))
12889	25821200	2B, left) and in PCa harboring ETS2 deletion (Fig.	('deletion', 'Var', (36, 44))	('ETS2', 'Gene', '2114', (31, 35))	('PCa', 'Disease', (17, 20))	('ETS2', 'Gene', (31, 35))
12890	25821200	NANOG protein is heterogeneously expressed as a gradient in PCa cells and enriched in CD44+ and CD44+CD133+ cells (compared to marker-negative cells) and in primary tumor samples (compared to long-term cultured cells).	('primary tumor', 'Disease', 'MESH:D009369', (157, 170))	('NANOG', 'Protein', (0, 5))	('CD44+', 'Var', (86, 91))	('CD44+CD133+', 'Var', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('primary tumor', 'Disease', (157, 170))
12891	25821200	Interestingly, NANOG appeared to inversely correlate with expression of androgen receptor, suggesting a possible mechanism by which NANOG may promote castration resistance.	('androgen receptor', 'Gene', (72, 89))	('castration resistance', 'CPA', (150, 171))	('androgen receptor', 'Gene', '367', (72, 89))	('NANOG', 'Var', (132, 137))	('promote', 'PosReg', (142, 149))
12897	25821200	That NANOG was epistatic to CD24 and critical for the tumorigenicity of these cells was demonstrated by the ability of NANOG overexpression to rescue tumor development in CD24 knockdown cells and to enhance serial sphere formation.	('enhance', 'PosReg', (199, 206))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CD24', 'Gene', '100133941', (171, 175))	('CD24', 'Gene', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CD24', 'Gene', '100133941', (28, 32))	('overexpression', 'PosReg', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (54, 59))	('CD24', 'Gene', (28, 32))	('rescue', 'PosReg', (143, 149))	('tumor', 'Disease', (150, 155))	('NANOG', 'Var', (119, 124))	('serial sphere formation', 'CPA', (207, 230))
12902	25821200	The co-expression of NANOG and P-SMAD3 may be a potential predictor of poor prognosis for HCC patients.	('patients', 'Species', '9606', (94, 102))	('co-expression', 'Var', (4, 17))	('NANOG', 'Gene', (21, 26))	('SMAD3', 'Gene', '4088', (33, 38))	('SMAD3', 'Gene', (33, 38))	('HCC', 'Disease', (90, 93))
12907	25821200	RNAi-mediated NANOG attenuation in T-ALL cells was associated with loss of proliferation, reduced self-renewal, and increased apoptosis via blocking cell cycle progression through p53 signaling.	('blocking', 'NegReg', (140, 148))	('RNAi-mediated', 'Gene', (0, 13))	('self-renewal', 'CPA', (98, 110))	('reduced', 'NegReg', (90, 97))	('NANOG', 'Var', (14, 19))	('p53', 'Gene', (180, 183))	('p53', 'Gene', '7157', (180, 183))	('apoptosis', 'CPA', (126, 135))	('cell cycle progression', 'CPA', (149, 171))	('loss', 'NegReg', (67, 71))	('attenuation', 'NegReg', (20, 31))	('proliferation', 'CPA', (75, 88))
12921	25821200	In a study of 163 lung cancer patients, the expression levels of NANOG protein in lung cancer tissues were upregulated compared to the normal lung tissues and positively correlated with clinical stages.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('NANOG', 'Var', (65, 70))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('correlated', 'Reg', (170, 180))	('patients', 'Species', '9606', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('lung cancer', 'Disease', (18, 29))	('upregulated', 'PosReg', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('expression levels', 'MPA', (44, 61))
12922	25821200	Furthermore, NANOG overexpression predicted a worse prognosis for lung cancer patients.	('overexpression', 'PosReg', (19, 33))	('NANOG', 'Var', (13, 18))	('lung cancer', 'Disease', (66, 77))	('patients', 'Species', '9606', (78, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
12926	25821200	For example, NANOG knockdown in MCF-7 cells inhibited tumor growth, sphere formation and drug resistance and blocked cell cycle progression, colony formation and migration.	('colony formation', 'CPA', (141, 157))	('cell cycle progression', 'CPA', (117, 139))	('migration', 'CPA', (162, 171))	('NANOG knockdown', 'Var', (13, 28))	('inhibited', 'NegReg', (44, 53))	('blocked', 'NegReg', (109, 116))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('sphere formation', 'CPA', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('MCF-7', 'CellLine', 'CVCL:0031', (32, 37))	('drug resistance', 'CPA', (89, 104))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))
12929	25821200	Regardless of the underlying mechanisms, there exists solid evidence linking NANOG to breast cancer chemotherapy resistance.	('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))	('NANOG', 'Var', (77, 82))
12930	25821200	In a tissue microarray analysis of 43 human pancreatic cancer, IHC for NANOG and OCT4 followed by Kaplan-Meier analysis revealed that high NANOG (and OCT4) expression predicted a worse prognosis and inversely correlated with patient survival.	('pancreatic cancer', 'Disease', 'MESH:D010190', (44, 61))	('human', 'Species', '9606', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('high', 'Var', (134, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('patient', 'Species', '9606', (225, 232))	('OCT4', 'Gene', (150, 154))	('pancreatic cancer', 'Disease', (44, 61))
12946	25821200	Furthermore, NANOG itself may represent a therapeutic target as its elimination is predicted to ablate CSC self-renewal and root out the cause of tumor recurrence and metastasis.	('ablate', 'NegReg', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('elimination', 'Var', (68, 79))	('CSC self-renewal', 'CPA', (103, 119))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
12956	25821200	In more advanced disease stages, could NANOGP8 expression preferentially potentiate metastatic propensity or resistance to conventional therapy?	('metastatic propensity', 'CPA', (84, 105))	('expression', 'Var', (47, 57))	('NANOGP8', 'Gene', (39, 46))	('potentiate', 'PosReg', (73, 83))	('NANOGP8', 'Gene', '388112', (39, 46))	('resistance', 'CPA', (109, 119))	('preferentially', 'PosReg', (58, 72))
12984	26157286	Few studies have evaluated the frequency and impact of MGMT methylation in pediatric GBM (pGBM) and it ranges from 11% to 60% in the reported literature and patients with methylated MGMT have superior survival as compared to their un-methylated counterparts.	('MGMT', 'Gene', (182, 186))	('MGMT', 'Gene', '4255', (55, 59))	('methylated', 'Var', (171, 181))	('MGMT', 'Gene', (55, 59))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('patients', 'Species', '9606', (157, 165))	('superior', 'PosReg', (192, 200))	('survival', 'CPA', (201, 209))	('pGBM', 'Chemical', '-', (90, 94))	('GBM', 'Disease', (85, 88))	('MGMT', 'Gene', '4255', (182, 186))
13021	26157286	of 8 patients, in whom sufficient biopsy material was available for testing promoter methylation of MGMT, 4 had methylated and 4 had unmethylated tumor.	('MGMT', 'Gene', '4255', (100, 104))	('patients', 'Species', '9606', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('promoter', 'MPA', (76, 84))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('methylated', 'Var', (112, 122))	('MGMT', 'Gene', (100, 104))
13038	26157286	Three of the 4 patients with methylated MGMT and only 1 of 4 patients with unmethylated MGMT were alive at the time of last follow-up.	('patients', 'Species', '9606', (15, 23))	('MGMT', 'Gene', '4255', (40, 44))	('patients', 'Species', '9606', (61, 69))	('MGMT', 'Gene', (40, 44))	('MGMT', 'Gene', (88, 92))	('MGMT', 'Gene', '4255', (88, 92))	('methylated', 'Var', (29, 39))
13040	26157286	Adjuvant TMZ was associated with better survival as compared to no adjuvant TMZ (median survival 41.9 months vs. 8.06 months; P = 0.0812) [Figure 2].	('Adjuvant', 'Var', (0, 8))	('TMZ', 'Chemical', 'MESH:D000077204', (9, 12))	('better', 'PosReg', (33, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (76, 79))
13044	26157286	Despite having a denovo occurrence, pGBM exhibit high incidence of p53 mutations and low incidence of epidermal growth-factor receptor (EGFR) amplification, which are features of adult secondary GBM.	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('epidermal growth-factor receptor', 'Gene', (102, 134))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('mutations', 'Var', (71, 80))	('GBM', 'Phenotype', 'HP:0012174', (195, 198))	('epidermal growth-factor receptor', 'Gene', '1956', (102, 134))	('pGBM', 'Chemical', '-', (36, 40))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
13046	26157286	have shown that p53 alteration is more frequent in pGBM to a tune of 63%, whereas EGFR over-expression was found in 23% with rare occurrence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deletion.	('deletion', 'Var', (207, 215))	('EGFR', 'Gene', (82, 86))	('PTEN', 'Gene', (201, 205))	('frequent', 'Reg', (39, 47))	('alteration', 'Var', (20, 30))	('p53', 'Gene', (16, 19))	('PTEN', 'Gene', '5728', (201, 205))	('p53', 'Gene', '7157', (16, 19))	('pGBM', 'Chemical', '-', (51, 55))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('EGFR', 'Gene', '1956', (82, 86))	('pGBM', 'Disease', (51, 55))
13051	26157286	In the study by Pollack et al., low levels of MGMT expression also correlated with improved progression-free survival (PFS).	('improved', 'PosReg', (83, 91))	('MGMT', 'Gene', (46, 50))	('MGMT', 'Gene', '4255', (46, 50))	('Pollack', 'Species', '185739', (16, 23))	('progression-free survival', 'CPA', (92, 117))	('low levels', 'Var', (32, 42))
13106	25240597	There have been efforts to overcome TMZ resistance by depleting MGMT using O6-benzylguanine, a pseudo-substrate of MGMT or inhibiting MGMT using interferon (IFN)-beta, a STAT3 inhibitor, levetiracetam or the wtp53 tumor suppressor gene.	('inhibiting', 'NegReg', (123, 133))	('STAT3', 'Gene', '20848', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('depleting', 'NegReg', (54, 63))	('TMZ', 'Chemical', 'MESH:D000077204', (36, 39))	('STAT3', 'Gene', (170, 175))	('O6-benzylguanine', 'Var', (75, 91))	('levetiracetam', 'Chemical', 'MESH:D000077287', (187, 200))	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (214, 219))
13107	25240597	Mutations in p53 are found frequently in GBM tumors (~30% and ~65% of primary and secondary GBM, respectively) and the p53 pathway is functionally inactivated in almost all GBM.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('p53 pathway', 'Pathway', (119, 130))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('GBM tumors', 'Disease', (41, 51))	('GBM tumors', 'Disease', 'MESH:D005910', (41, 51))
13108	25240597	Thus, p53 gene therapy has potential for use as an adjunct to conventional cancer treatments.	('p53', 'Gene', (6, 9))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('gene therapy', 'Var', (10, 22))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
13109	25240597	We have developed a tumor-targeting nanocomplex platform technology (designated as "scL") for delivery of molecular medicines - including plasmid DNA, small interfering RNA, and small molecules - selectively to both bulk tumor cells and cancer stem cells (CSCs) of primary and metastatic tumors.	('tumor', 'Disease', (288, 293))	('tumors', 'Disease', (288, 294))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('small', 'Var', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('cancer', 'Disease', (237, 243))	('tumor', 'Disease', (20, 25))
13115	25240597	In addition, we have previously demonstrated that abrogation of MGMT activity mediated by SGT-53 was able to reverse TMZ resistance and enhance the anti-cancer efficacy of TMZ in MGMT-proficient and inherently TMZ-resistant GBM cells both in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('TMZ', 'Chemical', 'MESH:D000077204', (210, 213))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('cancer', 'Disease', (153, 159))	('abrogation', 'Var', (50, 60))	('TMZ resistance', 'MPA', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('enhance', 'PosReg', (136, 143))	('SGT-53', 'Chemical', '-', (90, 96))	('SGT-53', 'Gene', (90, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (172, 175))
13134	25240597	In both cell lines, transfection with SGT-53 resulted in significantly increased response to TMZ compared to TMZ treatment alone or TMZ in combination with scL-vec.	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('TMZ', 'Chemical', 'MESH:D000077204', (93, 96))	('transfection', 'Var', (20, 32))	('SGT-53', 'Chemical', '-', (38, 44))	('TMZ', 'Chemical', 'MESH:D000077204', (109, 112))	('increased', 'PosReg', (71, 80))	('SGT-53', 'Gene', (38, 44))	('response to TMZ', 'MPA', (81, 96))
13135	25240597	In the U87 cells (Figure 1, A), transfection with SGT-53 decreased the IC50 from >40 muM to 16.3 muM, at least a 2.5-fold increase in sensitivity to TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (149, 152))	('muM', 'Gene', (85, 88))	('SGT-53', 'Chemical', '-', (50, 56))	('sensitivity to TMZ', 'MPA', (134, 152))	('SGT-53', 'Gene', (50, 56))	('muM', 'Gene', '56925', (85, 88))	('muM', 'Gene', '56925', (97, 100))	('IC50', 'MPA', (71, 75))	('muM', 'Gene', (97, 100))	('transfection', 'Var', (32, 44))	('decreased', 'NegReg', (57, 66))	('increase', 'PosReg', (122, 130))
13139	25240597	In both cell lines the survival curves after treatment with scL-vec are comparable to those after treatment with TMZ alone, demonstrating that the response in these cell lines is likely due to the presence of exogenous wtp53 and not a result of non-specific cytotoxicity of the delivery system.	('cytotoxicity', 'Disease', (258, 270))	('TMZ', 'Chemical', 'MESH:D000077204', (113, 116))	('cytotoxicity', 'Disease', 'MESH:D064420', (258, 270))	('wtp53', 'Var', (219, 224))
13155	25240597	Therefore, this experiment demonstrates that tumor-targeted delivery of wtp53 via the scL nanodelivery system (SGT-53) can further sensitize even TMZ-responsive GBM tumors to TMZ leading to enhanced tumor response (regression), not just tumor growth inhibition.	('tumor', 'Disease', (45, 50))	('TMZ', 'Chemical', 'MESH:D000077204', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('GBM tumors', 'Disease', (161, 171))	('wtp53', 'Var', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('enhanced', 'PosReg', (190, 198))	('tumor', 'Disease', (199, 204))	('GBM tumors', 'Disease', 'MESH:D005910', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('SGT-53', 'Chemical', '-', (111, 117))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', (237, 242))	('TMZ', 'Chemical', 'MESH:D000077204', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
13159	25240597	The tumors from animals that received both SGT-53 and TMZ showed significantly decreased size (16.2 +- 3.1 mg) compared to those which received vehicle control treatment (118.6 +- 16.9 mg) or single agent treatments (56.4 +- 11.2 and 40.1 +- 9.4 mg for SGT-53 and TMZ, respectively) (Figure 3, B).	('TMZ', 'Var', (54, 57))	('SGT-53', 'Chemical', '-', (43, 49))	('TMZ', 'Chemical', 'MESH:D000077204', (264, 267))	('decreased', 'NegReg', (79, 88))	('SGT-53', 'Var', (43, 49))	('SGT-53', 'Chemical', '-', (253, 259))	('tumors', 'Disease', (4, 10))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
13160	25240597	In addition, as shown in Figure 3, C, analysis of the level of apoptosis using the Annexin V assay showed an increase in the percent of Annexin V+ tumor cells after treatment with SGT-53 and TMZ combination (65.3 +- 7.7%) compared to vehicle-treated control (5.5 +- 1.0%) or either treatment alone (11.9 +- 1.8% and 37.2 +- 15.0% for SGT-53 and TMZ, respectively) (Figure 3, D).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('Annexin V', 'Gene', (136, 145))	('Annexin V', 'Gene', '11747', (136, 145))	('Annexin V', 'Gene', (83, 92))	('TMZ', 'Chemical', 'MESH:D000077204', (345, 348))	('increase', 'PosReg', (109, 117))	('TMZ', 'Chemical', 'MESH:D000077204', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Annexin V', 'Gene', '11747', (83, 92))	('SGT-53', 'Chemical', '-', (334, 340))	('SGT-53', 'Chemical', '-', (180, 186))	('SGT-53', 'Var', (180, 186))
13161	25240597	Furthermore, we also observed an increase in the percent of cells in sub-G1 confirming increased apoptosis in tumor treated with SGT-53 plus TMZ (27.2 +- 9.9%) compared to those treated with vehicle (1.4 +- 0.3%) or single agent (3.1 +- 0.9% and 12.6 +- 0.2% for SGT-53 and TMZ, respectively) (Figure 3, E).	('SGT-53', 'Chemical', '-', (263, 269))	('increased', 'PosReg', (87, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (141, 144))	('SGT-53', 'Chemical', '-', (129, 135))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('TMZ', 'Chemical', 'MESH:D000077204', (274, 277))	('SGT-53', 'Var', (129, 135))	('apoptosis', 'CPA', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
13170	25240597	In contrast, the combination of TMZ and SGT-53 clearly showed a strong, statistically significant survival benefit with a median survival of 53 days, which is prolongation of 29 days compared to the vehicle-treated controls.	('TMZ', 'Var', (32, 35))	('combination', 'Var', (17, 28))	('SGT-53', 'Chemical', '-', (40, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (32, 35))	('SGT-53', 'Gene', (40, 46))	('survival benefit', 'CPA', (98, 114))
13177	25240597	Thus, the combination of SGT-53 and TMZ resulted in a significant increase in long-term survival in this mouse model.	('long-term survival', 'CPA', (78, 96))	('increase', 'PosReg', (66, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (36, 39))	('SGT-53', 'Chemical', '-', (25, 31))	('SGT-53', 'Gene', (25, 31))	('combination', 'Interaction', (10, 21))	('mouse', 'Species', '10090', (105, 110))	('TMZ', 'Var', (36, 39))
13181	25240597	We found that SGT-53 treatment also sensitized CD133+ CSCs to TMZ treatment (Figure 4, C).	('treatment', 'Var', (21, 30))	('SGT-53', 'Chemical', '-', (14, 20))	('TMZ', 'Chemical', 'MESH:D000077204', (62, 65))	('sensitized', 'Reg', (36, 46))	('SGT-53', 'Gene', (14, 20))
13183	25240597	In contrast, in the mice treated with SGT-53 alone the percent of apoptotic cells was only 6.7 and 6.0% for CD133+ and CD133-, respectively, while in those treated with TMZ alone it was just 7.7 and 9.8% for CD133+ and CD133- cells, respectively.	('apoptotic cells', 'CPA', (66, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (169, 172))	('mice', 'Species', '10090', (20, 24))	('CD133-', 'Var', (119, 125))	('SGT-53', 'Chemical', '-', (38, 44))	('SGT-53', 'Gene', (38, 44))	('CD133+', 'Var', (108, 114))
13187	25240597	To assess the effect of repeated treatment cycles of SGT-53 plus TMZ, compared with TMZ alone, mice with established IC U87-luc2 tumors received either one or two cycles of SGT-53 plus TMZ, at a dose of only 7.5 mg/m2, an extremely low dose, as the standard dose for use in patients is 150 mg/m2.	('TMZ', 'Chemical', 'MESH:D000077204', (185, 188))	('mice', 'Species', '10090', (95, 99))	('SGT-53', 'Chemical', '-', (53, 59))	('IC U87-luc2 tumors', 'Disease', 'MESH:C537984', (117, 135))	('SGT-53', 'Var', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('patients', 'Species', '9606', (274, 282))	('IC U87-luc2 tumors', 'Disease', (117, 135))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('SGT-53', 'Chemical', '-', (173, 179))	('TMZ', 'Chemical', 'MESH:D000077204', (65, 68))
13196	25240597	However, the addition of SGT-53 to the TMZ treatment regimen did provide a significant survival benefit.	('survival benefit', 'CPA', (87, 103))	('TMZ', 'Chemical', 'MESH:D000077204', (39, 42))	('SGT-53', 'Chemical', '-', (25, 31))	('addition', 'Var', (13, 21))	('SGT-53', 'Gene', (25, 31))
13205	25240597	These results suggested that the addition of SGT-53 to the TMZ treatment regimen could help to abrogate or delay the development of TMZ resistance.	('development', 'MPA', (117, 128))	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('abrogate', 'NegReg', (95, 103))	('addition', 'Var', (33, 41))	('delay', 'NegReg', (107, 112))	('SGT-53', 'Chemical', '-', (45, 51))	('SGT-53', 'Gene', (45, 51))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
13210	25240597	Compared to untreated U87R cells, transfection with SGT-53 resulted in significant silencing of MGMT expression which inversely correlated with p53 expression.	('transfection', 'Var', (34, 46))	('SGT-53', 'Chemical', '-', (52, 58))	('SGT-53', 'Gene', (52, 58))	('U87R', 'CellLine', 'CVCL:0022', (22, 26))	('silencing', 'NegReg', (83, 92))	('MGMT', 'Gene', (96, 100))
13212	25240597	This down-modulation lasted to at least 72 h post-SGT-53 transfection.	('down-modulation', 'NegReg', (5, 20))	('SGT-53', 'Chemical', '-', (50, 56))	('post-SGT-53', 'Gene', (45, 56))	('transfection', 'Var', (57, 69))
13217	25240597	Mirroring the results with the western blot analysis showing MGMT down-modulation, transfection with SGT-53 resulted in a 27-fold increase in sensitization to TMZ in the U87R cells, compared to treatment with TMZ alone (IC50 values of 50 muM and 1350 muM, respectively) (Figure 6, B).	('muM', 'Gene', '56925', (251, 254))	('TMZ', 'Chemical', 'MESH:D000077204', (159, 162))	('SGT-53', 'Chemical', '-', (101, 107))	('SGT-53', 'Gene', (101, 107))	('muM', 'Gene', (251, 254))	('U87R', 'CellLine', 'CVCL:0022', (170, 174))	('muM', 'Gene', '56925', (238, 241))	('muM', 'Gene', (238, 241))	('transfection', 'Var', (83, 95))	('increase', 'PosReg', (130, 138))	('TMZ', 'Chemical', 'MESH:D000077204', (209, 212))	('down-modulation', 'NegReg', (66, 81))	('sensitization to TMZ', 'MPA', (142, 162))
13219	25240597	The most benefit was evident in a subset of GBM patients who have an aberrantly hypermethylated MGMT promoter, because they lack MGMT protein expression.	('lack', 'NegReg', (124, 128))	('aberrantly hypermethylated', 'Var', (69, 95))	('MGMT', 'MPA', (129, 133))	('patients', 'Species', '9606', (48, 56))	('MGMT promoter', 'Gene', (96, 109))
13226	25240597	None-the-less, transfection of TMZ-resistant U87R cells with SGT-53 yielded a time dependent inverse correlation between p53 and MGMT protein levels demonstrating that this increase in MGMT expression could be reversed by p53.	('SGT-53', 'Chemical', '-', (61, 67))	('SGT-53', 'Gene', (61, 67))	('MGMT protein levels', 'MPA', (129, 148))	('p53', 'MPA', (121, 124))	('U87R', 'CellLine', 'CVCL:0022', (45, 49))	('inverse', 'NegReg', (93, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (31, 34))	('transfection', 'Var', (15, 27))
13227	25240597	Moreover, in vitro studies showed that transfection of these TMZ-resistant U87R cells with SGT-53 also resulted in a dramatic increase in sensitivity to TMZ and an increased level of cell death.	('transfection', 'Var', (39, 51))	('SGT-53', 'Chemical', '-', (91, 97))	('SGT-53', 'Gene', (91, 97))	('U87R', 'CellLine', 'CVCL:0022', (75, 79))	('TMZ', 'Chemical', 'MESH:D000077204', (153, 156))	('sensitivity to TMZ', 'MPA', (138, 156))	('TMZ', 'Chemical', 'MESH:D000077204', (61, 64))	('increase', 'PosReg', (126, 134))	('cell death', 'CPA', (183, 193))
13230	25240597	In contrast, in the mice that received both SGT-53 and TMZ, survival benefit was maintained, and further extended, by adding a second treatment cycle.	('TMZ', 'Chemical', 'MESH:D000077204', (55, 58))	('SGT-53', 'Chemical', '-', (44, 50))	('mice', 'Species', '10090', (20, 24))	('SGT-53', 'Var', (44, 50))	('TMZ', 'Var', (55, 58))
13232	25240597	These findings suggest that SGT delivered p53 can, maintain U87 tumor sensitivity to TMZ during repeated cycles of treatments possibly through an effect on MGMT expression.	('SGT', 'Chemical', '-', (28, 31))	('tumor', 'Disease', (64, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (85, 88))	('maintain', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('p53', 'Var', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
13239	25240597	Importantly, this potentiation effect seems to exist independent of the endogenous p53 status as sensitization of both wild-type p53 (U87) and mutant p53 (U251), TMZ-sensitive, GBM cells was observed in vitro.	('p53', 'Gene', (150, 153))	('TMZ', 'Chemical', 'MESH:D000077204', (162, 165))	('mutant', 'Var', (143, 149))
13240	25240597	Transfection of these cells with SGT-53 resulted in a dramatic increase in response and level of apoptosis after TMZ treatment.	('increase', 'PosReg', (63, 71))	('SGT-53', 'Chemical', '-', (33, 39))	('SGT-53', 'Gene', (33, 39))	('response', 'MPA', (75, 83))	('Transfection', 'Var', (0, 12))	('TMZ', 'Chemical', 'MESH:D000077204', (113, 116))	('level of apoptosis', 'MPA', (88, 106))
13246	25240597	As such tumors will likely develop TMZ-resistance during treatment, our results also suggest that even in patients who initially respond to TMZ, the combination of SGT-53 and TMZ may delay development of TMZ-resistance resulting in improved outcome compared to TMZ treatment alone, the current standard of care.	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('outcome', 'MPA', (241, 248))	('TMZ', 'Chemical', 'MESH:D000077204', (261, 264))	('development', 'MPA', (189, 200))	('TMZ', 'Chemical', 'MESH:D000077204', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TMZ', 'Chemical', 'MESH:D000077204', (140, 143))	('SGT-53', 'Chemical', '-', (164, 170))	('combination', 'Var', (149, 160))	('tumors', 'Disease', (8, 14))	('TMZ', 'Chemical', 'MESH:D000077204', (175, 178))	('patients', 'Species', '9606', (106, 114))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('SGT-53', 'Gene', (164, 170))	('delay', 'NegReg', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('improved', 'PosReg', (232, 240))	('delay development', 'Phenotype', 'HP:0001263', (183, 200))
13248	25240597	Due to the tumor-targeting ability, BBB penetrance, and proven safety of SGT-53, we believe that the combination of SGT-53 plus conventional chemo- and/or radiotherapy could bring about a significant decrease in treatment resistance and recurrence, resulting in improvement in survival for GBM patients.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('improvement', 'PosReg', (262, 273))	('SGT-53', 'Chemical', '-', (116, 122))	('tumor', 'Disease', (11, 16))	('SGT-53', 'Var', (116, 122))	('patients', 'Species', '9606', (294, 302))	('SGT-53', 'Chemical', '-', (73, 79))	('treatment resistance', 'CPA', (212, 232))	('recurrence', 'CPA', (237, 247))	('GBM', 'Disease', (290, 293))	('survival', 'MPA', (277, 285))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('decrease', 'NegReg', (200, 208))	('combination', 'Interaction', (101, 112))
13249	24659686	COX-2 overexpression increases malignant potential of human glioma cells through Id1 Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients.	('increases', 'PosReg', (21, 30))	('patients', 'Species', '9606', (212, 220))	('Increased', 'PosReg', (85, 94))	('glioma', 'Disease', (60, 66))	('COX-2', 'Gene', (95, 100))	('COX-2', 'Gene', '5743', (0, 5))	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('expression', 'Species', '29278', (101, 111))	('glioma', 'Disease', (137, 143))	('glioblastoma', 'Disease', (193, 205))	('COX-2', 'Gene', '5743', (95, 100))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('GBM', 'Phenotype', 'HP:0012174', (207, 210))	('human', 'Species', '9606', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('expression', 'Species', '29278', (10, 20))	('shorter', 'NegReg', (173, 180))	('COX-2', 'Gene', (0, 5))	('expression', 'MPA', (101, 111))	('Id1', 'Var', (81, 84))
13254	24659686	GBM cells with COX-2 overexpression show increased growth of colonies in soft agar.	('agar', 'Chemical', 'MESH:D000362', (78, 82))	('expression', 'Species', '29278', (25, 35))	('increased', 'PosReg', (41, 50))	('overexpression', 'Var', (21, 35))	('growth', 'CPA', (51, 57))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('COX-2', 'Gene', (15, 20))
13256	24659686	COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma transformation', 'Disease', 'MESH:D005910', (95, 116))	('Id1', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('overexpression', 'Var', (6, 20))	('tumor', 'Disease', (117, 122))	('expression', 'Species', '29278', (10, 20))	('expression', 'Species', '29278', (33, 43))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('expression', 'MPA', (33, 43))	('glioma transformation', 'Disease', (95, 116))	('COX-2', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
13259	24659686	Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells.	('GBM', 'Phenotype', 'HP:0012174', (9, 12))	('expression', 'Species', '29278', (41, 51))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Id1', 'Gene', (33, 36))	('increased', 'PosReg', (146, 155))	('microvessel density', 'CPA', (156, 175))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('migration/invasive', 'CPA', (65, 83))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('rat', 'Species', '10116', (68, 71))	('overexpression', 'Var', (37, 51))	('COX-2', 'Gene', (24, 29))	('greater', 'PosReg', (57, 64))
13263	24659686	Elevated COX-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('COX-2', 'Gene', (9, 14))	('angiogenesis', 'CPA', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('promotion', 'PosReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('increased', 'PosReg', (34, 43))	('Elevated', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
13268	24659686	In fact, high Id1 levels correlate strongly with poor prognosis, chemoresistance and tumor metastases.	('poor prognosis', 'CPA', (49, 63))	('tumor metastases', 'Disease', (85, 101))	('high', 'Var', (9, 13))	('tumor metastases', 'Disease', 'MESH:D009362', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Id1', 'Protein', (14, 17))	('chemoresistance', 'CPA', (65, 80))
13293	24659686	Assessment of Id1 overexpressors and corresponding vector only controls revealed a significant increase in the colony forming capabilities of glioma cells expressing Id1 (Fig.	('glioma', 'Disease', (142, 148))	('increase', 'PosReg', (95, 103))	('colony forming capabilities', 'CPA', (111, 138))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('Id1', 'Var', (166, 169))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))
13297	24659686	In each case, Id1 knockdown resulted in significant decreases in the formation of soft agar colonies (Fig.	('knockdown', 'Var', (18, 27))	('decreases', 'NegReg', (52, 61))	('agar', 'Chemical', 'MESH:D000362', (87, 91))	('Id1', 'Gene', (14, 17))	('formation of soft agar colonies', 'CPA', (69, 100))
13298	24659686	We next sought to achieve long-term suppression of Id1 in preparation for in vivo analysis by infecting our glioma cells with a retroviral vector expressing shRNA against Id1.	('rat', 'Species', '10116', (63, 66))	('glioma', 'Disease', (108, 114))	('Id1', 'Gene', (171, 174))	('infecting', 'Reg', (94, 103))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('shRNA', 'Var', (157, 162))
13299	24659686	These results show that in vitro transformation of glioma cells is increased by expression of both COX-2 and Id1 and that Id1 appears to be a critical factor downstream of COX-2 important for this process.	('glioma', 'Disease', (51, 57))	('Id1', 'Gene', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('expression', 'Species', '29278', (80, 90))	('increased', 'PosReg', (67, 76))	('COX-2', 'Gene', (99, 104))	('expression', 'Var', (80, 90))
13308	24659686	As shown on the graph, COX-2 overexpression in SF767 significantly increased tumor growth in mice treated with vehicle only (Fig.	('overexpression', 'PosReg', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'Species', '29278', (33, 43))	('increased', 'PosReg', (67, 76))	('COX-2', 'Enzyme', (23, 28))	('mice', 'Species', '10090', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SF767', 'Var', (47, 52))	('tumor', 'Disease', (77, 82))
13310	24659686	As expected, the proliferative indices of flank tumors derived from SF767/COX-2 cells were significantly higher than those of tumors derived from SF767/Ctr cells (Fig.	('flank tumors', 'Disease', (42, 54))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('higher', 'PosReg', (105, 111))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('proliferative indices', 'CPA', (17, 38))	('SF767/COX-2', 'Var', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('rat', 'Species', '10116', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('flank tumors', 'Disease', 'MESH:D021501', (42, 54))
13314	24659686	Therefore, these results strongly suggest that COX-2 overexpression enhances not only in vitro transformation of glioma cells but also in vivo tumor growth in a process that is mainly mediated by Id1.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('tumor', 'Disease', (143, 148))	('enhances', 'PosReg', (68, 76))	('COX-2', 'Gene', (47, 52))	('glioma', 'Disease', (113, 119))	('overexpression', 'Var', (53, 67))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'Species', '29278', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
13317	24659686	Brain tumors derived from LN229/COX-2 and LN229/Id1 cells were visibly larger than those derived from corresponding control cells harvested at the same time point (Fig.	('LN229', 'CellLine', 'CVCL:0393', (42, 47))	('LN229/COX-2', 'Var', (26, 37))	('Brain tumors', 'Disease', 'MESH:D001932', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('larger', 'PosReg', (71, 77))	('LN229/Id1', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('Brain tumors', 'Phenotype', 'HP:0030692', (0, 12))	('LN229', 'CellLine', 'CVCL:0393', (26, 31))	('Brain tumors', 'Disease', (0, 12))
13320	24659686	Thus, both COX-2 and Id1 expression also enhances tumorigenicity of glioma cells in an intracranial tumor model.	('intracranial tumor', 'Disease', (87, 105))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('expression', 'Species', '29278', (25, 35))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Id1', 'Gene', (21, 24))	('enhances', 'PosReg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('intracranial tumor', 'Disease', 'MESH:D001932', (87, 105))	('glioma', 'Disease', (68, 74))	('expression', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (50, 55))	('COX-2', 'Gene', (11, 16))
13324	24659686	Microvessel density of flank tumors derived from SF767/Ctr and /COX-2 4L were initially compared.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('flank tumors', 'Disease', 'MESH:D021501', (23, 35))	('flank tumors', 'Disease', (23, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('SF767/Ctr', 'Var', (49, 58))
13329	24659686	Finally, similar to our results demonstrating a significant role for Id1 expression in COX-2-mediated transformation and tumorigenesis, we found that shRNA knockdown of Id1 in LN229/COX-2 cells results in about 60% decrease in microvessel density with this representing a statistically significant difference (Fig.	('decrease', 'NegReg', (215, 223))	('knockdown', 'Var', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('microvessel density', 'CPA', (227, 246))	('LN229', 'CellLine', 'CVCL:0393', (176, 181))	('expression', 'Species', '29278', (73, 83))	('tumor', 'Disease', (121, 126))	('rat', 'Species', '10116', (39, 42))	('Id1', 'Gene', (169, 172))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
13337	24659686	Repeat of the invasion assay with LN229/COX-2 cells transfected with either control (siC) or the two Id1 (si1/2) siRNAs and showed that knockdown of Id1 significantly reduced the ability of these cells to traverse through Matrigel in the invasion chamber (Fig.	('LN229', 'CellLine', 'CVCL:0393', (34, 39))	('knockdown', 'Var', (136, 145))	('si1/2', 'Gene', (106, 111))	('Id1', 'Gene', (149, 152))	('si1/2', 'Gene', '56731', (106, 111))	('reduced', 'NegReg', (167, 174))	('traverse through Matrigel in the invasion chamber', 'CPA', (205, 254))
13339	24659686	To assess whether Id1 enhances growth of glioma stem cells, we harvested flank tumors derived from LN229/Ctr and LN229/Id1 cells and made single cell suspensions that were then cultured in serum-free conditions designed to promote proliferation of neural stem cells within neurospheres.	('flank tumors', 'Disease', 'MESH:D021501', (73, 85))	('LN229/Id1', 'Var', (113, 122))	('flank tumors', 'Disease', (73, 85))	('promote', 'PosReg', (223, 230))	('enhances', 'PosReg', (22, 30))	('Id1', 'Var', (18, 21))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('LN229', 'CellLine', 'CVCL:0393', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('glioma', 'Disease', (41, 47))	('LN229', 'CellLine', 'CVCL:0393', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('rat', 'Species', '10116', (238, 241))
13342	24659686	Representative pictures show clear formation of cellular clusters representing early neurosphere formation in tumors overexpressing Id1 while corresponding cultures of cells from control tumors do not show this clustering (Fig.	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('overexpressing', 'Var', (117, 131))	('Id1', 'Gene', (132, 135))
13347	24659686	Finally, Id1 also enhances our ability to grow out GICs, or glioma stem cells as neurospheres in tumors that overexpress this transcriptional regulator.	('overexpress', 'PosReg', (109, 120))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('glioma', 'Disease', (60, 66))	('tumors', 'Disease', (97, 103))	('Id1', 'Var', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('enhances', 'PosReg', (18, 26))	('grow out GICs', 'CPA', (42, 55))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
13349	24659686	In our current report, we clearly show that COX-2 expression is pro-angiogenic in gliomas with increased microvessel density in tumors derived from glioma cells engineered to overexpress COX-2 (Fig.	('glioma', 'Disease', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('tumors', 'Disease', (128, 134))	('gliomas', 'Disease', (82, 89))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', (82, 88))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('pro-angiogenic', 'PosReg', (64, 78))	('expression', 'Var', (50, 60))	('COX-2', 'Gene', (44, 49))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('microvessel density', 'CPA', (105, 124))	('expression', 'Species', '29278', (50, 60))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('increased', 'PosReg', (95, 104))
13352	24659686	More importantly, knockdown of Id1 expression in glioma cells overexpressing COX-2 reduced the microvessel count in tumors derived from such cells by roughly half (Fig.	('microvessel', 'MPA', (95, 106))	('knockdown', 'Var', (18, 27))	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('reduced', 'NegReg', (83, 90))	('expression', 'Species', '29278', (35, 45))	('COX-2', 'Gene', (77, 82))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Id1', 'Gene', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('glioma', 'Disease', (49, 55))
13354	24659686	found that E2-2, a basic HLH transcription factor, can suppress expression of vascular endothelial growth factor receptor 2 (VEGFR2) and Id1-mediated inhibition of E2-2 may enhance VEGFR2 expression and angiogenesis.	('expression', 'Species', '29278', (188, 198))	('expression', 'MPA', (64, 74))	('E2-2', 'Gene', '106478911', (11, 15))	('inhibition', 'Var', (150, 160))	('expression', 'MPA', (188, 198))	('E2-2', 'Gene', (164, 168))	('enhance', 'PosReg', (173, 180))	('VEGFR2', 'Gene', (125, 131))	('VEGFR2', 'Gene', (181, 187))	('expression', 'Species', '29278', (64, 74))	('E2-2', 'Gene', (11, 15))	('E2-2', 'Gene', '106478911', (164, 168))	('angiogenesis', 'CPA', (203, 215))	('suppress', 'NegReg', (55, 63))
13355	24659686	Additionally, Id1 can downregulate the angiogenic inhibitor thrombospondin-1 (TSP1) and promote neovascularization.	('thrombospondin-1', 'Gene', '7057', (60, 76))	('downregulate', 'NegReg', (22, 34))	('neovascularization', 'CPA', (96, 114))	('promote', 'PosReg', (88, 95))	('Id1', 'Var', (14, 17))	('TSP1', 'Gene', '7057', (78, 82))	('TSP1', 'Gene', (78, 82))	('thrombospondin-1', 'Gene', (60, 76))
13369	24659686	However, this was a relatively small study with no selection for glioblastomas with high COX-2 expression, the subgroup that would be most likely to respond to CXB therapy.	('high', 'Var', (84, 88))	('CXB', 'Chemical', 'MESH:D000068579', (160, 163))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('expression', 'Species', '29278', (95, 105))	('COX-2', 'Gene', (89, 94))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('expression', 'MPA', (95, 105))
13375	24659686	found that TGF-beta signaling is linked to high Id1 expression in their glioblastoma models and specific inhibition of TGF-beta in their models can reduce the glioma initiating cell (GIC) population through suppression of Id1 expression.	('glioma', 'Disease', (159, 165))	('Id1', 'Gene', (222, 225))	('inhibition', 'Var', (105, 115))	('expression', 'Species', '29278', (226, 236))	('expression', 'Species', '29278', (52, 62))	('expression', 'MPA', (226, 236))	('suppression', 'NegReg', (207, 218))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('Id1', 'Gene', (48, 51))	('glioblastoma', 'Disease', (72, 84))	('TGF-beta', 'Gene', (119, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('reduce', 'NegReg', (148, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
13377	24659686	found that Id1 increases the invasive phenotype in gliomas and can similarly enhance the aggressiveness of orthotopic tumors.	('gliomas', 'Disease', (51, 58))	('aggressiveness of orthotopic tumors', 'Disease', 'MESH:D001523', (89, 124))	('Id1', 'Var', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('invasive phenotype', 'CPA', (29, 47))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('aggressiveness of orthotopic tumors', 'Disease', (89, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('increases', 'PosReg', (15, 24))	('enhance', 'PosReg', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (51, 58))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))
13380	24659686	While high COX-2 expression is clearly linked to increasing glioma grade and is associated with worse outcomes in patients with this disease, to our knowledge, our report is the first to demonstrate that COX-2 has direct transforming activity by increasing the malignancy of glioma cells both in vitro and in vivo.	('glioma', 'Disease', (275, 281))	('increasing', 'PosReg', (246, 256))	('glioma', 'Disease', 'MESH:D005910', (275, 281))	('glioma', 'Disease', (60, 66))	('associated', 'Reg', (80, 90))	('malignancy of glioma', 'Phenotype', 'HP:0012174', (261, 281))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('malignancy of glioma', 'Disease', (261, 281))	('COX-2', 'Gene', (204, 209))	('expression', 'MPA', (17, 27))	('high', 'Var', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('patients', 'Species', '9606', (114, 122))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('malignancy of glioma', 'Disease', 'MESH:D005910', (261, 281))	('transforming activity', 'MPA', (221, 242))	('COX-2', 'Gene', (11, 16))	('expression', 'Species', '29278', (17, 27))	('rat', 'Species', '10116', (194, 197))	('increasing', 'PosReg', (49, 59))
13383	24659686	The enhanced green fluorescent protein (EGFP) and rat COX-2 cDNAs were inserted downstream of the CMV promoter in an MuLV-based retroviral vector containing the neomycin resistance gene (pKX95) to create pKX139 and pKX104C, respectively, as described previously.	('neomycin', 'Chemical', 'MESH:D009355', (161, 169))	('rat', 'Species', '10116', (50, 53))	('pKX104C', 'Mutation', 'pKX104C', (215, 222))	('enhanced', 'Protein', (4, 12))	('pKX104C', 'Var', (215, 222))	('pKX139', 'Var', (204, 210))
13390	24659686	For transient Id1 knockdown by siRNA suppression, SF767 and LN229 cells were transfected with siRNA against Id1 (Integrated DNA Technologies, Coralville, IA) using Lipofectamine 2000 (Invitrogen).	('knockdown', 'Var', (18, 27))	('rat', 'Species', '10116', (118, 121))	('IA', 'Disease', 'MESH:C536041', (154, 156))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (164, 182))	('Id1', 'Gene', (14, 17))	('LN229', 'CellLine', 'CVCL:0393', (60, 65))	('Id1', 'Gene', (108, 111))
13391	24659686	For stable Id1 knockdown, SF767/COX-2 and LN229/COX-2 cells were successively infected with conditioned media from the Phoenix cells transfected with the shId1 retroviral construct or corresponding control and selected with 2 mug/ml puromycin.	('LN229', 'CellLine', 'CVCL:0393', (42, 47))	('puromycin', 'Chemical', 'MESH:D011691', (233, 242))	('Id1', 'Gene', (11, 14))	('knockdown', 'Var', (15, 24))
13425	33389825	The variation of array positioning increased skin-NTCP by a factor of only 3.54 (95%, CI: 2.36-5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes).	('skin-NTCP', 'MPA', (45, 54))	('NTCP', 'Chemical', '-', (50, 54))	('increased', 'PosReg', (35, 44))	('variation', 'Var', (4, 13))
13426	33389825	NTCP showed a significant rank correlation with D25cm2 over all patients and scenarios (rs = 0.76; P < 0.0001).	('patients', 'Species', '9606', (64, 72))	('D25cm2', 'Var', (48, 54))	('NTCP', 'Gene', (0, 4))	('NTCP', 'Chemical', '-', (0, 4))
13428	33389825	Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.	('NTCP', 'Chemical', '-', (95, 99))	('surface dose', 'CPA', (73, 85))	('mitigate', 'NegReg', (29, 37))	('skin-NTCP', 'CPA', (90, 99))	('variation', 'Var', (15, 24))
13431	33389825	4  Previous studies showed that concurrent TTField- and radiotherapy treatment may cause both, an increased buildup effect and an increased back scatter effect on exit dose, leading to increased skin toxicity.	('buildup effect', 'MPA', (108, 122))	('back scatter effect', 'MPA', (140, 159))	('TTField-', 'Var', (43, 51))	('men', 'Species', '9606', (74, 77))	('increased', 'PosReg', (130, 139))	('increased', 'PosReg', (185, 194))	('skin toxicity', 'Disease', (195, 208))	('skin toxicity', 'Disease', 'MESH:D012871', (195, 208))
13447	33389825	This variation of TTField array position from fixation period to fixation period resulted in 95% confidence ellipses with a mean half-length of the major axis of about 2.7 cm and of the minor axis of about 1.8 cm.	('ellipses', 'Species', '301928', (108, 116))	('TTField', 'Gene', (18, 25))	('variation', 'Var', (5, 14))	('resulted', 'Reg', (81, 89))
13474	33389825	Combining the variation of array position with irradiation without electrodes 2 days per week, the days of array change, reduced the increase in skin NTCP in comparison to irradiation without electrodes further to a factor 1.88 (95% CI: 1.24-2.83) (P = 0.0049, F-test, scenario 5 vs. scenario 1).	('variation', 'Var', (14, 23))	('reduced', 'NegReg', (121, 128))	('skin NTCP', 'MPA', (145, 154))	('NTCP', 'Chemical', '-', (150, 154))
13512	33364191	Patients with Ki-67 expression of >30% seemed to perform better than patients with expression levels of <=20% (p=0.03).	('a', 'Gene', '351', (70, 71))	('Ki-67', 'Gene', (14, 19))	('a', 'Gene', '351', (66, 67))	('expression', 'Var', (20, 30))	('a', 'Gene', '351', (1, 2))	('Patients', 'Species', '9606', (0, 8))	('Ki-67', 'Gene', '17345', (14, 19))	('patients', 'Species', '9606', (69, 77))	('better', 'PosReg', (57, 63))
13557	33364191	The markers were chosen from a larger molecular panel including MGMT promotor methylation, IDH1/2 mutation, BRAF (V600E) mutation, 1p19q-deletion, TERT promotor mutation as well as the IHC-markers (ATRX, CD44, EGFRvIII, TP53 etc.)	('TP53', 'Gene', (220, 224))	('EGFR', 'Gene', (210, 214))	('ATRX', 'Gene', '546', (198, 202))	('a', 'Gene', '351', (49, 50))	('a', 'Gene', '351', (190, 191))	('a', 'Gene', '351', (32, 33))	('MGMT', 'Gene', '4255', (64, 68))	('TERT', 'Gene', (147, 151))	('a', 'Gene', '351', (101, 102))	('TERT', 'Gene', '7015', (147, 151))	('a', 'Gene', '351', (29, 30))	('a', 'Gene', '351', (84, 85))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))	('IDH1/2', 'Gene', '3417;3418', (91, 97))	('V600E', 'Mutation', 'rs113488022', (114, 119))	('EGFR', 'Gene', '1956', (210, 214))	('TP53', 'Gene', '7157', (220, 224))	('1p19q-deletion', 'Var', (131, 145))	('a', 'Gene', '351', (164, 165))	('IDH1/2', 'Gene', (91, 97))	('a', 'Gene', '351', (170, 171))	('a', 'Gene', '351', (45, 46))	('a', 'Gene', '351', (124, 125))	('MGMT', 'Gene', (64, 68))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (178, 179))	('ATRX', 'Gene', (198, 202))
13593	33364191	Postponing SRT to 4-13 months after the end of primary radiotherapy was associated with prolonged survival (p < 0.05).	('a', 'Gene', '351', (64, 65))	('a', 'Gene', '351', (69, 70))	('a', 'Gene', '351', (72, 73))	('a', 'Gene', '351', (56, 57))	('a', 'Gene', '351', (51, 52))	('a', 'Gene', '351', (104, 105))	('Postponing', 'Var', (0, 10))	('a', 'Gene', '351', (78, 79))	('prolonged', 'PosReg', (88, 97))	('a', 'Gene', '351', (30, 31))
13662	32899203	It is characterized by a severe immunosuppressive milieu mostly triggered by suppressive CD163+ tumor-associated macrophages (TAMs).	('CD163+', 'Var', (89, 95))	('TAMs', 'Chemical', '-', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('severe immunosuppressive milieu', 'Phenotype', 'HP:0004430', (25, 56))
13665	32899203	Results: CD163+ cells were the most common cell type in both the PTA and TC.	('PTA', 'Disease', (65, 68))	('CD163+ cells', 'Var', (9, 21))	('common', 'Reg', (36, 42))	('TC', 'Chemical', '-', (73, 75))	('PTA', 'Chemical', '-', (65, 68))
13674	32899203	The most established molecular biomarker for predicting the outcome of GBM is methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter, associated with a positive response to temozolomide, which is used in first-line treatment in combination with radiotherapy.	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('methylation', 'Var', (78, 89))	('temozolomide', 'Chemical', 'MESH:D000077204', (192, 204))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (97, 135))	('O6-methylguanine-DNA methyltransferase', 'Gene', (97, 135))	('positive', 'PosReg', (171, 179))	('MGMT', 'Gene', (137, 141))	('MGMT', 'Gene', '4255', (137, 141))
13675	32899203	On the basis of the presence of recurrent hotspot mutations in isocitrate dehydrogenases (IDH1/2), GBMs are currently distinguished as isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype.	('isocitrate dehydrogenase', 'Gene', (135, 159))	('IDH', 'Gene', '3417', (161, 164))	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('IDH', 'Gene', (90, 93))	('isocitrate dehydrogenase', 'Gene', '3417', (135, 159))	('mutations', 'Var', (50, 59))	('IDH', 'Gene', (176, 179))	('IDH', 'Gene', '3417', (90, 93))	('isocitrate dehydrogenase', 'Gene', '3417', (63, 87))	('hotspot', 'PosReg', (42, 49))	('IDH1/2', 'Gene', '3417;3418', (90, 96))	('IDH', 'Gene', '3417', (176, 179))	('isocitrate dehydrogenase', 'Gene', (63, 87))	('IDH', 'Gene', (161, 164))	('IDH1/2', 'Gene', (90, 96))
13676	32899203	IDH mutations are found in the majority of secondary GBMs (70-80%) but only rarely in primary GBMs.	('IDH', 'Gene', (0, 3))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('IDH', 'Gene', '3417', (0, 3))	('found', 'Reg', (18, 23))	('mutations', 'Var', (4, 13))	('secondary GBMs', 'Disease', (43, 57))
13681	32899203	From an immunological point of view, GBM is characterized by a immunosuppressive microenvironment; even though the numbers of T-cells are typically normal among patients, an immunosuppressive population of CD163+ M2-like tumor-associated macrophages (M2-like TAMs) tends to be prevalent, spurring recent interest in this population as a possible target for novel strategies in immunotherapy.	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('patients', 'Species', '9606', (161, 169))	('CD163+ M2-like', 'Var', (206, 220))	('TAMs', 'Chemical', '-', (259, 263))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
13693	32899203	Automatic IHC was performed on an automated immunohistochemical stainer (Leica Bond III) with specific antibodies (Ab) against GFAP, R132H mutation in isocitrate dehydrogenase 1 (IDH1-R132H), vascular endothelial growth factor (VEGF), CD3, programmed death 1 (PD-1) and PD-1 ligand (PDL-1), diluted with BOND Primary Antibody Diluent (Leica Biosystems, Newcastle, United Kingdom) according to the manufacturer's instructions.	('IDH', 'Gene', (179, 182))	('IDH', 'Gene', '3417', (179, 182))	('vascular endothelial growth factor', 'Gene', (192, 226))	('PD-1', 'Gene', (260, 264))	('R132H', 'Mutation', 'p.R132H', (184, 189))	('GFAP', 'Gene', (127, 131))	('VEGF', 'Gene', (228, 232))	('death', 'Disease', (251, 256))	('death', 'Disease', 'MESH:D003643', (251, 256))	('vascular endothelial growth factor', 'Gene', '7422', (192, 226))	('R132H', 'Var', (133, 138))	('R132H', 'Mutation', 'p.R132H', (133, 138))	('GFAP', 'Gene', '2670', (127, 131))	('isocitrate dehydrogenase', 'Gene', '3417', (151, 175))	('isocitrate dehydrogenase', 'Gene', (151, 175))	('VEGF', 'Gene', '7422', (228, 232))
13697	32899203	The sections were then washed in phosphate-buffered saline (PBS) and Tween 20 (3 min, 0.1% Tween 20 in PBS; 3 min PBS), and each diluted primary Ab was added to the tissue; the mixtures were incubated overnight at 4  C. The following Abs were employed: anti-Foxp3, CD163, anti-IDO and anti-TIGIT (see Supplementary Table S1 for details).	('phosphate-buffered', 'Chemical', '-', (33, 51))	('IDO', 'Gene', '3620', (277, 280))	('Foxp3', 'Gene', (258, 263))	('Tween 20', 'Chemical', 'MESH:D011136', (69, 77))	('saline', 'Chemical', 'MESH:D012965', (52, 58))	('IDO', 'Gene', (277, 280))	('TIGIT', 'Gene', '201633', (290, 295))	('PBS', 'Chemical', '-', (60, 63))	('TIGIT', 'Gene', (290, 295))	('CD163', 'Var', (265, 270))	('Tween 20', 'Chemical', 'MESH:D011136', (91, 99))	('PBS', 'Chemical', '-', (114, 117))	('PBS', 'Chemical', '-', (103, 106))	('Foxp3', 'Gene', '50943', (258, 263))
13715	32899203	One (GBM07) tested positive for the IDH1 R132H mutation, proving evolution from a previously diagnosed anaplastic astrocytoma.	('GBM', 'Phenotype', 'HP:0012174', (5, 8))	('R132H', 'Var', (41, 46))	('R132H', 'Mutation', 'p.R132H', (41, 46))	('IDH', 'Gene', (36, 39))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (103, 125))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('IDH', 'Gene', '3417', (36, 39))	('anaplastic astrocytoma', 'Disease', (103, 125))
13722	32899203	The immune infiltrate was characterized by the presence of CD3+ cells (T-cells) and CD163+ cells (M2-like tumor associated macrophages, M2-TAMs), regarded as immunosuppressive and pro-tumoral cells, and FoxP3+ cells (activated T regulatory cells, Treg) in serial and consecutive sections.	('FoxP3', 'Gene', '50943', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('FoxP3', 'Gene', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (184, 189))	('CD163+ cells', 'Var', (84, 96))	('TAMs', 'Chemical', '-', (139, 143))	('CD3+', 'Var', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
13728	32899203	Notably, both the CD3 and CD163 staining in the PTA were positive mainly at the perivascular level, while in the TC, the same staining could be largely found inside the parenchyma, thus indicating a preferential infiltration of CD3+ and CD163+ cells into the tumor tissue when compared to the periphery, probably due to a strong recruitment exerted by the GBM cells.	('TC', 'Chemical', '-', (113, 115))	('CD3+', 'Var', (228, 232))	('CD163+', 'Var', (237, 243))	('CD163', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('GBM', 'Phenotype', 'HP:0012174', (356, 359))	('CD3', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Disease', (259, 264))	('PTA', 'Chemical', '-', (48, 51))
13733	32899203	This scenario highlights the fact that in the presence of a CD163+ population with such a direct negative effect on anti-tumor immune cells, treatment via the activation of effector cells would be difficult without either depleting CD163+ cells or reprogramming their immunosuppressive functions.	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('CD163+', 'Var', (60, 66))
13734	32899203	Moreover, it is possible to note that most of the patients showed a notable presence of immunological markers within the TC, at both the perivascular and infiltrating levels, with a significant prevalence of immunosuppressive markers such as CD163, IDO, PDL-1 and, to a lesser extent, TIGIT and FoxP3.	('TIGIT', 'Gene', (285, 290))	('FoxP3', 'Gene', (295, 300))	('patients', 'Species', '9606', (50, 58))	('immunosuppressive', 'MPA', (208, 225))	('IDO', 'Gene', (249, 252))	('PDL-1', 'Gene', (254, 259))	('TC', 'Chemical', '-', (121, 123))	('presence', 'Reg', (76, 84))	('CD163', 'Var', (242, 247))	('TIGIT', 'Gene', '201633', (285, 290))	('immunological markers', 'MPA', (88, 109))	('FoxP3', 'Gene', '50943', (295, 300))	('IDO', 'Gene', '3620', (249, 252))
13746	32899203	FoxP3 positivity, indicating the presence of Treg cells, was found only in the TC of GBM01 and 06 samples, while all the PTAs tested were negative.	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('FoxP3', 'Gene', (0, 5))	('positivity', 'Var', (6, 16))	('TC', 'Chemical', '-', (79, 81))	('FoxP3', 'Gene', '50943', (0, 5))	('PTA', 'Chemical', '-', (121, 124))
13750	32899203	Interestingly, the only patient showing PD-1 positivity in the PTA (GBM08) had no PD-1 in the TC.	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('positivity', 'Var', (45, 55))	('patient', 'Species', '9606', (24, 31))	('TC', 'Chemical', '-', (94, 96))	('PTA', 'Chemical', '-', (63, 66))	('PD-1', 'Gene', (40, 44))
13752	32899203	Another interesting observation is that while all the patients tested positive for CD3+ cells inside the TC, only four were also positive for PD-1.	('patients', 'Species', '9606', (54, 62))	('TC', 'Chemical', '-', (105, 107))	('positive', 'Reg', (70, 78))	('CD3+ cells', 'Var', (83, 93))
13766	32899203	In the PTA, the number of CD163+ cells was much higher than that of CD3+ cells.	('PTA', 'Chemical', '-', (7, 10))	('higher', 'PosReg', (48, 54))	('CD163+ cells', 'Var', (26, 38))
13772	32899203	Similarly to GBM03 and 04, GBM09 was characterized by the presence of CD3- and CD163-positive cells in both the PTA and TC, with a higher intensity and number of positive cells in neoplastic areas; TIGIT expression was found in the tumor core, while the periphery was almost completely negative for all the other analyzed markers.	('GBM09', 'Var', (27, 32))	('TC', 'Chemical', '-', (120, 122))	('TIGIT', 'Gene', '201633', (198, 203))	('CD3-', 'Gene', (70, 74))	('TIGIT', 'Gene', (198, 203))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('PTA', 'Chemical', '-', (112, 115))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('CD163-positive', 'Gene', (79, 93))	('higher', 'PosReg', (131, 137))
13779	32899203	A peculiar immune profile was found in the GBM08 sample; it was the only one to express PD-1+ cells in periphery of the tumor in association with a high expression of PDL-1 and CD163, while no positivity for PD-1 was found in the TC.	('PD-1+ cells', 'Var', (88, 99))	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('CD163', 'Gene', (177, 182))	('PDL-1', 'Gene', (167, 172))	('TC', 'Chemical', '-', (230, 232))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
13783	32899203	Interestingly, this sample was the only one to harbor the IDH1 mutation, which has been previously shown to be associated with an immune-quiescence of tumors.	('IDH', 'Gene', '3417', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (63, 71))	('IDH', 'Gene', (58, 61))
13803	32899203	It is important to note that we demonstrated how both CD163+ and CD3+ cells showed a similar gradient from the periphery to the tumor area, with most of them localizing in the bulk of the tumor.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('CD163+', 'Var', (54, 60))
13814	32899203	To strengthen these ideas, we reported that the only patient that tested positive for the IDH1 mutation showed a lack of immune cells in both the PTA and TC.	('IDH', 'Gene', (90, 93))	('TC', 'Chemical', '-', (154, 156))	('PTA', 'Chemical', '-', (146, 149))	('IDH', 'Gene', '3417', (90, 93))	('patient', 'Species', '9606', (53, 60))	('mutation', 'Var', (95, 103))
13878	28638001	However, other features can be preferentially striking in GBM compared with PCNSL, and vice versa.	('PCNSL', 'Chemical', '-', (76, 81))	('GBM', 'Var', (58, 61))	('striking', 'Reg', (46, 54))
13882	28638001	This may be explained by greater image heterogeneity (larger deviation of voxel intensity) of GBM compared with PCNSL.	('greater', 'PosReg', (25, 32))	('GBM', 'Var', (94, 97))	('PCNSL', 'Chemical', '-', (112, 117))
13911	27323851	WHO grade III, also known as anaplastic diffuse gliomas, are characterized by histological (astrocytic, oligodendrocytic) and molecular varieties (IDH1/2, ATRX, TERT promoter mutation, 1p/19q deletion, etc.).	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('1p/19q deletion', 'Var', (185, 200))	('IDH1/2', 'Gene', '3417;3418', (147, 153))	('TERT', 'Gene', (161, 165))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('oligodendrocytic', 'Disease', 'MESH:D056784', (104, 120))	('oligodendrocytic', 'Disease', (104, 120))	('TERT', 'Gene', '7015', (161, 165))	('ATRX', 'Gene', (155, 159))	('IDH1/2', 'Gene', (147, 153))	('ATRX', 'Gene', '546', (155, 159))	('gliomas', 'Disease', (48, 55))
13932	27323851	When the entire cohort was examined by univariate Cox analysis, mitotic index, age at initial diagnosis, IDH mutation status, radiotherapy and chemotherapy were all statistically significant or nearly significant (Table 1).	('IDH', 'Gene', '3417', (105, 108))	('mutation status', 'Var', (109, 124))	('mitotic', 'MPA', (64, 71))	('IDH', 'Gene', (105, 108))
13948	27323851	The majority of WHO grade II (110/126, chi-square test, p<0.01) and IDH1/2 mutated (93/112, chi-square test, p<0.01) samples were clustered into PN subtype (Supplementary Figure S1A).	('mutated', 'Var', (75, 82))	('IDH1/2', 'Gene', '3417;3418', (68, 74))	('IDH1/2', 'Gene', (68, 74))
13963	27323851	Collectively, these data suggest that MC phenotype was enriched by genes of EMT, whereas PN phenotype correlated strongly with the decrease of genes of EMT.	('decrease', 'NegReg', (131, 139))	('EMT', 'Disease', (76, 79))	('MC', 'Chemical', '-', (38, 40))	('genes', 'Var', (67, 72))
13975	27323851	We found that the effect of pHH3 on patient outcome was small in the high Ki-67 expression subset of tumors, while it was more substantial in low Ki-67 expression subset (Figure 1F).	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('high Ki-67', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('pHH3', 'Chemical', '-', (28, 32))	('tumors', 'Disease', (101, 107))	('patient', 'Species', '9606', (36, 43))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
13976	27323851	IDH1/2 mutation has been reported to have significant association with mitotic index, and the prognostic value of mitotic index varied according to IDH1/2 status.	('IDH1/2', 'Gene', (148, 154))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('IDH1/2', 'Gene', '3417;3418', (148, 154))	('mitotic index', 'MPA', (71, 84))	('mutation', 'Var', (7, 15))	('IDH1/2', 'Gene', (0, 6))	('association', 'Interaction', (54, 65))
13978	27323851	Although dozens of studies have given evidence of pHH3 expression contributing to mitosis, there are few ones trying to interpret pHH3 function precisely.	('pHH3', 'Chemical', '-', (50, 54))	('pHH3', 'Chemical', '-', (130, 134))	('contributing', 'Reg', (66, 78))	('mitosis', 'Disease', (82, 89))	('mitosis', 'Disease', 'None', (82, 89))	('pHH3', 'Gene', (50, 54))	('expression', 'Var', (55, 65))
13991	27323851	The clinical and molecular information (IDH1/2 mutation, MGMT promoter methylation, etc.)	('IDH1/2', 'Gene', (40, 46))	('mutation', 'Var', (47, 55))	('MGMT', 'Gene', '4255', (57, 61))	('MGMT', 'Gene', (57, 61))	('IDH1/2', 'Gene', '3417;3418', (40, 46))
14001	27323851	DNA pyro-sequencing for IDH1/2 mutation in 52 of the 61 anaplastic glioma samples was performed as previously reported.	('IDH1/2', 'Gene', '3417;3418', (24, 30))	('glioma', 'Disease', (67, 73))	('mutation', 'Var', (31, 39))	('IDH1/2', 'Gene', (24, 30))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
14002	27323851	In brief, the genomic regions spanning R132 of IDH1 and R172 of IDH2 were PCR amplified and subjected to pyrosequencing on PyroMark Q96 ID System (QIAGEN) using the primers as reported.	('IDH2', 'Gene', (64, 68))	('IDH1', 'Gene', (47, 51))	('IDH2', 'Gene', '3418', (64, 68))	('R172', 'Var', (56, 60))	('IDH1', 'Gene', '3417', (47, 51))
14008	27259253	Accordingly, depletion of HMGA2 in GICs resulted in compromised self-renewal and tumorigenic capability, as well as undermined mesenchymal or pericyte differentiation.	('self-renewal', 'CPA', (64, 76))	('depletion', 'Var', (13, 22))	('mesenchymal or pericyte differentiation', 'CPA', (127, 166))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('undermined', 'NegReg', (116, 126))	('compromised', 'NegReg', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('HMGA2', 'Protein', (26, 31))	('tumor', 'Disease', (81, 86))
14013	27259253	Mesenchymal features including uncontrolled ability to invade and stimulate angiogenesis, and the corresponding molecular signatures such as alterations of Neurofibromatosis-1 (NF1) expression can be found in a portion of GBMs.	('NF1', 'Gene', (177, 180))	('alterations', 'Var', (141, 152))	('angiogenesis', 'CPA', (76, 88))	('NF1', 'Gene', '4763', (177, 180))	('rat', 'Species', '10116', (145, 148))	('Neurofibromatosis-1', 'Gene', (156, 175))	('stimulate', 'PosReg', (66, 75))	('Neurofibromatosis-1', 'Gene', '4763', (156, 175))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (156, 173))
14037	27259253	Moreover, high HMGA2 expression levels correlate with shorter survival time in glioma patients using the CGGA (The Chinese Glioma Genome Atlas) dataset (Supplementary Figure S1E), which is consistent with reports showing higher levels of IL-6/HMGA2/SOX2 expression indicated shorter overall survival period in GBM patients.	('shorter', 'NegReg', (275, 282))	('IL-6', 'Gene', (238, 242))	('SOX2', 'Gene', '6657', (249, 253))	('survival time', 'CPA', (62, 75))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('SOX2', 'Gene', (249, 253))	('patients', 'Species', '9606', (86, 94))	('Glioma', 'Phenotype', 'HP:0009733', (123, 129))	('Glioma Genome Atlas', 'Disease', (123, 142))	('patients', 'Species', '9606', (314, 322))	('HMGA2', 'Protein', (15, 20))	('overall', 'MPA', (283, 290))	('glioma', 'Disease', (79, 85))	('IL-6', 'Gene', '3569', (238, 242))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('expression', 'MPA', (21, 31))	('high', 'Var', (10, 14))	('Glioma Genome Atlas', 'Disease', 'MESH:D005910', (123, 142))	('shorter', 'NegReg', (54, 61))
14047	27259253	Among them, shHMGA2#1 and shHMGA2#2 can efficiently down-regulate HMGA2 mRNA and protein levels in U251 cells (Supplementary Figure S3A-S3C).	('HMGA2', 'Protein', (66, 71))	('down-regulate', 'NegReg', (52, 65))	('shHMGA2', 'Var', (12, 19))	('shHMGA2', 'Var', (26, 33))	('U251', 'CellLine', 'CVCL:0021', (99, 103))
14049	27259253	In contrast, HMGA2 knockdown has minimal effects on proliferation of U251 and U87MG glioma cells, which is exemplified by much milder changes in MTT assays, ratios of Ki67-positive cells and BrdU incorporation (Figure 3D, Supplementary Figure S3D-S3F and data not shown).	('BrdU incorporation', 'CPA', (191, 209))	('U87MG', 'CellLine', 'CVCL:0022', (78, 83))	('knockdown', 'Var', (19, 28))	('glioma', 'Disease', (84, 90))	('U251', 'CellLine', 'CVCL:0021', (69, 73))	('MTT assays', 'CPA', (145, 155))	('rat', 'Species', '10116', (157, 160))	('MTT', 'Chemical', 'MESH:C070243', (145, 148))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('HMGA2', 'Gene', (13, 18))	('rat', 'Species', '10116', (59, 62))	('BrdU', 'Chemical', 'MESH:D001973', (191, 195))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('rat', 'Species', '10116', (203, 206))
14060	27259253	As expected, depleting of HMGA2 leads to significant downregulation of YKL40, FN1 and SNAIL2/SLUG in TNF-alpha, TGF-beta and C/EBPbeta induced differentiation of TPC1115 GICs (Supplementary Figure S4C-S4E).	('FN1', 'Gene', '2335', (78, 81))	('depleting', 'Var', (13, 22))	('downregulation', 'NegReg', (53, 67))	('FN1', 'Gene', (78, 81))	('TNF-alpha', 'Gene', '7124', (101, 110))	('YKL40', 'Gene', (71, 76))	('HMGA2', 'Gene', (26, 31))	('C/EBPbeta', 'Gene', (125, 134))	('YKL40', 'Gene', '1116', (71, 76))	('SNAIL2', 'Gene', (86, 92))	('TNF-alpha', 'Gene', (101, 110))	('TGF-beta', 'Gene', '7040', (112, 120))	('C/EBPbeta', 'Gene', '1051', (125, 134))	('SLUG', 'Gene', '6591', (93, 97))	('SNAIL2', 'Gene', '6591', (86, 92))	('SLUG', 'Gene', (93, 97))	('TGF-beta', 'Gene', (112, 120))	('differentiation', 'CPA', (143, 158))
14068	27259253	Since HMGA1/2 promotes loosening of chromatin, thus facilitates gene expression, we focused on genes down-regulated upon HMGA2 knockdown (KD).	('gene expression', 'MPA', (64, 79))	('HMGA2', 'Gene', (121, 126))	('HMGA1', 'Gene', (6, 11))	('facilitates', 'PosReg', (52, 63))	('HMGA1', 'Gene', '3159', (6, 11))	('loosening of chromatin', 'MPA', (23, 45))	('knockdown', 'Var', (127, 136))
14069	27259253	Consistent with reduced proliferation of GICs upon HMGA2 (Figure 3A-3C) or HMGA1 knockdown (data not shown), down-regulated transcripts shared in HMGA1-KD, HMGA2-KD and HMGA1/HMGA2-KD GICs are enriched with those encoding key regulators for cell-cycle progression (Figure 5A, Supplementary Table S1A).	('down-regulated', 'NegReg', (109, 123))	('HMGA1', 'Gene', (75, 80))	('HMGA1', 'Gene', '3159', (75, 80))	('transcripts', 'MPA', (124, 135))	('reduced', 'NegReg', (16, 23))	('knockdown', 'Var', (81, 90))	('rat', 'Species', '10116', (31, 34))	('HMGA1', 'Gene', (146, 151))	('HMGA1', 'Gene', (169, 174))	('HMGA1', 'Gene', '3159', (146, 151))	('HMGA1', 'Gene', '3159', (169, 174))
14072	27259253	U251 and U87MG) has neglected effects on cell proliferation (Figure 3D, Supplementary Figure S3D-S3F).	('U87MG', 'CellLine', 'CVCL:0022', (9, 14))	('U251', 'CellLine', 'CVCL:0021', (0, 4))	('U87MG', 'Var', (9, 14))	('cell proliferation', 'CPA', (41, 59))	('rat', 'Species', '10116', (53, 56))	('U251', 'Var', (0, 4))
14073	27259253	Surprisingly, the SOX2 expressions were not altered after HMGA2 knockdown or overexpression.	('SOX2', 'Gene', '6657', (18, 22))	('SOX2', 'Gene', (18, 22))	('HMGA2', 'Gene', (58, 63))	('knockdown', 'Var', (64, 73))	('expressions', 'MPA', (23, 34))
14082	27259253	Among them, PLAU, a serine protease involved in degradation of the extracellular matrix and tumor cell migration and proliferation, might mediate migration and invasion of U87MG glioma cells.	('rat', 'Species', '10116', (149, 152))	('rat', 'Species', '10116', (124, 127))	('migration', 'CPA', (146, 155))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('invasion', 'CPA', (160, 168))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('rat', 'Species', '10116', (106, 109))	('mediate', 'Reg', (138, 145))	('PLAU', 'Gene', '5328', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('PLAU', 'Gene', (12, 16))	('U87MG', 'CellLine', 'CVCL:0022', (172, 177))	('glioma', 'Disease', (178, 184))	('U87MG', 'Var', (172, 177))
14084	27259253	Using qRT-PCR, we confirmed that the expression levels of FOXM1, PLAU, CYR61, THBS1 and ADAM9 are indeed significantly down-regulated upon HMGA2 depletion in TPC1115 GICs, U87MG glioma cells and SK-N-SH neuroblastoma cells (Supplementary Figure S5B-S5D).	('ADAM9', 'Gene', (88, 93))	('ADAM9', 'Gene', '8754', (88, 93))	('glioma', 'Disease', (178, 184))	('down-regulated', 'NegReg', (119, 133))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('SK-N-SH neuroblastoma', 'Disease', (195, 216))	('CYR61', 'Gene', (71, 76))	('PLAU', 'Gene', '5328', (65, 69))	('expression levels', 'MPA', (37, 54))	('THBS1', 'Gene', (78, 83))	('FOXM1', 'Gene', (58, 63))	('depletion', 'Var', (145, 154))	('S5B', 'Gene', (245, 248))	('THBS1', 'Gene', '7057', (78, 83))	('SK-N-SH neuroblastoma', 'Disease', 'MESH:D009447', (195, 216))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('PLAU', 'Gene', (65, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('S5B', 'Gene', '5711', (245, 248))	('CYR61', 'Gene', '3491', (71, 76))	('FOXM1', 'Gene', '2305', (58, 63))	('U87MG', 'CellLine', 'CVCL:0022', (172, 177))
14085	27259253	Consistent with the transcriptome analysis, depletion of HMGA1 in these cells has minimum or opposite effects on the expressions of PLAU, CYR61 and ADAM9 (Supplementary Figure S5B-S5D).	('HMGA1', 'Gene', (57, 62))	('CYR61', 'Gene', '3491', (138, 143))	('ADAM9', 'Gene', '8754', (148, 153))	('depletion', 'Var', (44, 53))	('HMGA1', 'Gene', '3159', (57, 62))	('ADAM9', 'Gene', (148, 153))	('PLAU', 'Gene', (132, 136))	('S5B', 'Gene', '5711', (176, 179))	('PLAU', 'Gene', '5328', (132, 136))	('CYR61', 'Gene', (138, 143))	('S5B', 'Gene', (176, 179))
14087	27259253	The promoter region of FOXM1 (-2019 to +57 relative to the transcription starting site/TSS), and PLAU (-1886 to +26 relative to the TSS) were cloned into pGL3-Basic luciferase reporter vector.	('pGL3', 'Gene', '6391', (154, 158))	('FOXM1', 'Gene', '2305', (23, 28))	('FOXM1', 'Gene', (23, 28))	('-1886 to +26', 'Var', (103, 115))	('PLAU', 'Gene', (97, 101))	('PLAU', 'Gene', '5328', (97, 101))	('pGL3', 'Gene', (154, 158))	('-2019 to +57', 'Var', (30, 42))
14090	27259253	Knocking down or overexpressing HMGA2 significantly reduces or enhances the luciferase activities driven by the PLAU promoter respectively, whereas manipulating the expression of HMGA1 has no effect (Figure 5G).	('PLAU', 'Gene', '5328', (112, 116))	('Knocking down', 'Var', (0, 13))	('PLAU', 'Gene', (112, 116))	('HMGA2', 'Gene', (32, 37))	('HMGA1', 'Gene', (179, 184))	('reduces', 'NegReg', (52, 59))	('activities', 'MPA', (87, 97))	('HMGA1', 'Gene', '3159', (179, 184))	('enhances', 'PosReg', (63, 71))	('luciferase', 'Enzyme', (76, 86))	('overexpressing', 'PosReg', (17, 31))
14091	27259253	In limiting dilution assays (Figure 6A), adherent (Figure 6B) and neurosphere cultures (Figure 6C-6D, Supplementary Figure S6E-S6G), overexpression of FOXM1 or PLAU mostly reversed the proliferative defects of TPC0411 GICs caused by HMGA2 knockdown in both the first and second passages (Supplementary Figure S6F).	('FOXM1', 'Gene', '2305', (151, 156))	('TPC0411', 'Gene', (210, 217))	('knockdown', 'Var', (239, 248))	('rat', 'Species', '10116', (192, 195))	('HMGA2', 'Gene', (233, 238))	('PLAU', 'Gene', (160, 164))	('PLAU', 'Gene', '5328', (160, 164))	('proliferative defects', 'CPA', (185, 206))	('FOXM1', 'Gene', (151, 156))
14095	27259253	Intriguingly, it's the expression of the transcript variant 3 of FOXM1 (FOXM1v3/FOXM1b, NM_202003.2), but not FOXM1v2/FOXM1c (NM_021953.3) that is more prominently down-regulated upon HMGA2 knockdown (Supplementary Figure S6B).	('HMGA2', 'Gene', (184, 189))	('FOXM1', 'Gene', (72, 77))	('FOXM1', 'Gene', (80, 85))	('knockdown', 'Var', (190, 199))	('FOXM1', 'Gene', '2305', (110, 115))	('FOXM1', 'Gene', (110, 115))	('FOXM1', 'Gene', '2305', (80, 85))	('down-regulated', 'NegReg', (164, 178))	('FOXM1', 'Gene', '2305', (118, 123))	('FOXM1b', 'Gene', (80, 86))	('FOXM1', 'Gene', (118, 123))	('FOXM1', 'Gene', '2305', (72, 77))	('FOXM1b', 'Gene', '2305', (80, 86))	('FOXM1', 'Gene', (65, 70))	('FOXM1', 'Gene', '2305', (65, 70))	('expression', 'MPA', (23, 33))
14104	27259253	Although HMGA2 depletion has little effects on proliferation of regular glioma cells, it's essential for self-renewal of GICs.	('HMGA2', 'Gene', (9, 14))	('glioma', 'Disease', (72, 78))	('depletion', 'Var', (15, 24))	('rat', 'Species', '10116', (54, 57))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))
14113	27259253	The expression of PLAU is drastically reduced in HMGA2- but not HMGA1-depleted GICs.	('reduced', 'NegReg', (38, 45))	('HMGA1', 'Gene', (64, 69))	('expression', 'MPA', (4, 14))	('PLAU', 'Gene', (18, 22))	('HMGA1', 'Gene', '3159', (64, 69))	('PLAU', 'Gene', '5328', (18, 22))	('HMGA2-', 'Var', (49, 55))
14114	27259253	Further, overexpression of PLAU largely rescued self-renewal, migration, invasion and vascular formation defects induced by HMGA2 knockdown.	('migration', 'CPA', (62, 71))	('HMGA2', 'Gene', (124, 129))	('PLAU', 'Gene', (27, 31))	('vascular formation defects', 'CPA', (86, 112))	('PLAU', 'Gene', '5328', (27, 31))	('invasion', 'CPA', (73, 81))	('knockdown', 'Var', (130, 139))	('self-renewal', 'CPA', (48, 60))	('rat', 'Species', '10116', (65, 68))
14115	27259253	Interestingly, FOXM1 transactives PLAUR expression to promote colon cancer progression and metastasis.	('promote', 'PosReg', (54, 61))	('PLAUR', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('transactives', 'Var', (21, 33))	('colon cancer', 'Disease', (62, 74))	('FOXM1', 'Gene', '2305', (15, 20))	('FOXM1', 'Gene', (15, 20))	('metastasis', 'CPA', (91, 101))	('PLAUR', 'Gene', '5329', (34, 39))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))
14138	27259253	ShRNA targeting sequences: shHMGA1 (5'-CAA CTC CAG GAA GGA AAC CAA-3'); shHMGA2#1 (5'-AGT CCC TCT AAA GCA GCT CAA-3'); shHMGA2#2 (5'-GCC CAA GGC ACT TTC AAT CTC-3').	('HMGA1', 'Gene', (29, 34))	('AAC', 'Gene', (59, 62))	('HMGA1', 'Gene', '3159', (29, 34))	('AAC', 'Gene', '10249', (59, 62))	('GAA', 'Gene', '2548', (51, 54))	('shHMGA2#', 'Var', (119, 127))	('AAT', 'Gene', '5265', (153, 156))	('AAT', 'Gene', (153, 156))	('GAA', 'Gene', (51, 54))
14173	27259253	A total of 1x105 lentivirus-transduced GICs (in culture medium) were injected intracranially using a stereotactic device (RWD) and a Hamilton syringe at a depth of 2.5 mm into the right striata of cerebral hemisphere.	('RWD', 'Disease', (122, 125))	('lentivirus-transduced', 'Var', (17, 38))	('RWD', 'Disease', 'None', (122, 125))
14182	27259253	The promoter region of FOXM1 (-2019 to +57 relative to TSS), and PLAU (-1886 to +26 relative the TSS) were amplified from genomic DNA of human fetal brain using KOD polymerase (Toyobo, Osaka, Japan) and cloned into pGL3-Basic luciferase reporter vector and confirmed by sequencing.	('-2019', 'Var', (30, 35))	('human', 'Species', '9606', (137, 142))	('-1886 to +26', 'Var', (71, 83))	('FOXM1', 'Gene', '2305', (23, 28))	('FOXM1', 'Gene', (23, 28))	('PLAU', 'Gene', (65, 69))	('pGL3', 'Gene', (215, 219))	('PLAU', 'Gene', '5328', (65, 69))	('pGL3', 'Gene', '6391', (215, 219))
14209	26490736	Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia Acute myeloid leukemia (AML) is the second-most common form of leukemia in children.	('leukemia', 'Disease', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (99, 107))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('leukemia', 'Disease', (99, 107))	('Hypermethylation', 'Var', (0, 16))	('myeloid leukemia', 'Disease', (91, 107))	('children', 'Species', '9606', (183, 191))	('GATA binding protein 4', 'Gene', '2626', (24, 46))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (91, 107))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('GATA4', 'Gene', (48, 53))	('myeloid leukemia', 'Disease', 'MESH:D007951', (91, 107))	('Acute myeloid leukemia', 'Disease', (108, 130))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('myeloid leukemia', 'Disease', 'MESH:D007951', (114, 130))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('AML', 'Disease', 'MESH:D015470', (132, 135))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('leukemia', 'Disease', 'MESH:D007938', (171, 179))	('GATA binding protein 4', 'Gene', (24, 46))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('AML', 'Disease', (132, 135))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (85, 107))	('leukemia', 'Disease', (171, 179))	('GATA4', 'Gene', '2626', (48, 53))
14210	26490736	Aberrant DNA methylation patterns are a characteristic feature of AML.	('AML', 'Disease', 'MESH:D015470', (66, 69))	('AML', 'Disease', (66, 69))	('Aberrant', 'Var', (0, 8))	('DNA methylation', 'MPA', (9, 24))
14211	26490736	GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('AML', 'Disease', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('promoter hypermethylation', 'Var', (68, 93))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumor', 'Disease', (33, 38))	('AML', 'Disease', 'MESH:D015470', (199, 202))	('GATA4', 'Gene', (0, 5))
14216	26490736	Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples.	('Aberrant', 'Var', (0, 8))	('AML', 'Disease', 'MESH:D015470', (147, 150))	('observed', 'Reg', (34, 42))	('methylation', 'MPA', (9, 20))	('AML', 'Disease', (147, 150))	('GATA4', 'Gene', (24, 29))
14218	26490736	GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031).	('methylation', 'Var', (15, 26))	('GATA4', 'Gene', (0, 5))	('patient', 'Species', '9606', (47, 54))	('correlated', 'Reg', (31, 41))
14221	26490736	Kaplan-Meier survival analysis revealed significantly shorter overall survival in pediatric AML with GATA4 promoter methylation but multivariate analysis shows that it is not an independent factor.	('AML', 'Disease', 'MESH:D015470', (92, 95))	('methylation', 'Var', (116, 127))	('GATA4', 'Gene', (101, 106))	('shorter', 'NegReg', (54, 61))	('AML', 'Disease', (92, 95))	('overall survival', 'MPA', (62, 78))
14225	26490736	Epigenetic disturbances have been implicated in the development and pathogenesis of leukemia.	('leukemia', 'Disease', (84, 92))	('implicated', 'Reg', (34, 44))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('leukemia', 'Disease', 'MESH:D007938', (84, 92))	('Epigenetic disturbances', 'Var', (0, 23))
14226	26490736	These include aberrations in methylation, which is a key epigenetic event responsible for enhanced proliferation and self-renewal, differentiation arrest, and impaired apoptosis of leukemic cells.	('aberrations', 'Var', (14, 25))	('differentiation', 'CPA', (131, 146))	('impaired apoptosis of leukemic', 'Disease', (159, 189))	('enhanced', 'PosReg', (90, 98))	('self-renewal', 'CPA', (117, 129))	('impaired apoptosis of leukemic', 'Disease', 'MESH:D009422', (159, 189))	('methylation', 'MPA', (29, 40))
14229	26490736	Progression from myelodysplastic syndrome to AML has also been associated with increased aberrant DNA methylation.	('increased', 'PosReg', (79, 88))	('myelodysplastic syndrome', 'Disease', (17, 41))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (17, 41))	('aberrant', 'Var', (89, 97))	('AML', 'Disease', 'MESH:D015470', (45, 48))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (17, 41))	('DNA', 'Protein', (98, 101))	('AML', 'Disease', (45, 48))
14230	26490736	Identifying these aberrantly methylated genes may provide a better understanding of AML, thereby paving the way for the development of novel tumor markers and therapeutic targets.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('aberrantly methylated genes', 'Var', (18, 45))	('tumor', 'Disease', (141, 146))	('AML', 'Disease', (84, 87))
14235	26490736	Abnormal expression of these methylation-related enzymes may disturb DNA methylation in pediatric AML.	('AML', 'Disease', 'MESH:D015470', (98, 101))	('disturb', 'NegReg', (61, 68))	('Abnormal', 'Var', (0, 8))	('DNA methylation', 'MPA', (69, 84))	('AML', 'Disease', (98, 101))
14245	26490736	Mutations or defects in the GATA4 gene can lead to a variety of cardiac problems including congenital heart disease, abnormal ventral folding, and defects in the cardiac septum separating the atria and ventricles, and hypoplasia of the ventricular myocardium.	('GATA4', 'Gene', (28, 33))	('heart disease', 'Disease', (102, 115))	('atria', 'Disease', 'None', (192, 197))	('atria', 'Disease', (192, 197))	('congenital heart disease', 'Phenotype', 'HP:0001627', (91, 115))	('defects in the cardiac septum', 'Phenotype', 'HP:0001671', (147, 176))	('lead to', 'Reg', (43, 50))	('cardiac problems', 'Disease', (64, 80))	('Mutations', 'Var', (0, 9))	('heart disease', 'Disease', 'MESH:D006331', (102, 115))	('abnormal ventral folding', 'CPA', (117, 141))	('hypoplasia of the ventricular myocardium', 'Disease', (218, 258))	('defects', 'Var', (13, 20))	('defects', 'Var', (147, 154))	('hypoplasia of the ventricular myocardium', 'Disease', 'MESH:D056830', (218, 258))	('hypoplasia of the ventricular', 'Phenotype', 'HP:0002119', (218, 247))
14248	26490736	A previous investigation of the methylation status of GATA4 promoters by methylation-specific PCR in 99 glioblastoma patients showed that GATA4 was aberrantly methylated in 23.2 % of glioblastoma tumors, but not in normal brain.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (183, 195))	('aberrantly', 'Var', (148, 158))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (183, 202))	('glioblastoma', 'Disease', (104, 116))	('glioblastoma', 'Disease', (183, 195))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('glioblastoma tumors', 'Disease', (183, 202))	('patients', 'Species', '9606', (117, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (183, 195))	('GATA4', 'Gene', (138, 143))
14250	26490736	In ovarian cancer, methylation-specific PCR revealed GATA4 promoter methylation in 31.3 % (21/67) of specimens with ovarian cancer, and in none of the control ovarian tissue samples.	('promoter', 'MPA', (59, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('methylation', 'Var', (68, 79))	('ovarian cancer', 'Disease', (116, 130))	('GATA4', 'Gene', (53, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ovarian cancer', 'Disease', (3, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
14252	26490736	Methylation of GATA4 was found in human gastric mucosa samples, including normal gastric biopsies, gastric dysplasia (low-grade gastric intraepithelial neoplasia) and paired sporadic gastric carcinomas (SGC) as well as the adjacent non-neoplastic gastric tissues.GATA4 methylation was frequently observed in SGCs (53.8 %) by MSP.	('neoplastic gastric', 'Phenotype', 'HP:0006753', (236, 254))	('gastric carcinomas', 'Disease', 'MESH:D013274', (183, 201))	('gastric carcinomas', 'Disease', (183, 201))	('human', 'Species', '9606', (34, 39))	('gastric intraepithelial neoplasia', 'Disease', 'MESH:D019048', (128, 161))	('gastric mucosa', 'Disease', 'MESH:D013274', (40, 54))	('gastric mucosa', 'Disease', (40, 54))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (136, 161))	('gastric dysplasia', 'Disease', 'MESH:D013274', (99, 116))	('neoplasia', 'Phenotype', 'HP:0002664', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('SGCs', 'Disease', (308, 312))	('tissues.GATA4', 'Gene', (255, 268))	('methylation', 'Var', (269, 280))	('gastric intraepithelial neoplasia', 'Disease', (128, 161))	('gastric dysplasia', 'Disease', (99, 116))	('observed', 'Reg', (296, 304))
14253	26490736	Moreover, a high frequency of GATA-4 methylation was found in both gastric low-grade GIN (57.1 %) and indefinite for dysplasia (42.9 %).	('dysplasia', 'Disease', (117, 126))	('methylation', 'Var', (37, 48))	('found', 'Reg', (53, 58))	('dysplasia', 'Disease', 'MESH:D004476', (117, 126))	('GATA-4', 'Gene', (30, 36))	('GATA-4', 'Gene', '2626', (30, 36))	('gastric low-grade GIN', 'Disease', (67, 88))
14254	26490736	Epigenetic inactivation of GATA4 by methylation of CpG islands is an early frequent event during gastric carcinogenesis and is significantly correlated with H. pylori infection.	('gastric carcinogenesis', 'Disease', (97, 119))	('correlated', 'Reg', (141, 151))	('infection', 'Disease', 'MESH:D007239', (167, 176))	('H. pylori', 'Species', '210', (157, 166))	('CpG islands', 'Gene', (51, 62))	('H. pylori infection', 'Phenotype', 'HP:0005202', (157, 176))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (97, 119))	('infection', 'Disease', (167, 176))	('Epigenetic inactivation', 'Var', (0, 23))	('methylation', 'Var', (36, 47))	('GATA4', 'Gene', (27, 32))
14256	26490736	GATA4 methylation was observed in 70 % (63/90) of colorectal carcinomas and was independent of clinicopathologic features.	('colorectal carcinomas', 'Disease', (50, 71))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (50, 71))	('observed', 'Reg', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('methylation', 'Var', (6, 17))	('GATA4', 'Gene', (0, 5))
14261	26490736	In this study, we have provided the first evidence of GATA4 methylation in two AML cell lines and pediatric myeloid leukemia samples.	('AML', 'Disease', (79, 82))	('pediatric myeloid leukemia', 'Disease', (98, 124))	('methylation', 'Var', (60, 71))	('pediatric myeloid leukemia', 'Disease', 'MESH:D007951', (98, 124))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('GATA4', 'Gene', (54, 59))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (108, 124))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))
14313	26490736	The correlation between aberrant methylation and downregulation of GATA4 has been extensively documented in numerous cancers and cell lines; these are discussed in the Background.	('numerous cancers', 'Disease', (108, 124))	('methylation', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('GATA4', 'Gene', (67, 72))	('downregulation', 'NegReg', (49, 63))	('aberrant methylation', 'Var', (24, 44))	('numerous cancers', 'Disease', 'MESH:D009369', (108, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))
14326	26490736	In summary, these results showed that the GATA4 promoter was consistently and significantly methylated in the HL-60, MV4-11, SHI-1, U937 and K562 human myeloid leukemia cell lines.	('HL-60', 'CellLine', 'CVCL:0002', (110, 115))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (152, 168))	('GATA4 promoter', 'Gene', (42, 56))	('U937', 'CellLine', 'CVCL:0007', (132, 136))	('MV4-11', 'Chemical', '-', (117, 123))	('human', 'Species', '9606', (146, 151))	('myeloid leukemia', 'Disease', (152, 168))	('K562', 'CellLine', 'CVCL:0004', (141, 145))	('leukemia', 'Phenotype', 'HP:0001909', (160, 168))	('methylated', 'Var', (92, 102))	('myeloid leukemia', 'Disease', 'MESH:D007951', (152, 168))
14329	26490736	Aberrant GATA4 promoter methylation was observed in 15.0 % (3/20) of the NBM control samples compared to 56.2 % (59/105) of the pediatric AML samples (Fig.	('Aberrant', 'Var', (0, 8))	('methylation', 'MPA', (24, 35))	('AML', 'Disease', (138, 141))	('GATA4', 'Gene', (9, 14))	('observed', 'Reg', (40, 48))	('AML', 'Disease', 'MESH:D015470', (138, 141))	('NBM', 'Chemical', '-', (73, 76))	('NBM', 'Disease', (73, 76))
14332	26490736	In contrast, the CpG islands of the GATA4 promoter in the NBM samples were unmethylated (24.7, 14.1, and 10.6 % in NBM4#, NBM5#, and NBM9#, respectively).	('NBM', 'Chemical', '-', (133, 136))	('NBM', 'Chemical', '-', (115, 118))	('NBM', 'Chemical', '-', (58, 61))	('NBM', 'Chemical', '-', (122, 125))	('NBM4#', 'Var', (115, 120))	('GATA4', 'Gene', (36, 41))	('NBM5#', 'Var', (122, 127))	('NBM9#', 'Var', (133, 138))
14335	26490736	Figure 3d shows that patients with GATA4 promoter methylation (16.02 +- 17.59, n = 59) exhibited lower GATA4 transcript levels compared to those without GATA4 promoter methylation (54.92 +- 101.80, P < 0.01; n = 46).	('GATA4', 'Gene', (35, 40))	('GATA4 transcript levels', 'MPA', (103, 126))	('patients', 'Species', '9606', (21, 29))	('lower', 'NegReg', (97, 102))	('promoter methylation', 'Var', (41, 61))
14345	26490736	In summary, our results showed firstly that the GATA4 promoter was consistently significantly methylated in leukemia cells, such as HL-60, MV4-11, SHI-1, U937, and K562 human myeloid leukemia cell lines; the expression of GATA4 was significantly lower in pediatric AML compared to NBM control samples, patients with methylated GATA4 showed lower GATA4 transcript levels compared to those without methylated; GATA4 promoter methylation was correlated with leukocyte and MRD, Kaplan-Meier survival analysis revealed a significantly shorter overall survival times in pediatric AML with GATA4 promoter methylation.	('AML', 'Disease', (574, 577))	('myeloid leukemia', 'Disease', 'MESH:D007951', (175, 191))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (175, 191))	('leukemia', 'Disease', (183, 191))	('human', 'Species', '9606', (169, 174))	('leukemia', 'Disease', 'MESH:D007938', (183, 191))	('overall survival times', 'CPA', (538, 560))	('GATA4', 'Gene', (583, 588))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('HL-60', 'CellLine', 'CVCL:0002', (132, 137))	('NBM', 'Chemical', '-', (281, 284))	('K562', 'CellLine', 'CVCL:0004', (164, 168))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('MV4-11', 'Chemical', '-', (139, 145))	('leukemia', 'Disease', (108, 116))	('myeloid leukemia', 'Disease', (175, 191))	('U937', 'CellLine', 'CVCL:0007', (154, 158))	('shorter', 'NegReg', (530, 537))	('promoter methylation', 'Var', (589, 609))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('AML', 'Disease', 'MESH:D015470', (265, 268))	('AML', 'Disease', 'MESH:D015470', (574, 577))	('patients', 'Species', '9606', (302, 310))	('AML', 'Disease', (265, 268))
14348	26490736	Previous studies have demonstrated that promoters of TFPI-2 and miR-663 were hypermethylated in Chinese pediatric acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', (114, 136))	('hypermethylated', 'Var', (77, 92))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (114, 136))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (120, 136))	('TFPI-2', 'Gene', '7980', (53, 59))	('miR-663', 'Gene', (64, 71))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (114, 136))	('TFPI-2', 'Gene', (53, 59))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('miR-663', 'Gene', '724033', (64, 71))
14355	26490736	Aberrant GATA4 promoter methylation was observed 15.0 % (3/20) of the NBM control samples compared to 56.2 % (59/105) of the pediatric AML samples.	('AML', 'Disease', 'MESH:D015470', (135, 138))	('Aberrant', 'Var', (0, 8))	('methylation', 'MPA', (24, 35))	('GATA4', 'Gene', (9, 14))	('AML', 'Disease', (135, 138))	('NBM', 'Chemical', '-', (70, 73))	('NBM', 'Disease', (70, 73))
14357	26490736	Analysis of GATA4 transcript levels showed that GATA4 expression was significantly decreased in AML patients compared to 20 NBM/ITP control and patients with methylated GATA4 showed lower GATA4 transcript levels compared to those without methylated GATA4.	('expression', 'MPA', (54, 64))	('AML', 'Disease', (96, 99))	('GATA4', 'Gene', (48, 53))	('GATA4 transcript levels', 'MPA', (188, 211))	('methylated', 'Var', (158, 168))	('decreased', 'NegReg', (83, 92))	('lower', 'NegReg', (182, 187))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (100, 108))	('NBM', 'Chemical', '-', (124, 127))	('AML', 'Disease', 'MESH:D015470', (96, 99))
14358	26490736	Taken together, our results show hypermethylation of the GATA4 promoter in Chinese pediatric AML for the first time.	('AML', 'Disease', 'MESH:D015470', (93, 96))	('GATA4 promoter', 'Gene', (57, 71))	('hypermethylation', 'Var', (33, 49))	('AML', 'Disease', (93, 96))
14361	26490736	In high grade serous ovarian carcinoma (HGSOC), GATA4 promoter methylation was associated with disease recurrence.	('associated', 'Reg', (79, 89))	('GATA4', 'Gene', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('serous ovarian carcinoma', 'Disease', (14, 38))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (14, 38))	('methylation', 'Var', (63, 74))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (21, 38))
14364	26490736	These observations demonstrate that GATA4 promoter methylation correlates with poorer survival in Chinese pediatric AML.	('poorer', 'NegReg', (79, 85))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('methylation', 'Var', (51, 62))	('GATA4 promoter', 'Gene', (36, 50))	('AML', 'Disease', (116, 119))
14367	26490736	Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy.	('GATA4', 'Gene', (17, 22))	('sensitivity', 'MPA', (38, 49))	('Re-expression', 'Var', (0, 13))	('temozolomide', 'Chemical', 'MESH:D000077204', (66, 78))	('conferred', 'Reg', (28, 37))
14372	26490736	Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples.	('AML', 'Disease', (83, 86))	('promoter hypermethylation', 'Var', (36, 61))	('AML', 'Disease', 'MESH:D015470', (112, 115))	('AML', 'Disease', 'MESH:D015470', (83, 86))	('Epigenetic', 'Var', (0, 10))	('AML', 'Disease', (112, 115))	('GATA4', 'Gene', (27, 32))
14374	26490736	In addition, our findings indicate that GATA4 promoter methylation correlates with leukocyte counts, MRD and significantly shorter overall survival in pediatric AML.	('leukocyte counts', 'CPA', (83, 99))	('shorter', 'NegReg', (123, 130))	('overall survival', 'MPA', (131, 147))	('AML', 'Disease', 'MESH:D015470', (161, 164))	('AML', 'Disease', (161, 164))	('methylation', 'Var', (55, 66))	('GATA4 promoter', 'Gene', (40, 54))	('MRD', 'Disease', (101, 104))
14381	25657859	Animals received BDNF containing polymer had an increased recovery rate of fine motor function of forelimb, as assessed by stair case reaching task and single pellet reach to grasp task compared with control animals that received the polymer only.	('increased', 'PosReg', (48, 57))	('polymer', 'Chemical', 'MESH:D011108', (33, 40))	('rat', 'Species', '10116', (67, 70))	('polymer', 'Chemical', 'MESH:D011108', (234, 241))	('recovery', 'MPA', (58, 66))	('fine motor function', 'Phenotype', 'HP:0007010', (75, 94))	('fine motor function of forelimb', 'CPA', (75, 106))	('polymer', 'Var', (33, 40))
14410	25657859	The authors displayed a significant difference in 1-year local control rates in patients receiving high dose SRS as compared with the low dose regimen.	('local control', 'CPA', (57, 70))	('high dose', 'Var', (99, 108))	('patients', 'Species', '9606', (80, 88))	('rat', 'Species', '10116', (71, 74))
14454	25657859	The authors found mutations in NF2 in 37% of samples, and TRAF7 mutations in nearly 25% of samples (which were always exclusive from NF2 mutations).	('NF2', 'Gene', (31, 34))	('NF2', 'Gene', '4771', (133, 136))	('TRAF7', 'Gene', '84231', (58, 63))	('NF2', 'Gene', '4771', (31, 34))	('mutations', 'Var', (64, 73))	('TRAF7', 'Gene', (58, 63))	('NF2', 'Gene', (133, 136))	('mutations', 'Var', (18, 27))
14455	25657859	Two additional genes with frequent mutations were AKT1 and KLF4; these mutations almost always coexisted with those seen in TRAF7.	('TRAF7', 'Gene', (124, 129))	('KLF4', 'Gene', '9314', (59, 63))	('KLF4', 'Gene', (59, 63))	('TRAF7', 'Gene', '84231', (124, 129))	('AKT1', 'Gene', '207', (50, 54))	('AKT1', 'Gene', (50, 54))	('mutations', 'Var', (35, 44))
14456	25657859	Finally, 11 tumors (3.7%) had a mutation in SMO.	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('SMO', 'Gene', '6608', (44, 47))	('tumors', 'Disease', (12, 18))	('SMO', 'Gene', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mutation', 'Var', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
14457	25657859	Loss of chromosome 22 was seen in nearly half of tumors, and was associated with NF2 coding mutations.	('NF2', 'Gene', '4771', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('coding mutations', 'Var', (85, 101))	('Loss', 'NegReg', (0, 4))	('associated', 'Reg', (65, 75))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('NF2', 'Gene', (81, 84))
14460	25657859	Meningiomas with NF2 mutations were typically located in the hemispheres, posterior fossa, and spinal cord.	('mutations', 'Var', (21, 30))	('NF2', 'Gene', '4771', (17, 20))	('NF2', 'Gene', (17, 20))	('Meningiomas', 'Phenotype', 'HP:0002858', (0, 11))	('Meningiomas', 'Disease', 'MESH:D008577', (0, 11))	('Meningiomas', 'Disease', (0, 11))
14461	25657859	Those with TRAF7/KLF4 mutations were more likely found in the lateral skull base, whereas meningiomas with AKT1 and SMO mutations were more likely found along the medial and anterior skull base.	('meningiomas', 'Disease', 'MESH:D008577', (90, 101))	('KLF4', 'Gene', '9314', (17, 21))	('KLF4', 'Gene', (17, 21))	('TRAF7', 'Gene', '84231', (11, 16))	('AKT1', 'Gene', '207', (107, 111))	('meningiomas', 'Phenotype', 'HP:0002858', (90, 101))	('mutations', 'Var', (22, 31))	('AKT1', 'Gene', (107, 111))	('SMO', 'Gene', (116, 119))	('TRAF7', 'Gene', (11, 16))	('SMO', 'Gene', '6608', (116, 119))	('meningiomas', 'Disease', (90, 101))
14463	25657859	The results from this major study corroborated previous findings with regard to NF2 mutations and loss of chromosome 22 as a major subset of sporadic meningiomas.	('NF2', 'Gene', '4771', (80, 83))	('meningiomas', 'Phenotype', 'HP:0002858', (150, 161))	('sporadic meningiomas', 'Disease', (141, 161))	('mutations', 'Var', (84, 93))	('rat', 'Species', '10116', (41, 44))	('NF2', 'Gene', (80, 83))	('sporadic meningiomas', 'Disease', 'MESH:D008577', (141, 161))
14492	26217131	A recent large study showed that breast cancer survivors who received CMF chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil) on average 20 years previously were more likely to have lower performance on memory, information processing speed and psychomotor speed compared with women without a history of cancer.	('psychomotor speed', 'Phenotype', 'HP:0025356', (254, 271))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('women', 'Species', '9606', (286, 291))	('lower performance on memory', 'Phenotype', 'HP:0002354', (192, 219))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (120, 134))	('cancer', 'Disease', (40, 46))	('memory', 'CPA', (213, 219))	('psychomotor speed', 'Disease', (254, 271))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('lower', 'NegReg', (192, 197))	('information processing speed', 'CPA', (221, 249))	('5-fluorouracil', 'Var', (120, 134))	('methotrexate', 'Var', (106, 118))	('psychomotor speed', 'Disease', 'MESH:D011596', (254, 271))	('cyclophosphamide', 'Var', (88, 104))	('methotrexate', 'Chemical', 'MESH:D008727', (106, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (88, 104))	('performance', 'MPA', (198, 209))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Disease', (313, 319))	('breast cancer', 'Disease', (33, 46))
14494	26217131	There is concern that chemotherapy may induce accelerated ageing and that it can increase an individual's susceptibility to late-emerging cognitive decline or dementia.	('cognitive decline', 'Disease', (138, 155))	('dementia', 'Disease', 'MESH:D003704', (159, 167))	('cognitive decline', 'Disease', 'MESH:D003072', (138, 155))	('chemotherapy', 'Var', (22, 34))	('accelerated', 'PosReg', (46, 57))	('cognitive decline', 'Phenotype', 'HP:0001268', (138, 155))	('ageing', 'CPA', (58, 64))	('dementia', 'Phenotype', 'HP:0000726', (159, 167))	('dementia', 'Disease', (159, 167))	('increase', 'PosReg', (81, 89))
14516	26217131	However, surprisingly, studies in breast cancer patients seem generally to indicate that AIs less consistently adversely influence cognitive functioning compared with SERMs.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('AIs', 'Var', (89, 92))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('cognitive functioning', 'CPA', (131, 152))	('influence', 'Reg', (121, 130))	('patients', 'Species', '9606', (48, 56))
14542	26217131	The long-term outcomes and associated reanalysis from the RTOG 9402 trial recently reported a doubling of overall survival rates in pure or mixed anaplastic oligodendroglioma patients with 1p/19q co-deletion who received procarbazine, CCNU and vincristine (PCV) chemotherapy.	('procarbazine', 'Chemical', 'MESH:D011344', (221, 233))	('pure', 'Disease', (132, 136))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('1p/19q co-deletion', 'Var', (189, 207))	('oligodendroglioma', 'Disease', 'MESH:D009837', (157, 174))	('patients', 'Species', '9606', (175, 183))	('vincristine', 'Chemical', 'MESH:D014750', (244, 255))	('oligodendroglioma', 'Disease', (157, 174))	('CCNU', 'Gene', '10309', (235, 239))	('CCNU', 'Gene', (235, 239))
14559	26217131	Moreover there seems to be a link between the abnormal microstructural properties in white-matter regions and the cognitive impairments seen in breast cancer patients treated with chemotherapeutic agents; several studies observed correlations between abnormal diffusion properties and cognitive problems on neuropsychological testing.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('abnormal', 'Var', (251, 259))	('cognitive impairments', 'Phenotype', 'HP:0100543', (114, 135))	('cognitive impairments', 'Disease', 'MESH:D003072', (114, 135))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('cognitive problems', 'Disease', (285, 303))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('cognitive impairment', 'Phenotype', 'HP:0100543', (114, 134))	('cognitive impairments', 'Disease', (114, 135))	('correlations', 'Interaction', (230, 242))	('patients', 'Species', '9606', (158, 166))	('cognitive problems', 'Phenotype', 'HP:0100543', (285, 303))
14570	26217131	showed that N-acetyl cysteine, an antioxidant, ameliorated cognitive impairment in Wistar rats after combined administration of cyclophosphamide and doxorubicin.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (128, 144))	('cognitive impairment', 'Phenotype', 'HP:0100543', (59, 79))	('ameliorated', 'PosReg', (47, 58))	('cognitive impairment', 'Disease', (59, 79))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (12, 29))	('N-acetyl cysteine', 'Var', (12, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (149, 160))	('Wistar rats', 'Species', '10116', (83, 94))	('cognitive impairment', 'Disease', 'MESH:D003072', (59, 79))
14581	33477420	Assessment of Cannabidiol and Delta9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma Phytocannabinoids Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been demonstrated to exhibit anti-cancer activity in preclinical models of brain cancer leading to new clinical trials for adults with glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (321, 333))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('glioblastoma', 'Disease', (321, 333))	('brain cancer', 'Disease', (261, 273))	('Ependymoma', 'Phenotype', 'HP:0002888', (96, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (321, 333))	('Delta9-tetrahydrocannabinol', 'Chemical', 'MESH:D013759', (125, 152))	('cannabidiol', 'Chemical', 'MESH:D002185', (163, 174))	('cancer', 'Disease', (267, 273))	('Delta9-tetrahydrocannabinol', 'Var', (125, 152))	('Delta9-Tetrahydrocannabiol', 'Chemical', '-', (30, 56))	('Medulloblastoma and Ependymoma', 'Disease', 'MESH:D008527', (76, 106))	('brain cancer', 'Phenotype', 'HP:0030692', (261, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('Mouse', 'Species', '10090', (60, 65))	('cancer', 'Disease', (220, 226))	('Cannabidiol', 'Chemical', 'MESH:D002185', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Phytocannabinoids', 'Chemical', '-', (107, 124))	('brain cancer', 'Disease', 'MESH:D001932', (261, 273))	('CBD', 'Chemical', 'MESH:D002185', (176, 179))	('THC', 'Chemical', 'MESH:D013759', (154, 157))	('Delta9-Tetrahydrocannabiol', 'Var', (30, 56))	('Medulloblastoma', 'Phenotype', 'HP:0002885', (76, 91))
14598	33477420	Each subtype warrants different management regimes to maximize tumor response to treatment due to genetic differences, although these are yet to be defined.	('tumor', 'Disease', (63, 68))	('genetic differences', 'Var', (98, 117))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
14643	33477420	To determine if THC was exerting effects on medulloblastoma and ependymoma cells via the activation of CB1R, cells were pre-incubated with the CB1R-selective antagonist SR141716 (SR1) followed by incubation with a sub-effective dose of THC, and cell viability was assessed using alamar blue assay after 72 h. As expected, THC reduced the viability of the cells; however, this was not prevented by the addition of SR1 (Figure 3).	('viability of', 'CPA', (338, 350))	('THC', 'Var', (322, 325))	('CB1R', 'Gene', (143, 147))	('THC', 'Chemical', 'MESH:D013759', (16, 19))	('THC', 'Chemical', 'MESH:D013759', (236, 239))	('medulloblastoma', 'Phenotype', 'HP:0002885', (44, 59))	('CB1R', 'Gene', (103, 107))	('ependymoma', 'Phenotype', 'HP:0002888', (64, 74))	('medulloblastoma and ependymoma', 'Disease', 'MESH:D008527', (44, 74))	('CB1R', 'Gene', '1268', (143, 147))	('THC', 'Chemical', 'MESH:D013759', (322, 325))	('SR1', 'Chemical', 'MESH:D000077285', (179, 182))	('alamar blue', 'Chemical', 'MESH:C005843', (279, 290))	('SR1', 'Chemical', 'MESH:D000077285', (413, 416))	('SR1', 'Chemical', 'MESH:D000077285', (169, 172))	('CB1R', 'Gene', '1268', (103, 107))	('SR141716', 'Chemical', 'MESH:D000077285', (169, 177))	('reduced', 'NegReg', (326, 333))
14654	33477420	Phosphorylation of ERK1/2 was reduced in the presence of CBD in D283 medulloblastoma cells (Figure 4), although due to experimental variability, this was not statistically significantly different to controls (Figure S2).	('CBD', 'Var', (57, 60))	('D283', 'Chemical', '-', (64, 68))	('Phosphorylation', 'MPA', (0, 15))	('medulloblastoma', 'Disease', 'MESH:D008527', (69, 84))	('reduced', 'NegReg', (30, 37))	('ERK1/2', 'Gene', '5595;5594', (19, 25))	('medulloblastoma', 'Phenotype', 'HP:0002885', (69, 84))	('ERK1/2', 'Gene', (19, 25))	('CBD', 'Chemical', 'MESH:D002185', (57, 60))	('medulloblastoma', 'Disease', (69, 84))
14659	33477420	S6 phosphorylation was consistently reduced by THC in two out of the three cell lines tested (Figure 4), although the reduction did not achieve statistical significance (Figure S2).	('THC', 'Var', (47, 50))	('phosphorylation', 'MPA', (3, 18))	('THC', 'Chemical', 'MESH:D013759', (47, 50))	('reduced', 'NegReg', (36, 43))
14666	33477420	Altogether, immunoblotting has revealed that THC and CBD can induce a small but significant amount of autophagy in medulloblastoma and ependymoma cells, possibly through the inhibition of MAPK and AKT signaling pathways, leading to the induction of apoptosis.	('medulloblastoma', 'Phenotype', 'HP:0002885', (115, 130))	('AKT', 'Gene', '207', (197, 200))	('CBD', 'Var', (53, 56))	('MAPK', 'Pathway', (188, 192))	('AKT', 'Gene', (197, 200))	('CBD', 'Chemical', 'MESH:D002185', (53, 56))	('inhibition', 'NegReg', (174, 184))	('autophagy', 'CPA', (102, 111))	('THC', 'Chemical', 'MESH:D013759', (45, 48))	('ependymoma', 'Phenotype', 'HP:0002888', (135, 145))	('medulloblastoma and ependymoma', 'Disease', 'MESH:D008527', (115, 145))
14683	33477420	Inhibition of ERK1/2 phosphorylation was observed in vivo following CBD but not THC treatment (Figure 5D), consistent with our in vitro data and confirming that CBD was having some effect on the tumor cells in vivo, even though this did not lead to any change in survival outcome.	('tumor', 'Disease', (195, 200))	('THC', 'Chemical', 'MESH:D013759', (80, 83))	('ERK1/2', 'Gene', (14, 20))	('Inhibition', 'NegReg', (0, 10))	('CBD', 'Var', (68, 71))	('phosphorylation', 'MPA', (21, 36))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('CBD', 'Chemical', 'MESH:D002185', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('CBD', 'Chemical', 'MESH:D002185', (161, 164))
14697	33477420	Consistent with the effects of THC and CBD on medulloblastoma cell viability in vitro, the cannabinoids induced cell cycle arrest when used at sub-ED50 doses, with CBD significantly decreasing the number of cells undergoing active DNA synthesis after 48 h exposure (Figure 7A,B).	('arrest', 'Disease', (123, 129))	('medulloblastoma', 'Phenotype', 'HP:0002885', (46, 61))	('medulloblastoma', 'Disease', (46, 61))	('CBD', 'Var', (164, 167))	('decreasing', 'NegReg', (182, 192))	('cannabinoids', 'Chemical', 'MESH:D002186', (91, 103))	('CBD', 'Chemical', 'MESH:D002185', (39, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('CBD', 'Chemical', 'MESH:D002185', (164, 167))	('arrest', 'Disease', 'MESH:D006323', (123, 129))	('THC', 'Chemical', 'MESH:D013759', (31, 34))	('medulloblastoma', 'Disease', 'MESH:D008527', (46, 61))
14698	33477420	As expected, CPA also induced cell cycle arrest, reducing the proportion of cells traversing through S phase.	('CPA', 'Chemical', 'MESH:D003520', (13, 16))	('reducing', 'NegReg', (49, 57))	('arrest', 'Disease', (41, 47))	('CPA', 'Var', (13, 16))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (30, 47))	('arrest', 'Disease', 'MESH:D006323', (41, 47))
14702	33477420	Despite the presence of cleaved PARP in immunoblots within 48 h of exposure to THC or CBD (Figure 4), there was no significant increase in apoptosis observed by flow cytometry when the cannabinoids were used alone.	('cleaved', 'Var', (24, 31))	('cannabinoids', 'Chemical', 'MESH:D002186', (185, 197))	('CBD', 'Chemical', 'MESH:D002185', (86, 89))	('PARP', 'Gene', '1302', (32, 36))	('presence', 'Reg', (12, 20))	('PARP', 'Gene', (32, 36))	('THC', 'Chemical', 'MESH:D013759', (79, 82))
14726	33477420	As is well established, CPA causes hematopoietic toxicity, which is replicated in our mice by a reduction in white blood cells and neutrophils.	('hematopoietic toxicity', 'Disease', 'MESH:D019337', (35, 57))	('hematopoietic toxicity', 'Disease', (35, 57))	('mice', 'Species', '10090', (86, 90))	('CPA', 'Chemical', 'MESH:D003520', (24, 27))	('CPA', 'Var', (24, 27))	('reduction', 'NegReg', (96, 105))
14777	33477420	For example, modulation of the endocannabinoid system has been shown to prevent cisplatin-induced neuropathic pain in preclinical models, suggesting cannabinoids may potentially improve patient quality of life; however, these data have not yet been validated in a clinical setting.	('neuropathic pain', 'Disease', (98, 114))	('improve', 'PosReg', (178, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('neuropathic pain', 'Disease', 'MESH:D009437', (98, 114))	('cannabinoid', 'Chemical', 'MESH:D002186', (149, 160))	('cannabinoids', 'Chemical', 'MESH:D002186', (149, 161))	('cannabinoid', 'Chemical', 'MESH:D002186', (35, 46))	('pain', 'Phenotype', 'HP:0012531', (110, 114))	('modulation', 'Var', (13, 23))	('patient', 'Species', '9606', (186, 193))
14787	33477420	Two ependymoma datasets were analyzed: (1) GSE64415 and (2) RNA-seq from formalin-fixed paraffin embedded (FFPE) tissue in UK ependymomas (Ritzmann et al.	('ependymoma', 'Disease', (4, 14))	('PE', 'Chemical', '-', (109, 111))	('ependymomas', 'Disease', 'MESH:D004806', (126, 137))	('UK ependymomas', 'Phenotype', 'HP:0002888', (123, 137))	('ependymomas', 'Disease', (126, 137))	('ependymoma', 'Phenotype', 'HP:0002888', (126, 136))	('paraffin', 'Chemical', 'MESH:D010232', (88, 96))	('GSE64415', 'Var', (43, 51))	('ependymoma', 'Disease', 'MESH:D004806', (126, 136))	('ependymoma', 'Phenotype', 'HP:0002888', (4, 14))	('ependymoma', 'Disease', (126, 136))	('ependymoma', 'Disease', 'MESH:D004806', (4, 14))	('formalin', 'Chemical', 'MESH:D005557', (73, 81))
14792	33477420	D425 and D283 cells were a gift from Darell Bigner of Duke University (Durham, NC, USA), and PER547 cells were a gift from Ursula Kees of Telethon Kids Institute (Perth, Australia).	('D283', 'Chemical', '-', (9, 13))	('PE', 'Chemical', '-', (93, 95))	('D425', 'Var', (0, 4))	('D283', 'Var', (9, 13))
14797	33477420	Medulloblastoma cell lines were cultured in antibiotic-free media supplemented with Glutamax (Invitrogen, Carlsbad, CA, USA) at 37  C in 5% CO2 as follows: D283: MEM-alpha (Gibco, Waltham, MA, USA) with 10% fetal bovine serum (FBS) (CellSera, Rutherford, Australia); PER547: RPMI (Gibco) with 1 mM sodium pyruvate (Invitrogen), non-essential amino acids (Invitrogen), 50 microM 2-mercaptoethanol (Sigma-Aldrich, St Louis, MO, USA), and 10% FBS; D425: modified IMEM (Gibco) with 1 M HEPES (Gibco) and 10% FBS.	('MEM-alpha', 'Gene', '5411', (162, 171))	('Medulloblastoma', 'Disease', 'MESH:D008527', (0, 15))	('D425', 'Var', (445, 449))	('D283', 'Chemical', '-', (156, 160))	('Medulloblastoma', 'Disease', (0, 15))	('PE', 'Chemical', '-', (484, 486))	('MEM-alpha', 'Gene', (162, 171))	('ethanol', 'Chemical', 'MESH:D000431', (388, 395))	('PE', 'Chemical', '-', (267, 269))	('Medulloblastoma', 'Phenotype', 'HP:0002885', (0, 15))
14816	33477420	PER547, D283, and D425 cells were washed and resuspended twice in medium containing 1.5% FBS and incubated for 3 h before being treated with the ED50 and ED80 doses of THC and CBD.	('PE', 'Chemical', '-', (0, 2))	('ED80', 'Var', (154, 158))	('CBD', 'Chemical', 'MESH:D002185', (176, 179))	('D283', 'Chemical', '-', (8, 12))	('THC', 'Chemical', 'MESH:D013759', (168, 171))	('ED50', 'Var', (145, 149))
14820	33477420	Primary antibodies used were PRAS40 (Cell Signaling Technologies (CST, Danvers, MA, USA) #2691, 1:1000), phosphorylated PRAS40 Thr246 (CST #2997, 1:1000), p42/44 ERK1/2 (CST #9102, 1:1000), phosphorylated ERK1/2 Thr202/Tyr204 (CST #9101, 1:1000), S6 ribosomal protein (CST #2217, 1:1000), phosphorylated S6 ribosomal protein Ser235/236 (CST #2211, 1:1000), 4EBP1 (CST #9452, 1:1000), phosphorylated 4EBP1 Thr37/46 (CST #2855, 1:1000), LC3A/B (CST #12741, 1:1000), cleaved PARP Asp214 (CST #5625, 1:1000), and beta-actin (Sigma-Aldrich #A1978, 1:5000).	('4EBP1', 'Gene', (357, 362))	('4EBP1', 'Gene', '1978', (399, 404))	('ERK1/2', 'Gene', (162, 168))	('ERK1/2', 'Gene', '5595;5594', (162, 168))	('PARP', 'Gene', '1302', (472, 476))	('LC3A', 'Gene', (435, 439))	('PRAS40', 'Gene', (29, 35))	('Thr202', 'Chemical', '-', (212, 218))	('PRAS40', 'Gene', '84335', (120, 126))	('Tyr204', 'Chemical', '-', (219, 225))	('beta-actin', 'Protein', (509, 519))	('4EBP1', 'Gene', '1978', (357, 362))	('CST #12741', 'Var', (443, 453))	('PARP', 'Gene', (472, 476))	('4EBP1', 'Gene', (399, 404))	('ERK1/2', 'Gene', (205, 211))	('ERK1/2', 'Gene', '5595;5594', (205, 211))	('PRAS40', 'Gene', '84335', (29, 35))	('LC3A', 'Gene', '84557', (435, 439))	('PRAS40', 'Gene', (120, 126))	('CST #5625', 'Var', (485, 494))
14856	33029127	These data suggest that even in patients with GBM in or near primary brain regions, significant functional reorganization is possible.	('GBM in', 'Var', (46, 52))	('patients', 'Species', '9606', (32, 40))	('functional reorganization', 'CPA', (96, 121))
14867	33029127	GBM patients, in comparison to LGG patients, are more likely to have overt neurologic deficits with more rapid onset.	('overt neurologic deficits', 'Phenotype', 'HP:0002344', (69, 94))	('neurologic deficits', 'Disease', (75, 94))	('GBM', 'Var', (0, 3))	('neurologic deficits', 'Phenotype', 'HP:0000707', (75, 94))	('neurologic deficit', 'Phenotype', 'HP:0000707', (75, 93))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (35, 43))	('neurologic deficits', 'Disease', 'MESH:D009461', (75, 94))
14905	33029127	By definition, the patients who demonstrated plasticity had no deficits in motor or sensory function on their clinical neurologic exam.	('motor', 'CPA', (75, 80))	('patients', 'Species', '9606', (19, 27))	('plasticity', 'Var', (45, 55))
14917	33029127	Specifically, the key findings of our study are twofold: (1) plasticity can indeed occur in GBM, a rapidly growing and aggressive tumor, and (2) plasticity can occur in the primary motor and sensory cortices in the setting of GBM and is in fact a relatively common mechanism to preserve function in this cohort.	('aggressive tumor', 'Disease', 'MESH:D001523', (119, 135))	('aggressive tumor', 'Disease', (119, 135))	('plasticity', 'Var', (145, 155))	('occur', 'Reg', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('plasticity', 'MPA', (61, 71))	('GBM', 'Disease', (92, 95))
14950	31959027	The distribution of molecular markers, including alterations in TP53, IDH1, PI3K, ATRX, EGFR, H3F3A TERT, PDGFR, PTEN, distinguishes these tumor types based on their association with recurrent genetic lesions and histology.	('IDH1', 'Gene', '15926', (70, 74))	('tumor', 'Disease', (139, 144))	('A TERT', 'CellLine', 'CVCL:C452', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('H3F3A', 'Gene', '3020', (94, 99))	('PTEN', 'Gene', (113, 117))	('EGFR', 'Gene', (88, 92))	('IDH1', 'Gene', (70, 74))	('alterations', 'Var', (49, 60))	('ATRX', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('rat', 'Species', '10116', (53, 56))	('PTEN', 'Gene', '5728', (113, 117))	('TP53', 'Gene', (64, 68))	('H3F3A', 'Gene', (94, 99))	('EGFR', 'Gene', '1956', (88, 92))	('PDGFR', 'Gene', (106, 111))	('PDGFR', 'Gene', '5159', (106, 111))	('PI3K', 'Gene', (76, 80))
14951	31959027	One of the most distinctive criteria for the molecular classification in gliomas is the mutational status of isocitrate dehydrogenase 1 (IDH1).	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('mutational', 'Var', (88, 98))	('IDH1', 'Gene', (137, 141))	('IDH1', 'Gene', '15926', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('isocitrate', 'Chemical', 'MESH:C034219', (109, 119))	('gliomas', 'Disease', (73, 80))
14952	31959027	Almost 50% of adult glioma patients harbor mutations in IDH1, usually at arginine 132 (R132H).	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (20, 26))	('R132H', 'Mutation', 'rs1034749666', (87, 92))	('IDH1', 'Gene', '15926', (56, 60))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (43, 52))	('glioma', 'Disease', (20, 26))	('arginine', 'Chemical', 'MESH:D001120', (73, 81))	('IDH1', 'Gene', (56, 60))
14954	31959027	In addition, 70% of secondary HGG (WHO grade IV) also have IDH1 mutations.	('IDH1', 'Gene', (59, 63))	('IDH1', 'Gene', '15926', (59, 63))	('mutations', 'Var', (64, 73))
14956	31959027	In LGG, two mutant IDH1 glioma subtypes have been identified according to mutually exclusive genomic alterations: i) ATRX mutation or ii) loss of 1p/19q chromosomal segments (1p/19q-codel)(Table 1).	('IDH1 glioma', 'Disease', (19, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('loss', 'Var', (138, 142))	('rat', 'Species', '10116', (105, 108))	('mutation', 'Var', (122, 130))	('IDH1 glioma', 'Disease', 'MESH:D005910', (19, 30))	('ATRX', 'Gene', (117, 121))
14957	31959027	Mutant IDH1 LGGs with inactivating mutations in ATRX co-expresses TP53 mutation, and are associated with astrocytoma.	('associated', 'Reg', (89, 99))	('IDH1', 'Gene', '15926', (7, 11))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('ATRX', 'Gene', (48, 52))	('astrocytoma', 'Disease', 'MESH:D001254', (105, 116))	('inactivating mutations', 'Var', (22, 44))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('astrocytoma', 'Disease', (105, 116))	('astrocytoma', 'Phenotype', 'HP:0009592', (105, 116))
14958	31959027	Mutant IDH1 LGGs with 1p/19q-codel subtype present TERT promoter (TERTp) and CIC mutations are associated with oligodendroglioma) (Table 1).	('CIC', 'Disease', 'None', (77, 80))	('IDH1', 'Gene', '15926', (7, 11))	('TERTp', 'Gene', (66, 71))	('oligodendroglioma', 'Disease', (111, 128))	('TERT', 'Gene', (51, 55))	('TERTp', 'Gene', '7015', (66, 71))	('IDH1', 'Gene', (7, 11))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', '7015', (66, 70))	('mutations', 'Var', (81, 90))	('oligodendroglioma', 'Disease', 'MESH:D009837', (111, 128))	('Mutant', 'Var', (0, 6))	('CIC', 'Disease', (77, 80))	('associated', 'Reg', (95, 105))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
14960	31959027	In adults, IDH1 wild type glioma patients retain ATRX function and typically express TERTp mutations and alterations in regulators of the RTK-RAS-PI3K signaling cascade (Table 1).	('ATRX', 'MPA', (49, 53))	('patients', 'Species', '9606', (33, 41))	('TERTp', 'Gene', '7015', (85, 90))	('IDH1', 'Gene', '15926', (11, 15))	('TK', 'Gene', 'None', (139, 141))	('glioma', 'Disease', (26, 32))	('alterations', 'Reg', (105, 116))	('mutations', 'Var', (91, 100))	('rat', 'Species', '10116', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('TERTp', 'Gene', (85, 90))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('IDH1', 'Gene', (11, 15))
14961	31959027	Pediatric gliomas are mostly IDH1 wild type, harboring TP53 and ATRX inactivating mutations, as well as H3F3A mutations which are associated with malignancy and poor prognosis.	('ATRX', 'Gene', (64, 68))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('mutations', 'Var', (110, 119))	('IDH1', 'Gene', (29, 33))	('inactivating mutations', 'Var', (69, 91))	('TP53', 'Gene', (55, 59))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('IDH1', 'Gene', '15926', (29, 33))	('H3F3A', 'Gene', '3020', (104, 109))	('H3F3A', 'Gene', (104, 109))	('malignancy', 'Disease', (146, 156))	('gliomas', 'Disease', (10, 17))	('gliomas', 'Disease', 'MESH:D005910', (10, 17))
14969	31959027	A recent report showed a positive correlation between mutational load and the effectiveness of immune check point inhibition in several cancers, but not in glioma.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('glioma', 'Disease', (156, 162))	('immune', 'MPA', (95, 101))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('mutational load', 'Var', (54, 69))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
14970	31959027	This suggests that the mutational load is not a valid predictor for the response to immune check point inhibitors in glioma patients.	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))	('mutational load', 'Var', (23, 38))
14973	31959027	In GBM, preclinical testing suggests that blocking CTLA-4 alone results in enhanced long term survival.	('enhanced', 'PosReg', (75, 83))	('CTLA-4', 'Gene', (51, 57))	('blocking', 'Var', (42, 50))	('long term survival', 'CPA', (84, 102))	('CTLA-4', 'Gene', '1493', (51, 57))
14988	31959027	Mutation in the epidermal growth factor receptor (EGFR variant III (EGFRvIII)) is the most common gain of function mutation in high grade glioma.	('glioma', 'Disease', (138, 144))	('epidermal growth factor receptor', 'Gene', '1956', (16, 48))	('gain of function', 'PosReg', (98, 114))	('Mutation', 'Var', (0, 8))	('EGFR', 'Gene', '1956', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('EGFR', 'Gene', '1956', (68, 72))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('epidermal growth factor receptor', 'Gene', (16, 48))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', (68, 72))
14996	31959027	MAb806 (now known as ABT-806) inhibited growth of EGFRvIII-positive human glioma xenografts.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('human', 'Species', '9606', (68, 73))	('inhibited', 'NegReg', (30, 39))	('MAb806', 'Var', (0, 6))	('EGFR', 'Gene', '1956', (50, 54))	('glioma', 'Disease', (74, 80))	('MAb806', 'Chemical', 'MESH:C518939', (0, 6))	('growth', 'CPA', (40, 46))	('EGFR', 'Gene', (50, 54))	('ABT-806', 'Chemical', 'MESH:C000604456', (21, 28))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
15022	31959027	Moreover, other modifications have been tested to increase the proliferation and persistence of CAR T-cells in the tumor microenvironment.	('proliferation', 'CPA', (63, 76))	('rat', 'Species', '10116', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CAR', 'Gene', (96, 99))	('tumor', 'Disease', (115, 120))	('modifications', 'Var', (16, 29))	('increase', 'PosReg', (50, 58))	('persistence', 'CPA', (81, 92))	('CAR', 'Gene', '19674', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
15049	31959027	This trial also demonstrated that Delta-24-RGD replicates and spreads within the tumor, leading to immunogenic tumor cell death and enhancement of T lymphocyte tumor infiltration (Table 2).	('Delta-24', 'Chemical', '-', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('enhancement', 'PosReg', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('rat', 'Species', '10116', (23, 26))	('immunogenic tumor cell death', 'Disease', (99, 127))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (111, 116))	('Delta-24-RGD', 'Var', (34, 46))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('rat', 'Species', '10116', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (160, 165))	('immunogenic tumor cell death', 'Disease', 'MESH:D003643', (99, 127))	('tumor', 'Disease', (81, 86))	('T lymphocyte tumor', 'Phenotype', 'HP:0012190', (147, 165))
15066	31959027	As described, mutation in IDH1 (IDH1-R132H) is a hallmark genetic marker in a subset of gliomas.	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', (26, 30))	('gliomas', 'Disease', (88, 95))	('IDH1', 'Gene', '15926', (32, 36))	('mutation', 'Var', (14, 22))	('R132H', 'Mutation', 'rs1034749666', (37, 42))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('IDH1', 'Gene', '15926', (26, 30))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))
15070	31959027	As a consequence, mutant IDH1 glioma cells exhibit metabolic and epigenetic reprogramming that impacts tumor development and cellular signaling.	('IDH1 glioma', 'Disease', 'MESH:D005910', (25, 36))	('cellular signaling', 'MPA', (125, 143))	('epigenetic reprogramming', 'CPA', (65, 89))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('impacts tumor', 'Disease', 'MESH:D014095', (95, 108))	('impacts tumor', 'Disease', (95, 108))	('mutant', 'Var', (18, 24))	('IDH1 glioma', 'Disease', (25, 36))	('metabolic', 'CPA', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
15074	31959027	The mechanisms are likely closely related to the epigenetic changes in gene expression induced by mutant IDH1 activity.	('IDH1', 'Gene', (105, 109))	('IDH1', 'Gene', '15926', (105, 109))	('activity', 'MPA', (110, 118))	('mutant', 'Var', (98, 104))
15075	31959027	It has been reported that mutant IDH1 blocks cell differentiation and inhibition of 2-HG production decreases cell proliferation, delaying growth of mutant IDH1 expressing xenografts.	('inhibition', 'NegReg', (70, 80))	('cell differentiation', 'CPA', (45, 65))	('IDH1', 'Gene', (156, 160))	('blocks', 'NegReg', (38, 44))	('IDH1', 'Gene', (33, 37))	('delaying', 'NegReg', (130, 138))	('mutant', 'Var', (149, 155))	('growth', 'CPA', (139, 145))	('2-HG', 'Chemical', '-', (84, 88))	('decreases', 'NegReg', (100, 109))	('IDH1', 'Gene', '15926', (156, 160))	('IDH1', 'Gene', '15926', (33, 37))	('rat', 'Species', '10116', (122, 125))	('cell proliferation', 'CPA', (110, 128))	('mutant', 'Var', (26, 32))	('delaying growth', 'Phenotype', 'HP:0001510', (130, 145))
15076	31959027	Recently, use of a brain penetrant inhibitor resulted in improved median survival in an intracranial mutant IDH1 glioma model.	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('IDH1 glioma', 'Disease', 'MESH:D005910', (108, 119))	('mutant', 'Var', (101, 107))	('IDH1 glioma', 'Disease', (108, 119))	('median survival', 'MPA', (66, 81))	('improved', 'PosReg', (57, 65))
15078	31959027	Disruption of mutant IDH1 is a potential therapeutic target for glioma patients that express this molecular alteration.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('IDH1', 'Gene', '15926', (21, 25))	('mutant', 'Var', (14, 20))	('patients', 'Species', '9606', (71, 79))	('rat', 'Species', '10116', (112, 115))	('glioma', 'Disease', (64, 70))	('IDH1', 'Gene', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('Disruption', 'Var', (0, 10))
15079	31959027	A phase I clinical trial demonstrated a 70% of reduction of 2-HG in mutant IDH1 gliomas with an impact on metabolic reprograming and cell density.	('IDH1 gliomas', 'Disease', (75, 87))	('metabolic reprograming', 'CPA', (106, 128))	('rat', 'Species', '10116', (32, 35))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('reduction', 'NegReg', (47, 56))	('2-HG', 'Chemical', '-', (60, 64))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('2-HG', 'MPA', (60, 64))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (75, 87))	('mutant', 'Var', (68, 74))
15082	31959027	Our team recently reported that IDH1-R132H in combination with loss of TP53 and ATRX, increases HR DNA repair and induces radioresistance in glioma, a phenomenon that is reversed by using DDR response inhibitors.	('loss', 'Var', (63, 67))	('IDH1', 'Gene', (32, 36))	('increases', 'PosReg', (86, 95))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('radioresistance', 'CPA', (122, 137))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('IDH1', 'Gene', '15926', (32, 36))	('R132H', 'Mutation', 'rs1034749666', (37, 42))	('induces', 'Reg', (114, 121))	('ATRX', 'Gene', (80, 84))	('TP53', 'Gene', (71, 75))	('DDR', 'Chemical', '-', (188, 191))	('HR DNA repair', 'MPA', (96, 109))	('glioma', 'Disease', (141, 147))
15086	31959027	Although mutations in IDH1 are found in 50 to 80% of low-grade glioma, only 12% of GBMs express this mutation.	('mutations', 'Var', (9, 18))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('IDH1', 'Gene', (22, 26))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH1', 'Gene', '15926', (22, 26))	('found', 'Reg', (31, 36))	('glioma', 'Disease', (63, 69))
15089	31959027	For instance, in a longitudinal analysis of 50 mutant IDH1 patients, six cases had copy number alterations (CNA) at the IDH1 endogenous locus in recurrent tumors samples when compared to the primary mIDH1 glioma.	('IDH1', 'Gene', (200, 204))	('copy number alterations', 'Var', (83, 106))	('IDH1', 'Gene', (120, 124))	('IDH1 glioma', 'Disease', (200, 211))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('IDH1', 'Gene', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('patients', 'Species', '9606', (59, 67))	('mIDH1', 'Gene', '15926', (199, 204))	('mutant', 'Var', (47, 53))	('mIDH1', 'Gene', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('IDH1', 'Gene', '15926', (200, 204))	('rat', 'Species', '10116', (99, 102))	('tumors', 'Disease', (155, 161))	('IDH1', 'Gene', '15926', (120, 124))	('IDH1 glioma', 'Disease', 'MESH:D005910', (200, 211))	('IDH1', 'Gene', '15926', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
15090	31959027	Deletion or amplification of mutant IDH1 locus led to reduced 2HG and transformation to more aggressive grade IV glioblastoma.	('glioblastoma', 'Disease', (113, 125))	('transformation', 'Reg', (70, 84))	('IDH1', 'Gene', (36, 40))	('2HG', 'CPA', (62, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('mutant', 'Var', (29, 35))	('amplification', 'Var', (12, 25))	('IDH1', 'Gene', '15926', (36, 40))	('reduced', 'NegReg', (54, 61))	('Deletion', 'Var', (0, 8))
15091	31959027	These findings indicate that heterogeneity within the primary tumor could lead to resistance to mIDH1 inhibitor treatment, making mutant IDH1 a passenger upon tumor recurrence.	('IDH1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('IDH1', 'Gene', '15926', (97, 101))	('lead to', 'Reg', (74, 81))	('mIDH1', 'Gene', '15926', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mIDH1', 'Gene', (96, 101))	('IDH1', 'Gene', (137, 141))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (159, 164))	('resistance', 'MPA', (82, 92))	('IDH1', 'Gene', '15926', (137, 141))	('mutant', 'Var', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
15092	31959027	In conclusion, IDH1 mutant tumors are unique entities and understanding this biology may lead to novel treatment strategies.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('rat', 'Species', '10116', (115, 118))	('IDH1', 'Gene', (15, 19))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('lead', 'Reg', (89, 93))	('IDH1', 'Gene', '15926', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutant', 'Var', (20, 26))
15094	31959027	Therefore, subtypes of mutant IDH1 glioma should be studied independently in order to best define potential novel targeted therapies.	('IDH1 glioma', 'Disease', (30, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('IDH1 glioma', 'Disease', 'MESH:D005910', (30, 41))	('mutant', 'Var', (23, 29))
15095	31959027	Inhibition of 2-HG production and modulation of the signal cascade involved in IDH1-R132H activity, including DDR, may serve as effective adjuvant treatment approaches for patients with mutant IDH1 gliomas.	('IDH1', 'Gene', (193, 197))	('IDH1', 'Gene', '15926', (79, 83))	('IDH1', 'Gene', '15926', (193, 197))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (193, 205))	('mutant', 'Var', (186, 192))	('DDR', 'Chemical', '-', (110, 113))	('gliomas', 'Phenotype', 'HP:0009733', (198, 205))	('R132H', 'Mutation', 'rs1034749666', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('IDH1 gliomas', 'Disease', (193, 205))	('patients', 'Species', '9606', (172, 180))	('2-HG', 'Chemical', '-', (14, 18))	('IDH1', 'Gene', (79, 83))	('2-HG', 'MPA', (14, 18))
15102	31959027	One such modification using the tumor-penetrating peptide, iRGD, has been shown to facilitate the NP transport and CNS penetration for selective delivery of a variety of therapeutics or diagnostic agents to the tumor site.	('rat', 'Species', '10116', (124, 127))	('CNS penetration', 'CPA', (115, 130))	('NP transport', 'MPA', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('rat', 'Species', '10116', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('facilitate', 'PosReg', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (32, 37))	('modification', 'Var', (9, 21))
15116	31959027	Thus, a single stereotactic injection of GMX-1778 resulted in the suppression of the intracerebral mutant IDH1 tumor growth when compared to control mice that were injected with blank PLGA microparticles.	('intracerebral', 'Disease', 'MESH:D002543', (85, 98))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('GMX-1778', 'Var', (41, 49))	('tumor', 'Disease', (111, 116))	('IDH1', 'Gene', (106, 110))	('GMX-1778', 'Chemical', 'MESH:C401312', (41, 49))	('mice', 'Species', '10090', (149, 153))	('IDH1', 'Gene', '15926', (106, 110))	('intracerebral', 'Disease', (85, 98))	('suppression', 'NegReg', (66, 77))
15136	31959027	Patients receiving TMZ and IR after surgery showed a 2.5-month survival advantage compared with those receiving adjuvant radiotherapy alone.	('Patients', 'Species', '9606', (0, 8))	('TMZ', 'Var', (19, 22))	('advantage', 'PosReg', (72, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (19, 22))
15154	31959027	These therapies along with targeting known mutations, such as in mutant IDH1, represent exciting avenues for future drug development.	('mutant', 'Var', (65, 71))	('IDH1', 'Gene', (72, 76))	('IDH1', 'Gene', '15926', (72, 76))
15177	32034261	Tumors growth rates of the EP + Methotrexate group (1.02 +- 0.77) were significantly lower (p < 0.01) than the control (5.2 +- 1.0) 1-week post treatment.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('lower', 'NegReg', (85, 90))	('Methotrexate', 'Chemical', 'MESH:D008727', (32, 44))	('Tumors', 'Disease', (0, 6))	('EP + Methotrexate', 'Var', (27, 44))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('rat', 'Species', '10116', (14, 17))
15181	32034261	Increased survival was found in the EP + Cisplatin group, Chi2 = 7.54, p < 0.006 (Log Rank).	('Cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('Increased', 'PosReg', (0, 9))	('survival', 'MPA', (10, 18))	('EP + Cisplatin', 'Var', (36, 50))
15191	32034261	Furthermore, inducing necrosis was found to induce a tumor specific immune response.	('inducing', 'Var', (13, 21))	('necrosis', 'Disease', 'MESH:D009336', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('necrosis', 'Disease', (22, 30))	('induce', 'Reg', (44, 50))
15194	32034261	Tissue necrosis within the tumor mass surrounded by BBB disruption can be achieved by electroporation (EP).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('electroporation', 'Var', (86, 101))	('tumor', 'Disease', (27, 32))	('necrosis', 'Disease', (7, 15))	('rat', 'Species', '10116', (95, 98))	('Tissue necrosis', 'Phenotype', 'HP:0010885', (0, 15))	('necrosis', 'Disease', 'MESH:D009336', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
15225	32034261	The results of the statistical analysis demonstrate that EP-induced BBB disruption combined with MTX has the ability to slow tumor growth but has no significant additional benefit over treatment with MTX alone (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MTX', 'Chemical', 'MESH:D008727', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MTX', 'Chemical', 'MESH:D008727', (200, 203))	('rat', 'Species', '10116', (47, 50))	('tumor', 'Disease', (125, 130))	('EP-induced', 'Var', (57, 67))
15234	32034261	The results of this study suggest that EP + Cisplatin can delay tumors growth whereas Cisplatin alone has no effect on tumor growth compared to control.	('EP + Cisplatin', 'Var', (39, 53))	('tumors', 'Disease', (64, 70))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('Cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('delay', 'NegReg', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
15256	32034261	In brains of rats treated with EP + Cisplatin and extracted 48 hours post treatment it appears that the tumors were heavily bleeding.	('rats', 'Species', '10116', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('Cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('EP + Cisplatin', 'Var', (31, 45))	('bleeding', 'Disease', 'MESH:D006470', (124, 132))	('bleeding', 'Disease', (124, 132))
15269	32034261	Overall, tumors treated with EP + Cisplatin were smaller, seemed less infiltrative and appeared less viable than tumors treated with Cisplatin alone or EP alone.	('rat', 'Species', '10116', (76, 79))	('tumors', 'Disease', (113, 119))	('infiltrative', 'CPA', (70, 82))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('smaller', 'NegReg', (49, 56))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('less', 'NegReg', (96, 100))	('Cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('less', 'NegReg', (65, 69))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('EP + Cisplatin', 'Var', (29, 43))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
15274	32034261	Although tumors treated with EP alone showed EP-induced necrosis in the tumor core, the tumors cells seemed more viable than with the combined treatment and the tumors were larger and more infiltrative.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (161, 167))	('necrosis', 'Disease', 'MESH:D009336', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', (161, 166))	('necrosis', 'Disease', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('rat', 'Species', '10116', (195, 198))	('more', 'PosReg', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('EP-induced', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', (88, 94))
15339	32034261	Nevertheless, our results demonstrated that point-source EP as a single modality had no benefit in delaying tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('delaying', 'NegReg', (99, 107))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Disease', (108, 113))	('point-source', 'Var', (44, 56))
15342	32034261	On the other hand, tumors that were treated with EP + Cisplatin clearly demonstrated delayed tumor growth.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('Cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EP +', 'Var', (49, 53))	('tumor', 'Disease', (19, 24))	('rat', 'Species', '10116', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('delayed', 'NegReg', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
15353	32034261	Our results indicate that EP + Cisplatin can slow tumor growth (increase ORR) and increase survival.	('survival', 'CPA', (91, 99))	('EP + Cisplatin', 'Var', (26, 40))	('slow', 'NegReg', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('increase', 'PosReg', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('tumor', 'Disease', (50, 55))
15358	32034261	One limitation of using Cisplatin is that it may cause severe brain toxicity.	('toxicity', 'Disease', (68, 76))	('Cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('cause', 'Reg', (49, 54))	('Cisplatin', 'Var', (24, 33))	('toxicity', 'Disease', 'MESH:D064420', (68, 76))
15360	32034261	We found that rats in the EP + Cisplatin group suffered from immediate weight loss, potphyrin discharge around the eyes and nose, and some rats showed transient partial paralysis of the lower limbs.	('partial paralysis', 'Phenotype', 'HP:0002385', (161, 178))	('paralysis', 'Phenotype', 'HP:0003470', (169, 178))	('EP + Cisplatin', 'Var', (26, 40))	('paralysis', 'Disease', 'MESH:D010243', (169, 178))	('rats', 'Species', '10116', (14, 18))	('lower limbs', 'Phenotype', 'HP:0006385', (186, 197))	('weight loss', 'Disease', 'MESH:D015431', (71, 82))	('potphyrin discharge', 'MPA', (84, 103))	('potphyrin discharge', 'Phenotype', 'HP:0010473', (84, 103))	('rats', 'Species', '10116', (139, 143))	('weight loss', 'Disease', (71, 82))	('Cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('paralysis', 'Disease', (169, 178))	('weight loss', 'Phenotype', 'HP:0001824', (71, 82))
15363	32034261	As the MRI depicts the BBB disruption volume caused by the fenestrated and damaged blood vessels of the tumor, 48 hours might not be enough for the destruction of these vessels although tumor cells lysis has already occurred.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (104, 109))	('BBB', 'CPA', (23, 26))	('tumor', 'Disease', (186, 191))	('fenestrated', 'Var', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('rat', 'Species', '10116', (65, 68))
15385	32034261	Although complete elimination of the tumors was not achieved, increased survival and response rates as well as reduced tumor growth rates were found for rats treated with EP + Cisplatin compared with control and Cisplatin alone.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', (119, 124))	('rat', 'Species', '10116', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('rat', 'Species', '10116', (132, 135))	('rat', 'Species', '10116', (153, 156))	('EP +', 'Var', (171, 175))	('reduced', 'NegReg', (111, 118))	('Cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumors', 'Disease', (37, 43))	('rats', 'Species', '10116', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
15399	31244524	Consequently, there is a wide array of disparate data for this poorly managed condition, including alterations in microRNAs (miRNAs), 14-3-3 proteins, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), sirtuins, aryl hydrocarbon receptor (AhR), endoplasmic reticulum (ER), mTOR, sphingosine-1-phosphate (S1P) receptors and levels, small GTPases, kynurenine pathway products, tyrosine receptor kinase B (TrkB), chromosome 4q35, purinergic signalling, shifting between glycolysis and oxidative phosphorylation, and alterations in the melatonergic pathway regulation.	('mTOR', 'Gene', (219, 223))	('aryl hydrocarbon receptor', 'Gene', (236, 261))	('kynurenine', 'Chemical', 'MESH:D007737', (370, 380))	('mammalian target of rapamycin', 'Gene', '2475', (188, 217))	('melatonergic pathway regulation', 'Pathway', (556, 587))	('alterations', 'Var', (99, 110))	('TrkB', 'Gene', (427, 431))	('mTOR', 'Gene', (297, 301))	('mTOR', 'Gene', '2475', (219, 223))	('aryl hydrocarbon receptor', 'Gene', '196', (236, 261))	('alterations', 'Reg', (537, 548))	('AMP-activated protein kinase', 'Gene', '5562', (151, 179))	('kynurenine', 'MPA', (370, 380))	('mammalian target of rapamycin', 'Gene', (188, 217))	('AMPK', 'Gene', '5562', (181, 185))	('mTOR', 'Gene', '2475', (297, 301))	('AhR', 'Gene', (263, 266))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('purinergic signalling', 'MPA', (451, 472))	('N', 'Chemical', 'MESH:D009584', (128, 129))	('shifting', 'MPA', (474, 482))	('TrkB', 'Gene', '4915', (427, 431))	('AMP-activated protein kinase', 'Gene', (151, 179))	('tyrosine receptor kinase B', 'Gene', (399, 425))	('tyrosine receptor kinase B', 'Gene', '4915', (399, 425))	('AMPK', 'Gene', (181, 185))	('AhR', 'Gene', '196', (263, 266))
15406	31244524	A plethora of data show a role for alterations in the miRNA, miR-451, in the pathophysiology of GBM/GSC.	('GBM/GSC', 'Gene', (96, 103))	('GBM/GSC', 'Gene', '145258', (96, 103))	('alterations', 'Var', (35, 46))	('miR-451', 'Gene', '574411', (61, 68))	('plethora', 'Phenotype', 'HP:0001050', (2, 10))	('miR-451', 'Gene', (61, 68))
15410	31244524	Recent work suggests that the 14-3-3 protein, AMPK-mTOR pathway, and the small GTPase, Rac1, may be intimately associated with such alterations in miR-451 levels, highlighting the role that miR-451 can play in the heterogeneous biological underpinnings of GBM/GSC.	('AMPK', 'Gene', (46, 50))	('mTOR', 'Gene', (51, 55))	('miR-451', 'Gene', '574411', (190, 197))	('mTOR', 'Gene', '2475', (51, 55))	('miR-451', 'Gene', (147, 154))	('alterations', 'Var', (132, 143))	('miR-451', 'Gene', '574411', (147, 154))	('associated', 'Reg', (111, 121))	('miR-451', 'Gene', (190, 197))	('14-3-3', 'Protein', (30, 36))	('GBM/GSC', 'Gene', '145258', (256, 263))	('Rac1', 'Gene', '5879', (87, 91))	('GBM/GSC', 'Gene', (256, 263))	('Rac1', 'Gene', (87, 91))	('AMPK', 'Gene', '5562', (46, 50))
15412	31244524	Variations in miR-451 may therefore be associated with the differential regulation of the melatonergic pathways.	('miR-451', 'Gene', (14, 21))	('melatonergic pathways', 'Pathway', (90, 111))	('Variations', 'Var', (0, 10))	('associated', 'Reg', (39, 49))	('miR-451', 'Gene', '574411', (14, 21))
15420	31244524	The loss of 14-3-3 sensitizes GBM/GSC to apoptosis as well as preventing NAS synthesis, thereby preventing any trophic effects of NAS via the TrkB.	('preventing', 'NegReg', (62, 72))	('preventing', 'NegReg', (96, 106))	('TrkB', 'Gene', (142, 146))	('TrkB', 'Gene', '4915', (142, 146))	('NAS synthesis', 'MPA', (73, 86))	('14-3-3', 'Protein', (12, 18))	('NAS', 'Chemical', 'MESH:C006389', (130, 133))	('GBM/GSC', 'Gene', (30, 37))	('GBM/GSC', 'Gene', '145258', (30, 37))	('loss', 'Var', (4, 8))	('NAS', 'Chemical', 'MESH:C006389', (73, 76))	('trophic effects of NAS', 'CPA', (111, 133))
15421	31244524	N-acetylserotonin is a brain-derived neurotrophic factor (BDNF) mimic and activates the BDNF receptor, TrkB, which is significant driver of GSC proliferation.	('GSC', 'Gene', (140, 143))	('GSC', 'Gene', '145258', (140, 143))	('TrkB', 'Gene', (103, 107))	('TrkB', 'Gene', '4915', (103, 107))	('brain-derived neurotrophic factor', 'Gene', '627', (23, 56))	('activates', 'PosReg', (74, 83))	('N-acetylserotonin', 'Chemical', 'MESH:C006389', (0, 17))	('brain-derived neurotrophic factor', 'Gene', (23, 56))	('N-acetylserotonin', 'Var', (0, 17))
15429	31244524	Interestingly, GBM-derived kynurenine can significantly modulate the immune responses in the tumour microenvironment.	('modulate', 'Reg', (56, 64))	('tumour', 'Disease', (93, 99))	('kynurenine', 'Chemical', 'MESH:D007737', (27, 37))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('kynurenine', 'Var', (27, 37))
15430	31244524	These authors showed kynurenine to activate the AhR in tumour-associated macrophages, a process involving the suppression of macrophage NF-kappaB, in turn modulating macrophage responses and the influence of macrophages on the activity of other immune cells in the tumour environment.	('tumour', 'Disease', (55, 61))	('suppression', 'NegReg', (110, 121))	('AhR', 'Gene', (48, 51))	('NF-kappaB', 'Gene', '4790', (136, 145))	('AhR', 'Gene', '196', (48, 51))	('macrophage', 'MPA', (166, 176))	('NF-kappaB', 'Gene', (136, 145))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('activate', 'PosReg', (35, 43))	('modulating', 'Reg', (155, 165))	('kynurenine', 'Chemical', 'MESH:D007737', (21, 31))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('kynurenine', 'Var', (21, 31))	('tumour', 'Disease', (265, 271))
15433	31244524	It should also be noted that the AhR-activating effects of kynurenine may be distinct from those of kynurenic acid in the tumour microenvironment.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('kynurenic acid', 'Chemical', 'MESH:D007736', (100, 114))	('tumour', 'Disease', (122, 128))	('kynurenine', 'Chemical', 'MESH:D007737', (59, 69))	('AhR', 'Gene', (33, 36))	('AhR', 'Gene', '196', (33, 36))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('kynurenine', 'Var', (59, 69))
15436	31244524	As such, kynurenine may be more likely to benefit GBM/GSC survival and migration.	('kynurenine', 'Var', (9, 19))	('benefit', 'PosReg', (42, 49))	('migration', 'CPA', (71, 80))	('GBM/GSC', 'Gene', '145258', (50, 57))	('GBM/GSC', 'Gene', (50, 57))	('kynurenine', 'Chemical', 'MESH:D007737', (9, 19))
15444	31244524	This may be complicated by the effects of miR-451 on AMPK regulation and other processes in different cell types, with miR-451 antagonism increasing AMPK activity in intestinal epithelial cells, while in GBM it is proposed that miR-451 mediates the shifting of GBM from proliferation to migration in response to different environmental conditions.	('miR-451', 'Gene', (42, 49))	('AMPK', 'Gene', (149, 153))	('miR-451', 'Gene', '574411', (119, 126))	('AMPK', 'Gene', '5562', (53, 57))	('AMPK', 'Gene', (53, 57))	('miR-451', 'Gene', (228, 235))	('antagonism', 'Var', (127, 137))	('miR-451', 'Gene', '574411', (42, 49))	('miR-451', 'Gene', (119, 126))	('increasing', 'PosReg', (138, 148))	('AMPK', 'Gene', '5562', (149, 153))	('miR-451', 'Gene', '574411', (228, 235))
15448	31244524	As such, alterations in the availability of glucose, via changes in miR-451, may be associated with the proliferation/migration balance via changes in the AMPK-mTOR pathway.	('AMPK', 'Gene', (155, 159))	('availability of', 'MPA', (28, 43))	('mTOR', 'Gene', '2475', (160, 164))	('miR-451', 'Gene', '574411', (68, 75))	('changes', 'Reg', (57, 64))	('mTOR', 'Gene', (160, 164))	('alterations', 'Var', (9, 20))	('glucose', 'Chemical', 'MESH:D005947', (44, 51))	('changes', 'Reg', (140, 147))	('associated', 'Reg', (84, 94))	('miR-451', 'Gene', (68, 75))	('AMPK', 'Gene', '5562', (155, 159))	('proliferation/migration balance', 'CPA', (104, 135))
15456	31244524	It would seem likely that GBM/GSC proliferation and migration arises from an increase in S1P receptor-induced small GTPase and that variations in migration may be linked to alterations in the levels of S1P receptor subtypes and sphingosine kinase-induced S1P in rearranged rafts, paralleling such changes in neurogenesis.	('migration', 'CPA', (146, 155))	('migration', 'CPA', (52, 61))	('alterations', 'Reg', (173, 184))	('GBM/GSC', 'Gene', (26, 33))	('increase', 'PosReg', (77, 85))	('GBM/GSC', 'Gene', '145258', (26, 33))	('variations', 'Var', (132, 142))	('small GTPase', 'Protein', (110, 122))	('S1P receptor-induced', 'Protein', (89, 109))
15459	31244524	Recent work showing that dysregulating cholesterol synthesis and uptake in the tumour microenvironment is damaging to GBM/GSC likely reflects such alterations in raft-associated receptors and the changes in intracellular pathways that occur, including in S1P receptor subtype-driven small GTPases.	('cholesterol', 'Chemical', 'MESH:D002784', (39, 50))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('GBM/GSC', 'Gene', (118, 125))	('GBM/GSC', 'Gene', '145258', (118, 125))	('dysregulating', 'Var', (25, 38))	('changes', 'Reg', (196, 203))	('cholesterol synthesis', 'MPA', (39, 60))	('raft-associated receptors', 'Protein', (162, 187))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('alterations', 'Reg', (147, 158))	('tumour', 'Disease', (79, 85))
15460	31244524	As such, alterations in S1P receptor subtypes in rearranged rafts will be coordinated with alterations in AMPK/mTOR/miR-451 and the regulation of NAS levels and effects at TrkB.	('TrkB', 'Gene', (172, 176))	('mTOR', 'Gene', '2475', (111, 115))	('AMPK', 'Gene', '5562', (106, 110))	('mTOR', 'Gene', (111, 115))	('miR-451', 'Gene', '574411', (116, 123))	('alterations', 'Var', (9, 20))	('NAS levels', 'MPA', (146, 156))	('AMPK', 'Gene', (106, 110))	('alterations', 'Reg', (91, 102))	('TrkB', 'Gene', '4915', (172, 176))	('miR-451', 'Gene', (116, 123))	('NAS', 'Chemical', 'MESH:C006389', (146, 149))
15466	31244524	It may also be of note that NAS can increase BDNF synthesis and release, as shown in the murine dentate gyrus.	('NAS', 'Var', (28, 31))	('increase', 'PosReg', (36, 44))	('release', 'MPA', (64, 71))	('murine', 'Species', '10090', (89, 95))	('BDNF synthesis', 'MPA', (45, 59))	('NAS', 'Chemical', 'MESH:C006389', (28, 31))
15469	31244524	Chromosome region 4q35 is a not an uncommon deletion in GBM and some other cancers, often in association with the tumour suppressor gene, FAT1, which is sited at 4q35.	('FAT1', 'Gene', (138, 142))	('tumour', 'Disease', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('Chromosome region 4q35', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('FAT1', 'Gene', '2195', (138, 142))	('tumour', 'Disease', 'MESH:D009369', (114, 120))
15473	31244524	Being NAD+ dependent links sirtuin activity to the availability of cellular NAD+, including its induction at the end of the kynurenine pathway.	('kynurenine', 'Pathway', (124, 134))	('sirtuin activity', 'MPA', (27, 43))	('NAD+', 'Chemical', 'MESH:D009243', (6, 10))	('kynurenine', 'Chemical', 'MESH:D007737', (124, 134))	('NAD+', 'Chemical', 'MESH:D009243', (76, 80))	('NAD+', 'Var', (76, 80))
15479	31244524	In contrast, the induction of sirtuin-1 leads to apoptosis in some GBM cell lines, while other data indicate that sirtuin-1 inhibition is important for apoptosis via its regulation of p53.	('induction', 'Var', (17, 26))	('p53', 'Gene', (184, 187))	('sirtuin-1', 'Gene', (30, 39))	('p53', 'Gene', '7157', (184, 187))	('sirtuin-1', 'Gene', '23411', (114, 123))	('sirtuin-1', 'Gene', (114, 123))	('sirtuin-1', 'Gene', '23411', (30, 39))	('apoptosis', 'CPA', (49, 58))
15492	31244524	However, the presence of melatonin within GBM/GSC is likely to prove problematic, given that melatonin in these cells, as in most tumours, inhibits proliferation and migration as well as inducing apoptosis.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('GBM/GSC', 'Gene', (42, 49))	('GBM/GSC', 'Gene', '145258', (42, 49))	('melatonin', 'Var', (93, 102))	('proliferation', 'CPA', (148, 161))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (130, 137))	('inducing', 'Reg', (187, 195))	('apoptosis', 'CPA', (196, 205))	('melatonin', 'Chemical', 'MESH:D008550', (25, 34))	('inhibits', 'NegReg', (139, 147))	('melatonin', 'Chemical', 'MESH:D008550', (93, 102))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
15497	31244524	Given that TrkB is an important regulator of GBM/GSC survival and of the spread of aggressiveness, at least in part via GBM/GSC exosomes, variations in the regulation of the NAS/melatonin ratio may be of some importance.	('GBM/GSC', 'Gene', '145258', (45, 52))	('GBM/GSC', 'Gene', '145258', (120, 127))	('TrkB', 'Gene', (11, 15))	('aggressiveness', 'Disease', 'MESH:D001523', (83, 97))	('GBM/GSC', 'Gene', (45, 52))	('melatonin', 'Chemical', 'MESH:D008550', (178, 187))	('variations', 'Var', (138, 148))	('aggressiveness', 'Disease', (83, 97))	('NAS', 'Chemical', 'MESH:C006389', (174, 177))	('TrkB', 'Gene', '4915', (11, 15))	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('GBM/GSC', 'Gene', (120, 127))
15501	31244524	Perhaps more important in GBM/GSC, and many other tumours, melatonin can be directly converted back to NAS by CYP1B1, with CYP1B1 being predominantly present in mitochondria.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('CYP1B1', 'Var', (110, 116))	('tumours', 'Disease', (50, 57))	('melatonin', 'Chemical', 'MESH:D008550', (59, 68))	('GBM/GSC', 'Gene', (26, 33))	('GBM/GSC', 'Gene', '145258', (26, 33))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('NAS', 'Chemical', 'MESH:C006389', (103, 106))
15503	31244524	In nonneoplastic cells, AhR-induced CYP1B1 in mitochondria leads to increased oxidative stress and suboptimal mitochondria functioning, highlighting the clear impact that CYP1B1 can have on core mitochondria processes.	('AhR', 'Gene', '196', (24, 27))	('suboptimal mitochondria functioning', 'MPA', (99, 134))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (68, 94))	('CYP1B1', 'Var', (36, 42))	('oxidative stress', 'MPA', (78, 94))	('increased', 'PosReg', (68, 77))	('AhR', 'Gene', (24, 27))
15504	31244524	Importantly, CYP1B1 is highly overexpressed in a wide array of different tumours, including lung, breast, hepatic, kidney, skin, gastrointestinal, prostate, bladder, and ovarian cancers, while CYP1B1 is absent or shows very low expression in healthy tissue.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('bladder', 'Disease', (157, 164))	('ovarian cancers', 'Phenotype', 'HP:0100615', (170, 185))	('tumours', 'Disease', (73, 80))	('gastrointestinal', 'Disease', (129, 145))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('CYP1B1', 'Var', (13, 19))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('gastrointestinal', 'Disease', 'MESH:D005767', (129, 145))	('prostate', 'Disease', (147, 155))	('skin', 'Disease', (123, 127))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('kidney', 'Disease', (115, 121))	('lung', 'Disease', (92, 96))	('breast', 'Disease', (98, 104))	('ovarian cancers', 'Disease', (170, 185))	('ovarian cancers', 'Disease', 'MESH:D010051', (170, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('hepatic', 'Disease', (106, 113))	('overexpressed', 'PosReg', (30, 43))
15507	31244524	This would suggest that TDO induction and consequent kynurenine and kynurenic acid activation of the AhR may dramatically increase the NAS/melatonin ratio, via CYP1B1, while also decreasing the levels of tryptophan available for NAS and melatonin synthesis.	('kynurenic acid', 'Var', (68, 82))	('NAS', 'Chemical', 'MESH:C006389', (229, 232))	('NAS/melatonin ratio', 'MPA', (135, 154))	('melatonin', 'Chemical', 'MESH:D008550', (139, 148))	('NAS', 'Chemical', 'MESH:C006389', (135, 138))	('AhR', 'Gene', (101, 104))	('kynurenine', 'Var', (53, 63))	('AhR', 'Gene', '196', (101, 104))	('tryptophan', 'Chemical', 'MESH:D014364', (204, 214))	('decreasing', 'NegReg', (179, 189))	('melatonin', 'Chemical', 'MESH:D008550', (237, 246))	('TDO', 'Gene', (24, 27))	('CYP1B1', 'Var', (160, 166))	('decreasing the levels of tryptophan', 'Phenotype', 'HP:0500135', (179, 214))	('kynurenic acid', 'Chemical', 'MESH:D007736', (68, 82))	('increase', 'PosReg', (122, 130))	('TDO', 'Gene', '6999', (24, 27))	('kynurenine', 'Chemical', 'MESH:D007737', (53, 63))
15515	31244524	As such, AhR induction of mitochondria CYP1B1 may be linked to not only changes in the melatonergic pathways and other GBM/GSC factors but also to alterations in the intercellular interactions that occur in the tumour microenvironment.	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumour', 'Disease', (211, 217))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('melatonergic pathways', 'Pathway', (87, 108))	('AhR', 'Gene', '196', (9, 12))	('GBM/GSC', 'Gene', '145258', (119, 126))	('AhR', 'Gene', (9, 12))	('linked', 'Reg', (53, 59))	('intercellular interactions', 'Interaction', (166, 192))	('mitochondria', 'Var', (26, 38))	('changes', 'Reg', (72, 79))	('alterations', 'Reg', (147, 158))	('GBM/GSC', 'Gene', (119, 126))
15519	31244524	As well as CYP1B1 and CYP2C19 impacts on melatonin conversion to NAS, other factors and processes may also modulate the NAS/melatonin ratio.	('melatonin conversion to NAS', 'MPA', (41, 68))	('modulate', 'Reg', (107, 115))	('CYP1B1', 'Var', (11, 17))	('CYP2C19', 'Gene', (22, 29))	('impacts', 'Reg', (30, 37))	('CYP2C19', 'Gene', '1557', (22, 29))	('NAS', 'Chemical', 'MESH:C006389', (120, 123))	('melatonin', 'Chemical', 'MESH:D008550', (41, 50))	('NAS', 'Chemical', 'MESH:C006389', (65, 68))	('melatonin', 'Chemical', 'MESH:D008550', (124, 133))	('NAS/melatonin ratio', 'MPA', (120, 139))
15520	31244524	In pinealocytes, ATP via the P2Y1 receptor potentiates NE-induced NAS, which is also associated with an inhibition of NAS conversion to melatonin.	('N', 'Chemical', 'MESH:D009584', (55, 56))	('inhibition', 'NegReg', (104, 114))	('NAS conversion to melatonin', 'MPA', (118, 145))	('P2Y1 receptor', 'Gene', (29, 42))	('NAS', 'Chemical', 'MESH:C006389', (118, 121))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('melatonin', 'Chemical', 'MESH:D008550', (136, 145))	('P2Y1 receptor', 'Gene', '5028', (29, 42))	('ATP', 'Chemical', 'MESH:D000255', (17, 20))	('potentiates', 'PosReg', (43, 54))	('NE-induced NAS', 'Disease', (55, 69))	('ATP via', 'Var', (17, 24))	('NAS', 'Chemical', 'MESH:C006389', (66, 69))	('N', 'Chemical', 'MESH:D009584', (118, 119))
15527	31244524	There is increasing interest in the roles of mGluRs in GBM/GSC, which may include paracrine and autocrine effects on CYP1B1 and an increased NAS/melatonin ratio, as well as the classical role of glutamate in excitotoxicity-driven 'pathway clearance'.	('CYP1B1', 'Var', (117, 123))	('increased', 'PosReg', (131, 140))	('mGluRs', 'Gene', '2915', (45, 51))	('melatonin', 'Chemical', 'MESH:D008550', (145, 154))	('glutamate', 'Chemical', 'MESH:D018698', (195, 204))	('GBM/GSC', 'Gene', (55, 62))	('GBM/GSC', 'Gene', '145258', (55, 62))	('NAS/melatonin', 'MPA', (141, 154))	('NAS', 'Chemical', 'MESH:C006389', (141, 144))	('mGluRs', 'Gene', (45, 51))
15539	31244524	Such alterations in energy availability are likely to have significant impacts on mitochondria functioning in GBM/GSC, with melatonin's inhibition of glucose uptake via the GLUT1 likely to contribute to the suppression of melatonin synthesis in these cells.	('GLUT1', 'Gene', '6513', (173, 178))	('impacts', 'Reg', (71, 78))	('GBM/GSC', 'Gene', (110, 117))	('GBM/GSC', 'Gene', '145258', (110, 117))	('glucose uptake', 'MPA', (150, 164))	('melatonin', 'Chemical', 'MESH:D008550', (222, 231))	('melatonin synthesis', 'MPA', (222, 241))	('suppression', 'NegReg', (207, 218))	('glucose', 'Chemical', 'MESH:D005947', (150, 157))	('inhibition', 'NegReg', (136, 146))	('alterations', 'Var', (5, 16))	('melatonin', 'Chemical', 'MESH:D008550', (124, 133))	('GLUT1', 'Gene', (173, 178))	('mitochondria functioning', 'MPA', (82, 106))
15541	31244524	As such, alterations in the NAS/melatonin ratio have links to longstanding ideas regarding the nature of the tumour microenvironment and its influence on tumour survival, indicating that GBM/GSC may have a number of means in shaping this tumour microenvironment, including variations in the NAS/melatonin ratio.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('melatonin', 'Chemical', 'MESH:D008550', (32, 41))	('melatonin', 'Chemical', 'MESH:D008550', (295, 304))	('GBM/GSC', 'Gene', '145258', (187, 194))	('alterations', 'Var', (9, 20))	('tumour', 'Disease', (109, 115))	('tumour', 'Disease', (154, 160))	('GBM/GSC', 'Gene', (187, 194))	('NAS', 'Chemical', 'MESH:C006389', (291, 294))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (238, 244))	('variations', 'Var', (273, 283))	('NAS', 'Chemical', 'MESH:C006389', (28, 31))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
15543	31244524	It should be noted that CYP1B1 modulates oestrogen effects, suggesting that some of its effects in hormone-modulated cancers, such as breast cancer, may confound its putative effects via the NAS/melatonin ratio, especially as melatonin has some negative regulatory effects on the oestrogen receptor-alpha.	('oestrogen', 'MPA', (41, 50))	('breast cancer', 'Disease', (134, 147))	('NAS', 'Chemical', 'MESH:C006389', (191, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('modulates', 'Reg', (31, 40))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('melatonin', 'Chemical', 'MESH:D008550', (226, 235))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('melatonin', 'Chemical', 'MESH:D008550', (195, 204))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('CYP1B1', 'Var', (24, 30))	('cancers', 'Disease', (117, 124))
15544	31244524	It is also of note that the conversion of melatonin to NAS by CYP1B1 has been proposed to induce apoptosis in neural cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('neural cancer', 'Disease', (110, 123))	('neural cancer', 'Disease', 'MESH:D009369', (110, 123))	('induce', 'PosReg', (90, 96))	('melatonin', 'Chemical', 'MESH:D008550', (42, 51))	('NAS', 'Chemical', 'MESH:C006389', (55, 58))	('apoptosis', 'CPA', (97, 106))	('CYP1B1', 'Var', (62, 68))
15546	31244524	It should also be noted that CYP1B1, like CYP1A1 and CYP1A2, can be localized to the ERs, as well as mitochondria, as shown in the mouse.	('CYP1A2', 'Gene', '13077', (53, 59))	('CYP1A2', 'Gene', (53, 59))	('mouse', 'Species', '10090', (131, 136))	('CYP1B1', 'Var', (29, 35))
15550	31244524	Alterations in ER functioning are relevant to GSC survival, with stearoyl CoA desaturase (SCD1) being essential for ER homeostasis and GSC survival and proliferation.	('stearoyl CoA desaturase', 'Gene', (65, 88))	('Alterations', 'Var', (0, 11))	('GSC', 'Gene', '145258', (135, 138))	('GSC', 'Gene', '145258', (46, 49))	('stearoyl CoA desaturase', 'Gene', '6319', (65, 88))	('GSC', 'Gene', (46, 49))	('GSC', 'Gene', (135, 138))
15555	31244524	It is also notable that sodium butyrate induces senescence and inhibits GBM invasiveness.	('induces', 'Reg', (40, 47))	('inhibits', 'NegReg', (63, 71))	('senescence', 'MPA', (48, 58))	('sodium butyrate', 'Var', (24, 39))	('GBM invasiveness', 'CPA', (72, 88))	('sodium butyrate', 'Chemical', 'MESH:D020148', (24, 39))
15558	31244524	However, it should be noted that sodium butyrate can also induce an increase in AANAT, N-acetylserotonin O-methyltransferase (HIOMT), and therefore NAS and melatonin synthesis, as shown in intestinal epithelial cells.	('NAS', 'Chemical', 'MESH:C006389', (148, 151))	('N-acetylserotonin', 'MPA', (87, 104))	('sodium butyrate', 'Chemical', 'MESH:D020148', (33, 48))	('HIOMT', 'Gene', '438', (126, 131))	('AANAT', 'Gene', (80, 85))	('increase', 'PosReg', (68, 76))	('AANAT', 'Gene', '15', (80, 85))	('HIOMT', 'Gene', (126, 131))	('N-acetylserotonin', 'Chemical', 'MESH:C006389', (87, 104))	('sodium butyrate', 'Var', (33, 48))	('melatonin', 'Chemical', 'MESH:D008550', (156, 165))
15567	31244524	It is proposed that the normally highly beneficial effects of melatonin in mitochondria are toxic in GBM/GSC and other cancers, with many of the cellular organization and inductions driven by the need to shift melatonin to NAS synthesis, leading to trophic effects of NAS on TrkB, which increases GBM/GSC survival and proliferation.	('NAS', 'Var', (268, 271))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('GBM/GSC', 'Gene', '145258', (101, 108))	('TrkB', 'Gene', '4915', (275, 279))	('GBM/GSC', 'Gene', '145258', (297, 304))	('cancers', 'Disease', (119, 126))	('proliferation', 'CPA', (318, 331))	('GBM/GSC', 'Gene', (101, 108))	('GBM/GSC', 'Gene', (297, 304))	('increases', 'PosReg', (287, 296))	('trophic', 'MPA', (249, 256))	('melatonin', 'Chemical', 'MESH:D008550', (62, 71))	('melatonin', 'Chemical', 'MESH:D008550', (210, 219))	('TrkB', 'Gene', (275, 279))	('NAS', 'Chemical', 'MESH:C006389', (223, 226))	('NAS', 'Chemical', 'MESH:C006389', (268, 271))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
15568	31244524	A core aspect of this framework is the TDO induction of kynurenine and kynurenic acid, which activates the AhR, leading to a dramatic increase in mitochondria CYP1B1, in turn dramatically increasing the NAS/melatonin ratio.	('NAS/melatonin ratio', 'MPA', (203, 222))	('AhR', 'Gene', (107, 110))	('AhR', 'Gene', '196', (107, 110))	('melatonin', 'Chemical', 'MESH:D008550', (207, 216))	('mitochondria CYP1B1', 'MPA', (146, 165))	('TDO', 'Gene', (39, 42))	('kynurenic acid', 'Chemical', 'MESH:D007736', (71, 85))	('TDO', 'Gene', '6999', (39, 42))	('increasing', 'PosReg', (188, 198))	('kynurenine', 'Chemical', 'MESH:D007737', (56, 66))	('NAS', 'Chemical', 'MESH:C006389', (203, 206))	('increase', 'PosReg', (134, 142))	('kynurenic acid', 'Var', (71, 85))	('kynurenine', 'Var', (56, 66))
15570	31130597	The Up-Regulation of Oxidative Stress as a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment Gliomas are malignant brain tumors characterized by rapid spread and growth into neighboring tissues and graded I-IV by the World Health Organization.	('Inhibitors', 'Var', (78, 88))	('malignant brain tumors', 'Disease', (128, 150))	('malignant brain tumors', 'Disease', 'MESH:D001932', (128, 150))	('MAO', 'Gene', '25750', (72, 75))	('brain tumor', 'Phenotype', 'HP:0030692', (138, 149))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('Glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Glioblastoma', 'Disease', (93, 105))	('Gliomas', 'Disease', 'MESH:D005910', (116, 123))	('Gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('brain tumors', 'Phenotype', 'HP:0030692', (138, 150))	('Oxidative', 'MPA', (21, 30))	('Glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('Gliomas', 'Disease', (116, 123))	('MAO', 'Gene', (72, 75))	('Oxidative Stress', 'Phenotype', 'HP:0025464', (21, 37))	('Up-Regulation', 'PosReg', (4, 17))
15574	31130597	Cell cycle analysis, the Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) production were detected, revealing that Cmp3 and Cmp5 induce a G1 or G2/M cell cycle arrest, as well as a MMP depolarization and an overproduction of ROS; moreover, they inhibit the expression level of inducible nitric oxide synthase 2, thus contributing to fatal drug-induced oxidative stress.	('ROS', 'Chemical', 'MESH:D017382', (249, 252))	('nitric oxide synthase 2', 'Gene', (311, 334))	('arrest', 'Disease', 'MESH:D006323', (184, 190))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (173, 190))	('nitric oxide synthase 2', 'Gene', '24599', (311, 334))	('arrest', 'Disease', (184, 190))	('MMP', 'MPA', (205, 208))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('contributing', 'Reg', (341, 353))	('depolarization', 'NegReg', (209, 223))	('Cmp5', 'Var', (148, 152))	('overproduction', 'PosReg', (231, 245))	('expression level', 'MPA', (281, 297))	('oxidative stress', 'Phenotype', 'HP:0025464', (376, 392))	('inhibit', 'NegReg', (269, 276))	('Cmp3', 'Var', (139, 143))	('Reactive Oxygen Species', 'Chemical', 'MESH:D017382', (68, 91))	('ROS', 'Protein', (249, 252))
15576	31130597	This study demonstrated that our novel MAO-B inhibitors increase the oxidative stress level resulting in a cell cycle arrest and markedly reduces glioma cells migration thus reinforcing the hypothesis of a critical role-played by MAO-B in mediating oncogenesis in high-grade gliomas.	('glioma', 'Disease', (275, 281))	('rat', 'Species', '10116', (18, 21))	('increase', 'PosReg', (56, 64))	('reduces', 'NegReg', (138, 145))	('glioma', 'Disease', 'MESH:D005910', (275, 281))	('arrest', 'Disease', (118, 124))	('gliomas', 'Disease', 'MESH:D005910', (275, 282))	('glioma', 'Disease', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('gliomas', 'Phenotype', 'HP:0009733', (275, 282))	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('inhibitors', 'Var', (45, 55))	('oxidative stress level', 'MPA', (69, 91))	('MAO-B', 'Gene', (39, 44))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('rat', 'Species', '10116', (162, 165))	('gliomas', 'Disease', (275, 282))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (107, 124))
15586	31130597	Over the past several decades, MAO-B inhibitors showed to have potential use in the treatment of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease.	('inhibitors', 'Var', (37, 47))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (168, 187))	("Alzheimer's disease", 'Disease', (168, 187))	('MAO-B', 'Gene', (31, 36))	("Parkinson's disease", 'Disease', 'MESH:D010300', (144, 163))	("Parkinson's disease", 'Disease', (144, 163))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (105, 132))	('neurodegenerative disorders', 'Disease', (105, 132))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (105, 132))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (168, 187))
15593	31130597	The aim of this work is to investigate the biological response of rat C6 glioma cell line and CTX TNA2 astrocytes after treatment with these two novel MAO-B inhibitors in terms of cell proliferation, apoptosis occurrence, inflammatory events and cell migration.	('MAO-B', 'Gene', (151, 156))	('CTX', 'Disease', 'MESH:D019294', (94, 97))	('CTX', 'Disease', (94, 97))	('cell proliferation', 'CPA', (180, 198))	('inhibitors', 'Var', (157, 167))	('rat', 'Species', '10116', (192, 195))	('C6 glioma', 'Disease', 'MESH:C567307', (70, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('C6 glioma', 'Disease', (70, 79))	('cell migration', 'CPA', (246, 260))	('rat', 'Species', '10116', (66, 69))	('apoptosis', 'CPA', (200, 209))	('rat', 'Species', '10116', (254, 257))
15597	31130597	In CTX TNA2 astrocytes, Cmp5 at 100 muM evidences cell viability percentages of ~60% and ~50% after 24 h (Figure 2A) and 72 h of treatment (Figure 2B), respectively, whereas Cmp3 at 100 muM does not affect the cell viability after 24 h (Figure 2A) and displays a cell viability percentage of ~60% after 72 h (Figure 2B) of treatment.	('Cmp5', 'Var', (24, 28))	('CTX', 'Disease', (3, 6))	('CTX', 'Disease', 'MESH:D019294', (3, 6))	('cell viability', 'CPA', (50, 64))
15598	31130597	Conversely, TMZ at 500 muM is shown to present cell viability percentages of ~70% and ~60% after 24 h (Figure 2C) and 72 h of treatment (Figure 2D), respectively.	('TMZ', 'Chemical', 'MESH:D000077204', (12, 15))	('TMZ at 500 muM', 'Var', (12, 26))	('cell viability', 'CPA', (47, 61))
15599	31130597	Cmp3 and Cmp5 drastically reduce the viable C6 cells at doses between 50 and 100 muM after 24 h and 72 h of treatment (Figure 3A,B, respectively), while TMZ at 500 muM shows similar C6 cell viability percentages reported for CTX TNA2 at the same time points.	('reduce', 'NegReg', (26, 32))	('C6', 'CellLine', 'CVCL:X905', (182, 184))	('Cmp3', 'Var', (0, 4))	('CTX', 'Disease', 'MESH:D019294', (225, 228))	('TMZ', 'Chemical', 'MESH:D000077204', (153, 156))	('CTX', 'Disease', (225, 228))	('C6', 'CellLine', 'CVCL:X905', (44, 46))	('Cmp5', 'Var', (9, 13))
15607	31130597	A slight, but not significant decrease in the viability of cells exposed to the Cmp5 can be established after 48 h of treatment (90.07%) as well as a rise in the percentage of the PI-stained necrotic population (8.05%) compared to that of DMSO-treated cells (6.47%).	('rise', 'PosReg', (150, 154))	('DMSO', 'Chemical', 'MESH:D004121', (239, 243))	('decrease', 'NegReg', (30, 38))	('necrotic', 'Disease', (191, 199))	('Cmp5', 'Var', (80, 84))	('necrotic', 'Disease', 'MESH:D009336', (191, 199))
15608	31130597	In order to establish whether the two MAO-B inhibitors could induce cell cycle arrest checkpoints and decrease the C6 cells proliferation, the DNA content profiles of cultures exposed to the Cmp3 and Cmp5 after 24 h (Figure 5, upper panel) obtaining percentages of cells found in G1, S and G2 phase (Figure 5, lower panel) were analyzed.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('induce', 'PosReg', (61, 67))	('rat', 'Species', '10116', (131, 134))	('inhibitors', 'Var', (44, 54))	('MAO-B', 'Gene', (38, 43))	('decrease', 'NegReg', (102, 110))	('C6 cells proliferation', 'CPA', (115, 137))	('arrest', 'Disease', (79, 85))	('C6', 'CellLine', 'CVCL:X905', (115, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))
15610	31130597	The Cmp3 causes a delay of the cell cycle in the G1 phase, being the percentage of cells increased in respect to DMSO-exposed cells (58.46%).	('DMSO', 'Chemical', 'MESH:D004121', (113, 117))	('cell cycle in the G1 phase', 'CPA', (31, 57))	('delay', 'NegReg', (18, 23))	('Cmp3', 'Var', (4, 8))	('increased', 'PosReg', (89, 98))
15612	31130597	Oxidative stress, as detected by the oxidation of CM-H2DCF-DA, significantly increases when the C6 cells are exposed to Cmp3 and Cmp5 after 6 h (Figure 6).	('Cmp5', 'Var', (129, 133))	('Cmp3', 'Var', (120, 124))	('C6', 'CellLine', 'CVCL:X905', (96, 98))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('Oxidative stress', 'MPA', (0, 16))	('increases', 'PosReg', (77, 86))	('oxidation', 'MPA', (37, 46))	('CM-H2DCF-DA', 'Chemical', '-', (50, 61))	('CM-H2DCF-DA', 'Gene', (50, 61))
15614	31130597	After a 24 h exposure, the Cmp3 dramatically rises the ROS production, with a 6.2-fold increase in respect to cells exposed to DMSO while the DCF levels related to Cmp5-exposed culture are comparable with the one exposed to DMSO.	('rises', 'PosReg', (45, 50))	('increase', 'PosReg', (87, 95))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('Cmp3', 'Var', (27, 31))	('DCF', 'Chemical', 'MESH:D015649', (142, 145))	('DMSO', 'Chemical', 'MESH:D004121', (127, 131))	('DMSO', 'Chemical', 'MESH:D004121', (224, 228))	('ROS production', 'MPA', (55, 69))
15615	31130597	In more detail, after 6 h treatment Cmp3 halves the MMP as compared to exposure to DMSO control.	('MMP', 'MPA', (52, 55))	('Cmp3', 'Var', (36, 40))	('DMSO', 'Chemical', 'MESH:D004121', (83, 87))	('halves', 'NegReg', (41, 47))
15617	31130597	After longer experimental times (24 h), Cmp3 retains a consistent and significant disturbance of the MMP, in respect to the DMSO sample, being Mean Fluorescence Intensities (MFIs) assessed at 2.23 x 105 (Cmp3) and 3.13 x 105 (DMSO).	('DMSO', 'Chemical', 'MESH:D004121', (226, 230))	('MMP', 'MPA', (101, 104))	('disturbance', 'MPA', (82, 93))	('DMSO', 'Chemical', 'MESH:D004121', (124, 128))	('Cmp3', 'Var', (40, 44))
15618	31130597	To identify the effects of Cmp3 at 100 muM and Cmp5 at 50 muM on the inflammatory event induction, a Western Blot Analysis of neuronal NOS-1 and inducible NOS-2 was performed after 6 and 24 h of treatment.	('NOS-1', 'Gene', (135, 140))	('NOS-1', 'Gene', '24598', (135, 140))	('Cmp5', 'Var', (47, 51))
15619	31130597	After 6 h of treatment, no significant difference in NOS-1 expression level is recorded in samples treated with both Cmp3 and Cmp5 with respect to the DMSO sample.	('NOS-1', 'Gene', '24598', (53, 58))	('NOS-1', 'Gene', (53, 58))	('Cmp5', 'Var', (126, 130))	('DMSO', 'Chemical', 'MESH:D004121', (151, 155))	('Cmp3', 'Var', (117, 121))	('expression level', 'MPA', (59, 75))
15620	31130597	After 24 h of treatment, the NOS-1 expression level is significantly lower in cells treated with Cmp5 in respect to cells treated with Cmp3.	('expression level', 'MPA', (35, 51))	('NOS-1', 'Gene', (29, 34))	('lower', 'NegReg', (69, 74))	('Cmp5', 'Var', (97, 101))	('NOS-1', 'Gene', '24598', (29, 34))
15621	31130597	Moreover, from 6 h to 24 h of treatment, a statistically significant decrease of the NOS-1 expression is detectable for Cmp3 and Cmp5 (Figure 7A,B).	('expression', 'MPA', (91, 101))	('Cmp3', 'Var', (120, 124))	('Cmp5', 'Var', (129, 133))	('NOS-1', 'Gene', '24598', (85, 90))	('NOS-1', 'Gene', (85, 90))	('decrease', 'NegReg', (69, 77))
15622	31130597	After 6 h of treatment a statistically significant increase in the NOS-2 expression level is appreciable in samples treated with both Cmp3 and Cmp5 with respect to DMSO sample.	('increase', 'PosReg', (51, 59))	('NOS-2', 'Gene', (67, 72))	('expression level', 'MPA', (73, 89))	('Cmp5', 'Var', (143, 147))	('Cmp3', 'Var', (134, 138))	('DMSO', 'Chemical', 'MESH:D004121', (164, 168))
15623	31130597	After 24 h of treatment the NOS-2 expression is markedly reduced in cells treated with both Cmp3 and Cmp5 in respect to the DMSO sample.	('Cmp3', 'Var', (92, 96))	('Cmp5 in', 'Var', (101, 108))	('expression', 'MPA', (34, 44))	('NOS-2', 'Gene', (28, 33))	('reduced', 'NegReg', (57, 64))	('DMSO', 'Chemical', 'MESH:D004121', (124, 128))
15625	31130597	After 6 h, the protein is significantly higher in cells treated with Cmp3 in respect to the DMSO sample; conversely, no significant differences are found in C6 cells treated with Cmp5 as compared to DMSO.	('DMSO', 'Chemical', 'MESH:D004121', (92, 96))	('C6', 'CellLine', 'CVCL:X905', (157, 159))	('higher', 'PosReg', (40, 46))	('Cmp5', 'Var', (179, 183))	('DMSO', 'Chemical', 'MESH:D004121', (199, 203))	('protein', 'Protein', (15, 22))
15626	31130597	In addition, a significant reduction of the VEGF expression is evidenced for cells treated with Cmp3 from 6 to 24 h (Figure 7A,D).	('Cmp3', 'Var', (96, 100))	('expression', 'MPA', (49, 59))	('VEGF', 'Gene', (44, 48))	('VEGF', 'Gene', '83785', (44, 48))	('reduction', 'NegReg', (27, 36))
15627	31130597	The ELISA assay for PGE-2 secretion was performed on the C6 cell line treated with Cmp5 and Cmp3 at 50 muM and 100 muM, respectively, for 24 and 72 h (Figure 8).	('Cmp3', 'Var', (92, 96))	('PGE-2', 'Chemical', 'MESH:D015232', (20, 25))	('Cmp5', 'Var', (83, 87))	('C6', 'CellLine', 'CVCL:X905', (57, 59))
15633	31130597	The MMP-2 expression is significantly reduced when cells are treated with Cmp5 with respect to the DMSO sample after both time points.	('Cmp5', 'Var', (74, 78))	('reduced', 'NegReg', (38, 45))	('MMP-2', 'Gene', (4, 9))	('DMSO', 'Chemical', 'MESH:D004121', (99, 103))	('expression', 'MPA', (10, 20))
15634	31130597	After 24 h of treatment, the MMP-2 expression appears significantly increased in cells treated with Cmp3 in respect to DMSO and Cmp5 samples (Figure 10A,B).	('DMSO', 'Chemical', 'MESH:D004121', (119, 123))	('expression', 'MPA', (35, 45))	('Cmp3', 'Var', (100, 104))	('MMP-2', 'Gene', (29, 34))	('increased', 'PosReg', (68, 77))
15635	31130597	In parallel, the MMP-9 protein level is markedly augmented in cells treated for 6 h with Cmp3 compared to Cmp5 and DMSO samples.	('Cmp3', 'Var', (89, 93))	('MMP-9 protein level', 'MPA', (17, 36))	('DMSO', 'Chemical', 'MESH:D004121', (115, 119))	('augmented', 'PosReg', (49, 58))
15637	31130597	In addition, Cmp3 provokes a marked reduction of MMP-9 from 6 to 24 h treatment, whereas Cmp5 downregulates both MMPs (Figure 10A-C).	('downregulates', 'NegReg', (94, 107))	('MMPs', 'Gene', (113, 117))	('MMP-9', 'MPA', (49, 54))	('Cmp3', 'Var', (13, 17))	('reduction', 'NegReg', (36, 45))	('Cmp5', 'Var', (89, 93))	('MMPs', 'Gene', '4313;81686;4318;81687;81707', (113, 117))
15640	31130597	Therefore, we evaluated for the first time the biological effects of two novel MAO-B inhibitors, which were synthesized in our medicinal chemistry laboratory, on the C6 glioma cell line and on CTX TNA2 non-tumoral astrocytes, in terms of cell proliferation, apoptosis occurrence, inflammatory events and cell migration in order to improve the design and the assessment of anti-glioma therapies.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('MAO-B', 'Gene', (79, 84))	('glioma', 'Disease', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (377, 383))	('rat', 'Species', '10116', (250, 253))	('glioma', 'Phenotype', 'HP:0009733', (377, 383))	('inhibitors', 'Var', (85, 95))	('tumor', 'Disease', (206, 211))	('CTX', 'Disease', 'MESH:D019294', (193, 196))	('rat', 'Species', '10116', (312, 315))	('CTX', 'Disease', (193, 196))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('C6 glioma', 'Disease', 'MESH:C567307', (166, 175))	('rat', 'Species', '10116', (151, 154))	('C6 glioma', 'Disease', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('glioma', 'Disease', (377, 383))
15642	31130597	Surprisingly, we also found that Cmp3 and Cmp5 were capable of blocking tumor cell proliferation while sparing normal astrocytes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('blocking', 'NegReg', (63, 71))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Cmp5', 'Var', (42, 46))	('Cmp3', 'Var', (33, 37))	('rat', 'Species', '10116', (90, 93))
15646	31130597	We found that our novel MAO-B inhibitors, especially Cmp5, were responsible for an accumulation of C6 cells in the G1 phase and in parallel to a notable reduction of cells in the S phase.	('Cmp5', 'Var', (53, 57))	('MAO-B', 'Gene', (24, 29))	('reduction', 'NegReg', (153, 162))	('accumulation', 'PosReg', (83, 95))	('cells in the S phase', 'CPA', (166, 186))	('C6 cells', 'CPA', (99, 107))	('C6', 'CellLine', 'CVCL:X905', (99, 101))
15648	31130597	Furthermore, we measured the ROS production leading us to assume that the ROS increase after treatment with both MAO-B inhibitors could be largely responsible for the reduction of the S phase of C6 glioma cells, as already hypothesized.	('C6 glioma', 'Disease', 'MESH:C567307', (195, 204))	('C6 glioma', 'Disease', (195, 204))	('inhibitors', 'Var', (119, 129))	('ROS increase', 'Phenotype', 'HP:0025464', (74, 86))	('reduction', 'NegReg', (167, 176))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('ROS', 'MPA', (29, 32))	('ROS', 'MPA', (74, 77))	('increase', 'PosReg', (78, 86))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('S phase', 'MPA', (184, 191))	('MAO-B', 'Gene', (113, 118))
15649	31130597	It is possible to assume that our data on cell cycle report a clear temporal distinction between the ROS induction by Cmp3 and Cmp5.	('ROS', 'Protein', (101, 104))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('Cmp3', 'Gene', (118, 122))	('Cmp5', 'Var', (127, 131))
15654	31130597	The ability of our tested compounds to increase the base level of oxidative stress is also confirmed by the augmented PGE-2 secretion level measured after 24 h and 72 h of treatment, thus underlining the critical role played by oxidative stress in the mechanism of action of chemotherapeutic agents, as also hypothesized by Sun and colleagues.	('oxidative stress', 'Phenotype', 'HP:0025464', (228, 244))	('compounds', 'Var', (26, 35))	('augmented', 'PosReg', (108, 117))	('increase', 'PosReg', (39, 47))	('oxidative stress', 'Phenotype', 'HP:0025464', (66, 82))	('PGE-2 secretion level', 'MPA', (118, 139))	('PGE-2', 'Chemical', 'MESH:D015232', (118, 123))	('base level of oxidative stress', 'MPA', (52, 82))
15659	31130597	Given that the VEGF expression is Nitric Oxide dependent, we evaluated the protein level, finding as expected, that the signaling pathway triggered by MAO-B inhibitors, involving ROS and NOS-2, is also supported by VEGF recruitment.	('ROS', 'Chemical', 'MESH:D017382', (179, 182))	('MAO-B', 'Gene', (151, 156))	('VEGF', 'Gene', (215, 219))	('VEGF', 'Gene', (15, 19))	('Nitric Oxide', 'Chemical', 'MESH:D009569', (34, 46))	('VEGF', 'Gene', '83785', (215, 219))	('inhibitors', 'Var', (157, 167))	('VEGF', 'Gene', '83785', (15, 19))
15662	31130597	Surprisingly, both novel MAO-B inhibitors markedly reduced glioma cell migration, thus significantly preventing the invasiveness of brain tumors and their ability to infiltrate the neighbouring tissues as already demonstrated for several anti-glioma agents.	('reduced', 'NegReg', (51, 58))	('glioma', 'Disease', (243, 249))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('preventing', 'NegReg', (101, 111))	('invasiveness of brain tumors', 'Disease', (116, 144))	('rat', 'Species', '10116', (172, 175))	('rat', 'Species', '10116', (220, 223))	('inhibitors', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('MAO-B', 'Gene', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('brain tumors', 'Phenotype', 'HP:0030692', (132, 144))	('brain tumor', 'Phenotype', 'HP:0030692', (132, 143))	('rat', 'Species', '10116', (74, 77))	('invasiveness of brain tumors', 'Disease', 'MESH:D001932', (116, 144))
15664	31130597	We evidenced that Cmp5 notably reduces glioma cell migration via the down-regulation of MMP-2 and MMP-9.	('glioma', 'Disease', (39, 45))	('reduces', 'NegReg', (31, 38))	('rat', 'Species', '10116', (54, 57))	('Cmp5', 'Var', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('MMP-9', 'Gene', (98, 103))	('MMP-2', 'Gene', (88, 93))	('down-regulation', 'NegReg', (69, 84))
15667	31130597	In conclusion, this study demonstrates that our novel MAO-B inhibitors are able to contrast glioma proliferation by arresting the cell cycle and drastically increasing oxidative stress conditions, as well as the invasiveness by markedly reducing the migration of malignant cells.	('inhibitors', 'Var', (60, 70))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('contrast', 'PosReg', (83, 91))	('increasing', 'PosReg', (157, 167))	('glioma', 'Disease', (92, 98))	('reducing', 'NegReg', (237, 245))	('rat', 'Species', '10116', (253, 256))	('rat', 'Species', '10116', (33, 36))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('oxidative stress', 'Phenotype', 'HP:0025464', (168, 184))	('MAO-B', 'Gene', (54, 59))	('rat', 'Species', '10116', (106, 109))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('cell cycle', 'CPA', (130, 140))	('oxidative stress conditions', 'MPA', (168, 195))	('invasiveness', 'CPA', (212, 224))	('migration of malignant cells', 'CPA', (250, 278))	('arrest', 'Disease', (116, 122))
15702	31130597	Secretion levels of PGE-2 were analyzed in different wells after treatment with Cmp5 at 50 muM and Cmp3 at 100 muM, normalized for relative optical density (pg/mL/OD) as previously determined by the MTT assay.	('PGE-2', 'Chemical', 'MESH:D015232', (20, 25))	('PGE-2', 'Gene', (20, 25))	('Cmp3', 'Var', (99, 103))	('MTT', 'Chemical', 'MESH:C070243', (199, 202))	('Cmp5', 'Var', (80, 84))
15704	31130597	For this purpose, suspended C6 rat glioma cells were separately treated with 50 microM Cmp5 and 100 microM Cmp3 in serum-free Ham's F12 at cell density of 50,000/150 muL, and then added to the upper chamber of a 8 mum pore size insert.	('C6', 'CellLine', 'CVCL:X905', (28, 30))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('rat', 'Species', '10116', (57, 60))	('Cmp5', 'Var', (87, 91))	('rat', 'Species', '10116', (31, 34))	('glioma', 'Disease', (35, 41))
15750	29883968	Immunohistochemistry for the IDH1 p.R132H mutation and FISH to assess 1p/19q codeletion status were performed as previously described.	('p.R132H', 'Mutation', 'rs121913500', (34, 41))	('IDH1', 'Gene', '3417', (29, 33))	('p.R132H', 'Var', (34, 41))	('IDH1', 'Gene', (29, 33))
15752	29883968	Note that the IDH wild-type status was not confirmed with IDH1 and IDH2 codon sequencing, and hence, the IDH1 R132H immunonegative astrocytomas were included in the astrocytoma, NOS category.	('IDH', 'Gene', '3417', (58, 61))	('R132H', 'Var', (110, 115))	('IDH1', 'Gene', '3417', (105, 109))	('astrocytomas', 'Disease', 'MESH:D001254', (131, 143))	('IDH', 'Gene', '3417', (105, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (131, 142))	('astrocytoma', 'Disease', 'MESH:D001254', (165, 176))	('IDH1', 'Gene', '3417', (58, 62))	('astrocytoma', 'Disease', (165, 176))	('IDH', 'Gene', (14, 17))	('IDH2', 'Gene', (67, 71))	('astrocytoma', 'Disease', 'MESH:D001254', (131, 142))	('IDH', 'Gene', (67, 70))	('IDH2', 'Gene', '3418', (67, 71))	('R132H', 'Mutation', 'rs121913500', (110, 115))	('astrocytoma', 'Disease', (131, 142))	('IDH', 'Gene', (58, 61))	('astrocytomas', 'Disease', (131, 143))	('IDH1', 'Gene', (105, 109))	('IDH', 'Gene', '3417', (14, 17))	('astrocytoma', 'Phenotype', 'HP:0009592', (165, 176))	('IDH', 'Gene', (105, 108))	('IDH', 'Gene', '3417', (67, 70))	('IDH1', 'Gene', (58, 62))
15754	29883968	For anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO grade III, brisk mitotic activity (>/=6 per 10 high-power fields) or conspicuous microvascular proliferation was required.	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (4, 32))	('anaplastic oligodendroglioma', 'Disease', (4, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('1p/19q-codeleted', 'Var', (49, 65))
15760	29883968	All patients with 1p/19q co-deleted oligodendroglioma were classified as being WHO grade II.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('oligodendroglioma', 'Disease', 'MESH:D009837', (36, 53))	('1p/19q co-deleted', 'Var', (18, 35))	('patients', 'Species', '9606', (4, 12))	('oligodendroglioma', 'Disease', (36, 53))
15768	29883968	For the subset of samples from 1p19q co-deleted oligodendroglioma, the median nADC values also increased with tumor score but with lower values (1.45 to 1.98 for tumor scores of 1 to 3).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('1p19q co-deleted', 'Var', (31, 47))	('nADC', 'Chemical', '-', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Disease', (162, 167))	('oligodendroglioma', 'Disease', 'MESH:D009837', (48, 65))	('tumor', 'Disease', (110, 115))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('nADC values', 'MPA', (78, 89))	('increased', 'PosReg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('oligodendroglioma', 'Disease', (48, 65))
15772	29883968	Within samples with 1p19q co-deleted oligodendroglioma, the relationship between tumor score and nCBV did not reach significance.	('1p19q co-deleted', 'Var', (20, 36))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('oligodendroglioma', 'Disease', (37, 54))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('oligodendroglioma', 'Disease', 'MESH:D009837', (37, 54))	('tumor', 'Disease', (81, 86))
15781	29883968	When comparing between WHO 2016 subgroups, there were significant differences in the 10th percentile, median, and 90th percentile nADC and the 10th percentile and median nFA, as well as in the median CNI (see Figure 3C), nCho, CCrI (see Figure 3D), and nLac between the IDH-mutant astrocytomas and the 1p19q co-deleted oligodendroglioma.	('CCrI', 'MPA', (227, 231))	('nADC', 'Chemical', '-', (130, 134))	('1p19q', 'Var', (302, 307))	('IDH', 'Gene', (270, 273))	('CNI', 'Gene', (200, 203))	('nFA', 'Chemical', '-', (170, 173))	('astrocytomas', 'Disease', 'MESH:D001254', (281, 293))	('Lac', 'Chemical', 'MESH:D007785', (254, 257))	('oligodendroglioma', 'Disease', 'MESH:D009837', (319, 336))	('astrocytoma', 'Phenotype', 'HP:0009592', (281, 292))	('glioma', 'Phenotype', 'HP:0009733', (330, 336))	('Cho', 'Chemical', 'MESH:C034482', (222, 225))	('oligodendroglioma', 'Disease', (319, 336))	('IDH', 'Gene', '3417', (270, 273))	('Cr', 'Chemical', 'MESH:D002857', (228, 230))	('CNI', 'Gene', '84618', (200, 203))	('nCho', 'Gene', (221, 225))	('astrocytomas', 'Disease', (281, 293))	('differences', 'Reg', (66, 77))
15808	29883968	Another is that, because the sample sizes for some of the molecular subgroups of LrGG was small, the comparative analysis was restricted to the two most common types (IDH-mutant astrocytomas and 1p19q co-deleted oligodendroglioma).	('astrocytomas', 'Disease', 'MESH:D001254', (178, 190))	('IDH', 'Gene', '3417', (167, 170))	('1p19q co-deleted', 'Var', (195, 211))	('oligodendroglioma', 'Disease', 'MESH:D009837', (212, 229))	('astrocytoma', 'Phenotype', 'HP:0009592', (178, 189))	('astrocytomas', 'Disease', (178, 190))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('oligodendroglioma', 'Disease', (212, 229))	('IDH', 'Gene', (167, 170))
15840	29872625	SP peptide (with a sequence as Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met) one of the NK-1 binding ligands, could be exploited as a targeting ligand on albumin NPs easily via a PEG linker.	('Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met', 'Var', (31, 74))	('Arg', 'Chemical', 'MESH:D001120', (31, 34))	('NK-1', 'Gene', '21333', (87, 91))	('SP peptide', 'Chemical', '-', (0, 10))	('PEG', 'Chemical', '-', (178, 181))	('NK-1', 'Gene', (87, 91))	('albumin', 'Gene', (153, 160))	('albumin', 'Gene', '11657', (153, 160))
15858	29872625	SP-HSA or PEGylated HSA was first treated with 50 mmol/L GSH in deionized water for 4 h at 37  C to cleave the inner intramolecular disulfide bonds to free sulfhydryl groups.	('water', 'Chemical', 'MESH:D014867', (74, 79))	('inner intramolecular disulfide bonds', 'MPA', (111, 147))	('disulfide', 'Chemical', 'MESH:D004220', (132, 141))	('cleave', 'Var', (100, 106))	('PEG', 'Chemical', '-', (10, 13))	('sulfhydryl', 'Chemical', 'MESH:D013438', (156, 166))	('SP-HSA', 'Chemical', '-', (0, 6))	('GSH', 'Chemical', 'MESH:D005978', (57, 60))
15908	29872625	Besides that, owing to the targeted binding of SP peptide to U87 cells, the SP-HSA-PTX NPs (IC50 = 121.1 ng/mL) showed much more toxicity than HSA-PTX NPs (IC50 = 294.8 ng/mL, Supplementary Information Table S2).	('toxicity', 'Disease', (129, 137))	('HSA-PTX', 'Chemical', '-', (143, 150))	('SP peptide', 'Chemical', '-', (47, 57))	('HSA-PTX', 'Chemical', '-', (79, 86))	('PTX NP', 'Chemical', '-', (83, 89))	('PTX NP', 'Chemical', '-', (147, 153))	('binding', 'Interaction', (36, 43))	('SP-HSA-PTX', 'Var', (76, 86))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))	('SP-HSA-PTX', 'Chemical', '-', (76, 86))
15911	29872625	Meanwhile, the level of internalization of SP-HSA-Cou-6 NPs was concentration-dependent.	('SP-HSA', 'Chemical', '-', (43, 49))	('SP-HSA-Cou-6', 'Var', (43, 55))	('Cou-6', 'Chemical', 'MESH:C517282', (50, 55))	('internalization', 'MPA', (24, 39))
15912	29872625	Consistent with the qualitative analysis, quantitative analysis with flow cytometry exhibited the corresponding internalization manner in which the fluorescent intensities of SP-HSA-Cou-6 NPs were higher than HSA-Cou-6 NPs (Fig.	('SP-HSA-Cou-6 NPs', 'Var', (175, 191))	('SP-HSA', 'Chemical', '-', (175, 181))	('higher', 'PosReg', (197, 203))	('Cou-6', 'Chemical', 'MESH:C517282', (213, 218))	('Cou-6', 'Chemical', 'MESH:C517282', (182, 187))	('fluorescent intensities', 'MPA', (148, 171))
15913	29872625	To further investigate the possible internalization mechanism of SP-HSA-Cou-6 NPs, the endocytosis pathways were inhibited by various inhibitors, including free SP peptide, PhAsO, filipin and colchicine.	('Cou-6', 'Chemical', 'MESH:C517282', (72, 77))	('inhibited', 'NegReg', (113, 122))	('SP peptide', 'Chemical', '-', (161, 171))	('PhAsO', 'Chemical', 'MESH:C029341', (173, 178))	('SP-HSA', 'Chemical', '-', (65, 71))	('colchicine', 'Chemical', 'MESH:D003078', (192, 202))	('endocytosis pathways', 'Pathway', (87, 107))	('SP-HSA-Cou-6', 'Var', (65, 77))
15914	29872625	5B shows that the internalization of SP-HSA-Cou-6 NPs was inhibited remarkably both on BCECs and U87 cells after treatment with free SP peptide.	('SP peptide', 'Chemical', '-', (133, 143))	('SP-HSA', 'Chemical', '-', (37, 43))	('internalization', 'MPA', (18, 33))	('SP-HSA-Cou-6', 'Var', (37, 49))	('Cou-6', 'Chemical', 'MESH:C517282', (44, 49))	('inhibited', 'NegReg', (58, 67))
15915	29872625	Among the three endocytic inhibitors, PhAsO exhibited the most significant inhibitory effect, indicating that the main endocytosis pathway of SP-HSA-Cou-6 NPs was clathrin-mediated endocytosis.	('SP-HSA-Cou-6 NPs', 'Var', (142, 158))	('Cou-6', 'Chemical', 'MESH:C517282', (149, 154))	('endocytosis', 'MPA', (119, 130))	('SP-HSA', 'Chemical', '-', (142, 148))	('clathrin-mediated endocytosis', 'MPA', (163, 192))	('PhAsO', 'Chemical', 'MESH:C029341', (38, 43))
15917	29872625	7, SP-HSA-PTX NPs exhibited the highest cell percentage in the G2 phase (49.74%) compared with HSA-PTX NPs (42.12%) and free PTX (39.81%), suggesting the distinct inhibitory effect on cell proliferation.	('PTX', 'Chemical', 'MESH:D017239', (125, 128))	('HSA-PTX', 'Chemical', '-', (6, 13))	('PTX NP', 'Chemical', '-', (99, 105))	('cell percentage in the G2 phase', 'CPA', (40, 71))	('PTX', 'Chemical', 'MESH:D017239', (99, 102))	('PTX NP', 'Chemical', '-', (10, 16))	('SP-HSA-PTX NPs', 'Var', (3, 17))	('PTX', 'Chemical', 'MESH:D017239', (10, 13))	('HSA-PTX', 'Chemical', '-', (95, 102))	('SP-HSA-PTX', 'Chemical', '-', (3, 13))
15919	29872625	8A, mice treated with SP-HSA-BODIPY NPs exhibited a stronger fluorescent signal in the tumor area 24 h after injection compared with the HSA-BODIPY NPs, which was mainly due to the specific binding of SP peptide to the BBB and brain tumors.	('SP-HSA-BODIPY', 'Var', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('fluorescent signal', 'MPA', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mice', 'Species', '10090', (4, 8))	('SP-HSA', 'Chemical', '-', (22, 28))	('tumor', 'Disease', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('brain tumor', 'Phenotype', 'HP:0030692', (227, 238))	('brain tumors', 'Phenotype', 'HP:0030692', (227, 239))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('SP peptide', 'Chemical', '-', (201, 211))	('brain tumors', 'Disease', 'MESH:D001932', (227, 239))	('stronger', 'PosReg', (52, 60))	('binding', 'Interaction', (190, 197))	('brain tumors', 'Disease', (227, 239))
15921	29872625	8C, the SP peptide targeting group exhibited less fluorescent signal in the liver compared with non-targeting group, suggesting lower toxicity to the liver.	('SP peptide', 'Var', (8, 18))	('toxicity', 'Disease', 'MESH:D064420', (134, 142))	('toxicity', 'Disease', (134, 142))	('less', 'NegReg', (45, 49))	('SP peptide', 'Chemical', '-', (8, 18))	('fluorescent signal in the liver', 'MPA', (50, 81))
15926	29872625	From the collected data from four groups, the luminescence intensity in SP-HSA-PTX NP group was weaker than other three groups, exhibiting the most remarkable antitumor efficacy.	('SP-HSA-PTX', 'Var', (72, 82))	('SP-HSA-PTX', 'Chemical', '-', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('weaker', 'NegReg', (96, 102))	('PTX NP', 'Chemical', '-', (79, 85))	('luminescence intensity', 'MPA', (46, 68))
15955	29872625	In addition, the MTT results demonstrated that the SP-HSA-PTX NPs gave rise to the strongest anti-tumor effects resulting from the synergistic role of the enhanced cellular uptake and redox-responsive behavior in cells (Fig.	('cellular uptake', 'CPA', (164, 179))	('SP-HSA-PTX', 'Chemical', '-', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PTX NP', 'Chemical', '-', (58, 64))	('redox-responsive behavior', 'MPA', (184, 209))	('MTT', 'Chemical', 'MESH:C070243', (17, 20))	('enhanced', 'PosReg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('SP-HSA-PTX', 'Var', (51, 61))
15962	29872625	Based on the enhanced permeability and retention (EPR) effect, the GP60, SPARC and NK-1 receptor-mediated targeted pathway, the BODIPY signal of mice treated with SP-HSA-BODIPY NPs was sustained until 24 h and was stronger than the non-targeted group (Fig.	('stronger', 'PosReg', (214, 222))	('enhanced', 'PosReg', (13, 21))	('NK-1 receptor', 'Gene', '21336', (83, 96))	('permeability', 'MPA', (22, 34))	('SP-HSA', 'Chemical', '-', (163, 169))	('mice', 'Species', '10090', (145, 149))	('BODIPY signal', 'MPA', (128, 141))	('SP-HSA-BODIPY', 'Var', (163, 176))	('SPARC', 'Gene', (73, 78))	('NK-1 receptor', 'Gene', (83, 96))	('SPARC', 'Gene', '20692', (73, 78))
15963	29872625	The ex vivo images also confirmed the brain-tumor-targeting ability of SP-HSA-BODIPY NPs (Fig.	('brain-tumor', 'Disease', (38, 49))	('SP-HSA', 'Chemical', '-', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('SP-HSA-BODIPY', 'Var', (71, 84))	('brain-tumor', 'Disease', 'MESH:D001932', (38, 49))
15964	29872625	It should be noted that the fluorescence signal obtained from SP-HSA-BODIPY NPs in liver, one of the vital organs of metabolism, was lower than HSA-BODIPY NP group, which showed that the fabricated nanoparticle could decrease elimination and alleviate the burden of liver.	('burden of liver', 'MPA', (256, 271))	('alleviate', 'NegReg', (242, 251))	('elimination', 'MPA', (226, 237))	('SP-HSA-BODIPY NPs', 'Var', (62, 79))	('SP-HSA', 'Chemical', '-', (62, 68))	('decrease', 'NegReg', (217, 225))	('fluorescence signal', 'MPA', (28, 47))	('lower', 'NegReg', (133, 138))
15969	29872625	In summary, taken together the results of the lowest luminescence intensity in tumor foci, the strongest apoptotic signal, the longest survival time and the slowest body weight loss (Figure 9, Figure 10, Figure 11), indicated that SP-HSA-PTX NPs exhibited the best therapeutic efficacy compared with HSA-PTX NPs and Taxol, which may be attributed to the sufficient PTX accumulation at tumor site and reduced systemic adverse effects.	('HSA-PTX', 'Chemical', '-', (234, 241))	('PTX', 'Chemical', 'MESH:D017239', (304, 307))	('weight loss', 'Disease', 'MESH:D015431', (170, 181))	('tumor foci', 'Disease', 'MESH:C565785', (79, 89))	('weight loss', 'Phenotype', 'HP:0001824', (170, 181))	('PTX', 'Chemical', 'MESH:D017239', (238, 241))	('lowest', 'NegReg', (46, 52))	('tumor', 'Disease', (385, 390))	('SP-HSA-PTX', 'Var', (231, 241))	('therapeutic efficacy', 'CPA', (265, 285))	('weight loss', 'Disease', (170, 181))	('tumor', 'Disease', 'MESH:D009369', (385, 390))	('PTX', 'Chemical', 'MESH:D017239', (365, 368))	('tumor foci', 'Disease', (79, 89))	('tumor', 'Disease', (79, 84))	('HSA-PTX', 'Chemical', '-', (300, 307))	('SP-HSA-PTX', 'Chemical', '-', (231, 241))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (385, 390))	('PTX NP', 'Chemical', '-', (304, 310))	('Taxol', 'Chemical', 'MESH:D017239', (316, 321))	('PTX NP', 'Chemical', '-', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
16010	28694032	Recent genetic association studies have unraveled linkages between specific genetic mutations and glioma sub-phenotypes, leading to the identification of common molecular pathways that are critical for the maintenance, progression and/or recurrence of brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (252, 264))	('brain tumors', 'Phenotype', 'HP:0030692', (252, 264))	('brain tumor', 'Phenotype', 'HP:0030692', (252, 263))	('brain tumors', 'Disease', (252, 264))	('mutations', 'Var', (84, 93))	('glioma', 'Disease', (98, 104))
16041	28694032	F98 GBM forms highly aggressive tumors that mimic many of the hallmarks of human GBM, including a highly invasive pattern of growth, overexpression of protein-based tumor markers and resistance to many chemotherapeutics and irradiation.	('aggressive tumors', 'Disease', (21, 38))	('GBM', 'Phenotype', 'HP:0012174', (81, 84))	('human', 'Species', '9606', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('GBM', 'Phenotype', 'HP:0012174', (4, 7))	('F98', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('overexpression', 'PosReg', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('aggressive tumors', 'Disease', 'MESH:D001523', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (165, 170))
16044	28694032	We discovered that the in vitro transfection efficiencies of PBAE-BPN in F98 GBM and 9L GS cells, as well as differentiated mouse hippocampal neuronal cells (HT22), were significantly lower than those achieved using PBAE-CN (p < 0.05; Fig.	('PBAE-BPN', 'Var', (61, 69))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('mouse', 'Species', '10090', (124, 129))	('PBAE-CN', 'Chemical', '-', (216, 223))	('GS', 'Disease', 'MESH:D011125', (88, 90))	('lower', 'NegReg', (184, 189))	('HT22', 'CellLine', 'CVCL:0321', (158, 162))	('PBAE-BPN', 'Chemical', '-', (61, 69))
16045	28694032	This result is in agreement with previous findings that PEGylation reduces in vitro transfection efficiency of non-viral gene delivery systems by reducing cellular uptake and/or intracellular processing.	('PEG', 'Chemical', 'MESH:D011092', (56, 59))	('cellular uptake', 'CPA', (155, 170))	('reduces', 'NegReg', (67, 74))	('reducing', 'NegReg', (146, 154))	('PEGylation', 'Var', (56, 66))
16046	28694032	However, despite the dense PEGylation, PBAE-BPN exhibited a similar or significantly higher in vitro transfection efficiency compared to non-PEGylated PEI-CN and conventionally PEGylated PLL-CN in rat brain tumors cells (Figs.	('CN', 'Chemical', '-', (191, 193))	('PEG', 'Chemical', 'MESH:D011092', (141, 144))	('vitro transfection', 'CPA', (95, 113))	('PLL', 'Chemical', '-', (187, 190))	('brain tumors', 'Phenotype', 'HP:0030692', (201, 213))	('higher', 'PosReg', (85, 91))	('brain tumors', 'Disease', (201, 213))	('rat', 'Species', '10116', (197, 200))	('PEG', 'Chemical', 'MESH:D011092', (177, 180))	('brain tumor', 'Phenotype', 'HP:0030692', (201, 212))	('PEI', 'Chemical', 'MESH:D011094', (151, 154))	('PEG', 'Chemical', 'MESH:D011092', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('PBAE-BPN', 'Chemical', '-', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('PBAE-BPN', 'Var', (39, 47))	('CN', 'Chemical', '-', (155, 157))	('brain tumors', 'Disease', 'MESH:D001932', (201, 213))
16058	28694032	Overall, the median mean squared displacements (MSD; a measure of particle diffusion rate) of PBAE-BPN at the timescale of 1 s were 33-fold, 10-fold, and 38-fold greater than those of PBAE-CN in healthy, F98 GBM, and 9L GS tissues, respectively (p < 0.05) (Fig.	('GS', 'Disease', 'MESH:D011125', (220, 222))	('PBAE-CN', 'Chemical', '-', (184, 191))	('PBAE-BPN', 'Chemical', '-', (94, 102))	('MSD', 'Disease', (48, 51))	('MSD', 'Disease', 'MESH:D052517', (48, 51))	('rat', 'Species', '10116', (85, 88))	('displacements', 'MPA', (33, 46))	('greater', 'PosReg', (162, 169))	('PBAE-BPN', 'Var', (94, 102))	('GBM', 'Phenotype', 'HP:0012174', (208, 211))
16065	28694032	In support of this hypothesis, smaller differences in diffusion rates in healthy brain versus 9L GS tissues were observed with 70 nm PEGylated PS compared to their 100 nm particle counterparts, implying that the difference may be even smaller for smaller (< 70 nm) PEGylated PS.	('PEG', 'Chemical', 'MESH:D011092', (265, 268))	('GS', 'Disease', 'MESH:D011125', (97, 99))	('PEG', 'Chemical', 'MESH:D011092', (133, 136))	('PEGylated PS', 'Var', (133, 145))	('rat', 'Species', '10116', (64, 67))	('PS', 'Chemical', 'MESH:D011137', (143, 145))	('PS', 'Chemical', 'MESH:D011137', (275, 277))	('diffusion', 'MPA', (54, 63))
16069	28694032	We first confirmed our previous finding that PBAE-BPN achieves greater distribution and volume of transgene expression in healthy rat brain compared to PBAE-CN (Figs.	('PBAE-BPN', 'Chemical', '-', (45, 53))	('volume', 'MPA', (88, 94))	('PBAE-BPN', 'Var', (45, 53))	('greater', 'PosReg', (63, 70))	('rat', 'Species', '10116', (130, 133))	('distribution', 'MPA', (71, 83))	('PBAE-CN', 'Chemical', '-', (152, 159))
16072	28694032	Similar to the observations with healthy rat brain tissues, PBAE-BPN exhibited greater distribution and volume of transgene expression in the tumor tissues compared to PBAE-CN (Figs.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('distribution', 'MPA', (87, 99))	('tumor', 'Disease', (142, 147))	('greater', 'PosReg', (79, 86))	('PBAE-CN', 'Chemical', '-', (168, 175))	('PBAE-BPN', 'Chemical', '-', (60, 68))	('rat', 'Species', '10116', (41, 44))	('PBAE-BPN', 'Var', (60, 68))	('volume', 'MPA', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
16073	28694032	Quantitatively, the volume of transgene expression achieved by PBAE-BPN was 6- and 5-fold greater compared to PBAE-CN in healthy tissues and tumor rat brain tissues following CED, respectively (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PBAE-BPN', 'Chemical', '-', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('greater', 'PosReg', (90, 97))	('PBAE-BPN', 'Var', (63, 71))	('volume', 'MPA', (20, 26))	('tumor', 'Disease', (141, 146))	('rat', 'Species', '10116', (147, 150))	('PBAE-CN', 'Chemical', '-', (110, 117))
16075	28694032	3E), the transgene expression appeared to span a greater inclusive area in tumors than in healthy brain tissue (Figs.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('transgene', 'Var', (9, 18))
16093	28694032	3, 4), we sought to investigate whether CED of PBAE-BPN may provide enhanced therapeutic efficacy in highly aggressive orthotopic models of rat brain tumors based on F98 GBM or 9L GS.	('GBM', 'Phenotype', 'HP:0012174', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('F98', 'Var', (166, 169))	('enhanced', 'PosReg', (68, 76))	('GS', 'Disease', 'MESH:D011125', (180, 182))	('rat', 'Species', '10116', (140, 143))	('therapeutic efficacy', 'CPA', (77, 97))	('ether', 'Chemical', 'MESH:D004986', (34, 39))	('brain tumors', 'Disease', 'MESH:D001932', (144, 156))	('brain tumors', 'Phenotype', 'HP:0030692', (144, 156))	('brain tumor', 'Phenotype', 'HP:0030692', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('brain tumors', 'Disease', (144, 156))	('PBAE-BPN', 'Chemical', '-', (47, 55))
16096	28694032	The cancer cells expressing HSV-tk are capable of inducing the death of neighboring untransfected cancer cells via a bystander effect; the mechanism involves transfer of toxic metabolites of GCV through intercellular gap junctions.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('death of neighboring untransfected cancer', 'Disease', (63, 104))	('GCV', 'Chemical', 'MESH:D015774', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('death of neighboring untransfected cancer', 'Disease', 'MESH:D003643', (63, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('transfer', 'MPA', (158, 166))	('inducing', 'Reg', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('HSV-tk', 'Var', (28, 34))
16098	28694032	In contrast, p53 gene therapy effectively reduced the viability of 9L GS cells, but not F98 GBM cells (Figs.	('GS', 'Disease', 'MESH:D011125', (70, 72))	('gene therapy', 'Var', (17, 29))	('reduced', 'NegReg', (42, 49))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('viability', 'CPA', (54, 63))	('p53', 'Gene', (13, 16))
16108	28694032	Again, PBAE-BPN provided improved anti-cancer efficacy, in terms of survival, as compared to PBAE-CN (p < 0.01), suggesting that the superior distribution pattern and/or overall level of transgene expression plays a significant role in therapeutic outcomes.	('improved', 'PosReg', (25, 33))	('PBAE-BPN', 'Chemical', '-', (7, 15))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('PBAE-BPN', 'Var', (7, 15))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('PBAE-CN', 'Chemical', '-', (93, 100))
16109	28694032	In a recent next generation sequencing study exploring genetic variations in gliomas from 121 different patients, p53 mutation was found in approximately 40% and 80% of the entire and recurrent GBM cases, respectively.	('found', 'Reg', (131, 136))	('GBM', 'Phenotype', 'HP:0012174', (194, 197))	('p53', 'Gene', (114, 117))	('gliomas', 'Disease', (77, 84))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('GBM', 'Disease', (194, 197))	('rat', 'Species', '10116', (21, 24))	('mutation', 'Var', (118, 126))	('patients', 'Species', '9606', (104, 112))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
16110	28694032	Importantly, human high-grade gliomas with p53 mutation were found less responsive to 28 different chemotherapeutics, including carmustine:the active pharmaceutical ingredient in Gliadel :than gliomas with wild-type p53.	('human', 'Species', '9606', (13, 18))	('gliomas', 'Disease', (193, 200))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('mutation', 'Var', (47, 55))	('less', 'NegReg', (67, 71))	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('gliomas', 'Disease', (30, 37))	('carmustine', 'Chemical', 'MESH:D002330', (128, 138))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('p53', 'Gene', (43, 46))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
16111	28694032	Likewise, p53 mutation has been found to be associated with resistance to temozolomide, the standard of care chemotherapeutic agent used in glioma patients.	('associated', 'Reg', (44, 54))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('resistance to temozolomide', 'MPA', (60, 86))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('mutation', 'Var', (14, 22))	('patients', 'Species', '9606', (147, 155))	('glioma', 'Disease', (140, 146))	('temozolomide', 'Chemical', 'MESH:D000077204', (74, 86))	('p53', 'Gene', (10, 13))
16112	28694032	Thus, widespread transgene expression of wild-type p53 throughout the tumor tissue, achieved by CED of PBAE-BPN, may enhance the therapeutic efficacy of current chemotherapies or increase the repertoire of effective chemotherapeutics previously dropped due to the generation of drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('rat', 'Species', '10116', (268, 271))	('PBAE-BPN', 'Chemical', '-', (103, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (278, 293))	('tumor', 'Disease', (70, 75))	('therapeutic efficacy', 'CPA', (129, 149))	('enhance', 'PosReg', (117, 124))	('increase', 'PosReg', (179, 187))	('transgene expression', 'Var', (17, 37))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
16115	28694032	Specifically, we show that anti-cancer genes delivered via PBAE-BPN offer significantly improved survival of brain tumor-bearing rats compared to rats treated with conventional DNA-loaded nanocomplexes that are unable to efficiently penetrate brain tumor tissues.	('brain tumor', 'Disease', (243, 254))	('brain tumor', 'Disease', 'MESH:D001932', (243, 254))	('rats', 'Species', '10116', (146, 150))	('improved', 'PosReg', (88, 96))	('rats', 'Species', '10116', (129, 133))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('brain tumor', 'Phenotype', 'HP:0030692', (109, 120))	('PBAE-BPN', 'Chemical', '-', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('brain tumor', 'Disease', 'MESH:D001932', (109, 120))	('brain tumor', 'Disease', (109, 120))	('rat', 'Species', '10116', (146, 149))	('PBAE-BPN', 'Var', (59, 67))	('rat', 'Species', '10116', (129, 132))	('brain tumor', 'Phenotype', 'HP:0030692', (243, 254))	('survival', 'CPA', (97, 105))	('rat', 'Species', '10116', (238, 241))
16154	28694032	Likewise, to assess the tumor suppressive effect of p53, we treated the tumor cells with PBAE-CN carrying pC53-SN3 at 0.2 mug plasmid DNA/well.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PBAE-CN', 'Chemical', '-', (89, 96))	('tumor', 'Disease', (24, 29))	('pC53-SN3', 'Var', (106, 114))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
16198	28694032	At 5 and 10 days after the tumor inoculation, rats were treated with PBAE-BPN or PBAE-CN carrying pC53-SN3 at 1 mg/ml plasmid DNA concentration or normal saline (days 5 and 10 in Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('pC53-SN3', 'Var', (98, 106))	('PBAE-BPN', 'Chemical', '-', (69, 77))	('rat', 'Species', '10116', (46, 49))	('tumor inoculation', 'Disease', 'MESH:D002372', (27, 44))	('PBAE-CN', 'Chemical', '-', (81, 88))	('rat', 'Species', '10116', (137, 140))	('tumor inoculation', 'Disease', (27, 44))	('rats', 'Species', '10116', (46, 50))
16206	29435134	Therefore, in our study we decided to assess the ability of AgNPs to kill pancreatic cancer cells, and then to identify the molecular mechanism underlying this effect.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('AgNPs', 'Var', (60, 65))	('kill', 'CPA', (69, 73))	('pancreatic cancer', 'Disease', (74, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
16210	29435134	Moreover, AgNPs significantly elevated the level of tumor suppressor p53 protein as well as necroptosis- and autophagy-related proteins: RIP-1, RIP-3, MLKL and LC3-II, respectively.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('level', 'MPA', (43, 48))	('MLKL', 'Gene', (151, 155))	('MLKL', 'Gene', '197259', (151, 155))	('autophagy-related', 'CPA', (109, 126))	('RIP-1', 'Gene', (137, 142))	('RIP-1', 'Gene', '8737', (137, 142))	('tumor', 'Disease', (52, 57))	('RIP-3', 'Gene', (144, 149))	('LC3', 'Gene', '84557', (160, 163))	('AgNPs', 'Var', (10, 15))	('elevated', 'PosReg', (30, 38))	('necroptosis-', 'CPA', (92, 104))	('LC3', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RIP-3', 'Gene', '11035', (144, 149))
16248	29435134	2.6 nm AgNPs exerted about 16-fold higher cytotoxicity than 18 nm AgNPs.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('AgNPs', 'Var', (7, 12))	('cytotoxicity', 'Disease', (42, 54))	('higher', 'PosReg', (35, 41))
16270	29435134	Moreover, we found PANC-1 cells increase in size with multiple nuclei (multinucleation) after exposure to 2.6 nm AgNPs at concentration of 0.5 mug/mL (Figure 6D).	('AgNPs', 'Var', (113, 118))	('PANC-1', 'CellLine', 'CVCL:0480', (19, 25))	('rat', 'Species', '10116', (129, 132))	('increase', 'PosReg', (32, 40))
16286	29435134	Statistically significant increase of RIP3 and MLKL protein level was found after treatment with 2.5 mug/mL 2.6 nm AgNPs and after exposure to 25 mug/mL and 50 mug/mL 18 nm AgNPs.	('MLKL', 'Gene', (47, 51))	('RIP3', 'Gene', '11035', (38, 42))	('2.6 nm AgNPs', 'Var', (108, 120))	('MLKL', 'Gene', '197259', (47, 51))	('AgNPs', 'Var', (115, 120))	('RIP3', 'Gene', (38, 42))	('increase', 'PosReg', (26, 34))
16301	29435134	In our previous study, we demonstrated that AgNO3 exerted more cytotoxic effect against human gingival fibroblast cells in comparison to 10 nm AgNPs.	('AgNO3', 'Chemical', 'MESH:D012835', (44, 49))	('cytotoxic effect', 'CPA', (63, 79))	('rat', 'Species', '10116', (33, 36))	('AgNO3', 'Var', (44, 49))	('human', 'Species', '9606', (88, 93))
16313	29435134	found that AgNPs may be approximately 2-fold more cytotoxic to acute myeloid leukemia compared to healthy human bone marrow cells.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (63, 85))	('human', 'Species', '9606', (106, 111))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (63, 85))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (69, 85))	('AgNPs', 'Var', (11, 16))	('acute myeloid leukemia', 'Disease', (63, 85))
16323	29435134	What is more, AgNPs showed more than a hundred thousand-fold higher efficiency compared with gemcitabine to decrease pancreatic cancer cell viability and induced pancreatic cancer cells death.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('higher', 'PosReg', (61, 67))	('induced', 'Reg', (154, 161))	('pancreatic cancer', 'Disease', (162, 179))	('pancreatic cancer', 'Disease', (117, 134))	('AgNPs', 'Var', (14, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (162, 179))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('decrease', 'NegReg', (108, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (162, 179))
16345	29435134	found that human squamous carcinoma cells exposed to 10 nm AgNPs resulted in an increase of pro-apoptotic proteins (Bax).	('Bax', 'Gene', '581', (116, 119))	('human', 'Species', '9606', (11, 16))	('squamous carcinoma', 'Disease', 'MESH:D002294', (17, 35))	('increase', 'PosReg', (80, 88))	('squamous carcinoma', 'Disease', (17, 35))	('AgNPs', 'Var', (59, 64))	('Bax', 'Gene', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (17, 35))
16349	29435134	We noticed that both 2.6 and 18 nm AgNPs caused an elevation of p53 protein level in PANC-1 cells.	('AgNPs', 'Var', (35, 40))	('elevation', 'PosReg', (51, 60))	('p53 protein level', 'MPA', (64, 81))	('PANC-1', 'CellLine', 'CVCL:0480', (85, 91))
16352	29435134	Also, AgNPs are known to induce p53-mediated apoptosis in human breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('human', 'Species', '9606', (58, 63))	('AgNPs', 'Var', (6, 11))	('induce', 'PosReg', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('p53-mediated apoptosis', 'CPA', (32, 54))	('breast cancer', 'Disease', (64, 77))
16356	29435134	indicated that activation of p53 enhanced autophagy levels in cells, which might contribute to the tumor suppressor functions of p53.	('tumor', 'Disease', (99, 104))	('autophagy levels in cells', 'CPA', (42, 67))	('p53', 'Gene', (29, 32))	('activation', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('enhanced', 'PosReg', (33, 41))
16362	29435134	It has been found that inhibition of autophagy may be a new therapeutic approach in the treatment of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (101, 118))	('inhibition', 'Var', (23, 33))	('pancreatic cancer', 'Disease', (101, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (101, 118))	('autophagy', 'CPA', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
16368	29435134	Indeed, in our study we have observed that 2.6 and 18 nm AgNPs-induced apoptotic as well necroptotic PANC-1 cell death was associated with increased level of autophagy markers (LC-3) and formation of autophagosomes.	('formation of autophagosomes', 'CPA', (187, 214))	('LC-3', 'Gene', '84557', (177, 181))	('increased', 'PosReg', (139, 148))	('PANC-1', 'CellLine', 'CVCL:0480', (101, 107))	('AgNPs-induced', 'Gene', (57, 70))	('2.6', 'Var', (43, 46))	('level', 'MPA', (149, 154))	('LC-3', 'Gene', (177, 181))	('apoptotic', 'CPA', (71, 80))
16413	29435134	M300F- 500) (3:1 ratio) with 2 mM L-glutamine adjusted to 1.5 g/L sodium bicarbonate and supplemented with 5% FBS, 10 ng/ml human recombinant EGF, 5.5 mM D-glucose (1g/L) and 750 ng/mL puromycin, at 37 C in a humidified atmosphere of 5% CO2.	('sodium bicarbonate', 'Chemical', 'MESH:D017693', (66, 84))	('M300F- 500', 'Var', (0, 10))	('FBS', 'Disease', (110, 113))	('FBS', 'Disease', 'MESH:D005198', (110, 113))	('glutamine', 'Chemical', 'MESH:D005973', (36, 45))	('human', 'Species', '9606', (124, 129))	('CO2', 'Chemical', '-', (237, 240))	('D-glucose', 'Chemical', 'MESH:D005947', (154, 163))	('rat', 'Species', '10116', (17, 20))	('puromycin', 'Chemical', 'MESH:D011691', (185, 194))	('M300F', 'Mutation', 'p.M300F', (0, 5))
16453	29435134	The samples (40 mug protein per lane) were boiled for 5 minutes and separated by SDS-PAGE on polyacrylamide gel and transferred onto nitrocellulose membrane, which was blocked with 5% non-fat dry milk-PBST buffer (phosphate-buffered saline (PBS) containing 0.1% Tween-20) for 1 hour at room temperature and incubated at 4 C overnight with rabbit polyclonal antibody: anti-Bax, anti-Bcl-2, anti-RIP-1, anti-RIP-3, anti-LC3, anti-p53, and goat polyclonal anti-MLKL (diluted 1:500).	('RIP-3', 'Gene', '11035', (406, 411))	('goat', 'Species', '9925', (437, 441))	('rat', 'Species', '10116', (72, 75))	('LC3', 'Gene', (418, 421))	('SDS', 'Chemical', 'MESH:D012967', (81, 84))	('PBS', 'Chemical', '-', (241, 244))	('MLKL', 'Gene', (458, 462))	('PBS', 'Chemical', '-', (201, 204))	('RIP-1', 'Gene', '8737', (394, 399))	('Bax', 'Gene', (372, 375))	('Bcl-2', 'Gene', (382, 387))	('Bax', 'Gene', '581', (372, 375))	('RIP-3', 'Gene', (406, 411))	('MLKL', 'Gene', '197259', (458, 462))	('rat', 'Species', '10116', (296, 299))	('LC3', 'Gene', '84557', (418, 421))	('RIP-1', 'Gene', (394, 399))	('boiled', 'Phenotype', 'HP:0020083', (43, 49))	('Bcl-2', 'Gene', '596', (382, 387))	('Tween', 'Chemical', 'MESH:D011136', (262, 267))	('rabbit', 'Species', '9986', (339, 345))	('anti-p53', 'Var', (423, 431))
16467	29435134	Our results lead us to assume that AgNPs could bypass drug resistance by inducing mixed type of cell death in pancreatic ductal adenocarcinoma cells.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (110, 142))	('inducing', 'Reg', (73, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('AgNPs', 'Var', (35, 40))	('mixed type of cell death', 'CPA', (82, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))	('pancreatic ductal adenocarcinoma', 'Disease', (110, 142))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (110, 142))
16468	28412740	Combination epidermal growth factor receptor variant III peptide-pulsed dendritic cell vaccine with miR-326 results in enhanced killing on EGFRvIII-positive cells The mutant Type III variant of epidermal growth factor receptor (EGFRvIII) is present in approximately one-third of glioblastoma (GBM) patients.	('epidermal growth factor receptor', 'Gene', '1956', (12, 44))	('miR-326', 'Gene', (100, 107))	('epidermal growth factor receptor', 'Gene', '1956', (194, 226))	('miR-326', 'Gene', '442900', (100, 107))	('patients', 'Species', '9606', (298, 306))	('glioblastoma', 'Disease', (279, 291))	('glioblastoma', 'Disease', 'MESH:D005909', (279, 291))	('epidermal growth factor receptor', 'Gene', (12, 44))	('variant', 'Var', (45, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('GBM', 'Phenotype', 'HP:0012174', (293, 296))	('epidermal growth factor receptor', 'Gene', (194, 226))	('enhanced', 'PosReg', (119, 127))
16479	28412740	The type III EGF receptor deletion-mutant (EGFRvIII) is one of the most common mutations in glioblastoma.	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('common', 'Reg', (72, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('deletion-mutant', 'Var', (26, 41))
16480	28412740	In the mutant allele, the EGFRvIII gene has an in-frame deletion of 801 base pairs, corresponding to exons 2-7 of mRNA, resulting in the deletion of amino acids 6-273 in the extracellular domain and the generation of a glycine at the fusion point.	('glycine', 'Chemical', 'MESH:D005998', (219, 226))	('mutant', 'Var', (7, 13))	('deletion', 'Var', (137, 145))	('EGFRvIII', 'Gene', (26, 34))	('glycine at the', 'MPA', (219, 233))
16506	28412740	As shown in Figure 2B, the cytotoxicity of U87-MG was 3.84% when the E/T ratio was 2:1 and 0.12% at 1:1.	('U87-MG', 'Var', (43, 49))	('cytotoxicity', 'Disease', (27, 39))	('cytotoxicity', 'Disease', 'MESH:D064420', (27, 39))	('U87-MG', 'CellLine', 'CVCL:0022', (43, 49))
16554	28412740	Taken together, this finding indicates that miR-326 transfection potentiates the EGFRvIII-DC-CTL-induced killing effect in glioma cells by down-regulating TGF-beta1.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('DC', 'Gene', '20299', (90, 92))	('potentiates', 'PosReg', (65, 76))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('TGF-beta1', 'Gene', '7040', (155, 164))	('TGF-beta1', 'Gene', (155, 164))	('miR-326', 'Gene', (44, 51))	('down-regulating', 'NegReg', (139, 154))	('transfection', 'Var', (52, 64))	('glioma', 'Disease', (123, 129))	('miR-326', 'Gene', '442900', (44, 51))
16563	28412740	In addition, EGFRvIII and the IDH1 mutant (R132H) represent truly tumour-specific targets that occur within a subset of tumours.	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Disease', (120, 126))	('IDH1', 'Gene', (30, 34))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumours', 'Disease', (120, 127))	('R132H', 'Var', (43, 48))	('R132H', 'Mutation', 'rs121913500', (43, 48))	('IDH1', 'Gene', '3417', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
16570	28412740	Once GBM recurs, most patients lost EGFRvIII expression as a result of the elimination of a specific population of tumour cells that express EGFRvIII or downregulation the expression of a mutated tyrosine kinase.	('EGFRvIII', 'Gene', (141, 149))	('EGFRvIII', 'Gene', (36, 44))	('GBM', 'Phenotype', 'HP:0012174', (5, 8))	('patients', 'Species', '9606', (22, 30))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('lost', 'NegReg', (31, 35))	('expression', 'MPA', (172, 182))	('expression', 'MPA', (45, 55))	('elimination', 'NegReg', (75, 86))	('tyrosine kinase', 'Enzyme', (196, 211))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('mutated', 'Var', (188, 195))	('tumour', 'Disease', (115, 121))	('downregulation', 'NegReg', (153, 167))
16574	28412740	To some extent, inhibition of TGF-beta1 may also induce autoimmunity because TGF-beta1 plays a key role in regulating the homeostasis of the immune system.	('autoimmunity', 'Disease', (56, 68))	('autoimmunity', 'Disease', 'MESH:D001327', (56, 68))	('induce', 'Reg', (49, 55))	('autoimmunity', 'Phenotype', 'HP:0002960', (56, 68))	('TGF-beta1', 'Gene', '7040', (77, 86))	('TGF-beta1', 'Gene', (77, 86))	('TGF-beta1', 'Gene', '7040', (30, 39))	('homeostasis of the immune system', 'MPA', (122, 154))	('TGF-beta1', 'Gene', (30, 39))	('inhibition', 'Var', (16, 26))
16593	28412740	It was dissolved as recommended in ultrapure water to yield a stock solution (1000 mug/ml) and further dissolved in RPMI-1640 with 10% FBS to generate a working solution at a concentration of 40 mug/ml.	('1000', 'Var', (78, 82))	('RPMI-1640', 'Chemical', '-', (116, 125))	('FBS', 'Disease', (135, 138))	('water', 'Chemical', 'MESH:D014867', (45, 50))	('FBS', 'Disease', 'MESH:D005198', (135, 138))
16635	28412740	EGFRvIII type III variant of epidermal growth factor receptor PEPvIII EGFRvIII peptide sequence DCs Dendritic cells GBM Glioblastoma Shh sonic hedgehog GLI Glioma-associated oncogene homologue SMO smoothened LNs lymph nodes IL-13Ra2 interleukin-13 receptor alpha 2 GSA glioma-specific antigen MDSCs marrow-derived stem cells MoDC monocyte-derived dendritic cells mDC mature DC CTL cytotoxic T lymphocytes PBS Phosphate-buffered solution IFN-gamma gamma-interferon ELISA Enzyme-linked immunosorbent assay TGF-beta1 Transforming growth factor-beta 1	('IFN-gamma', 'Gene', '3458', (437, 446))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('IFN-gamma', 'Gene', (437, 446))	('Phosphate-buffered solution', 'Chemical', '-', (409, 436))	('DC', 'Gene', '20299', (374, 376))	('IL-13Ra2', 'Gene', '3598', (224, 232))	('Glioma', 'Disease', 'MESH:D005910', (156, 162))	('DC', 'Gene', '20299', (96, 98))	('TGF-beta1', 'Gene', '7040', (504, 513))	('variant', 'Var', (18, 25))	('Glioma', 'Phenotype', 'HP:0009733', (156, 162))	('GLI', 'Gene', (152, 155))	('smoothened LNs lymph nodes', 'Phenotype', 'HP:0002732', (197, 223))	('Glioblastoma', 'Disease', (120, 132))	('interleukin-13 receptor alpha 2', 'Gene', '3598', (233, 264))	('DC', 'Gene', '20299', (327, 329))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('SMO', 'Gene', '6608', (193, 196))	('Shh', 'Gene', (133, 136))	('Transforming growth factor-beta', 'Gene', (514, 545))	('epidermal growth factor receptor', 'Gene', (29, 61))	('smoothened', 'Gene', (197, 207))	('epidermal growth factor receptor', 'Gene', '1956', (29, 61))	('Glioma', 'Disease', (156, 162))	('SMO', 'Gene', (193, 196))	('GLI', 'Gene', '2735', (152, 155))	('Transforming growth factor-beta', 'Gene', '7040', (514, 545))	('Shh', 'Gene', '6469', (133, 136))	('DC', 'Gene', '20299', (364, 366))	('glioma', 'Disease', (269, 275))	('smoothened', 'Gene', '6608', (197, 207))	('Glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('mDC', 'Gene', (363, 366))	('mDC', 'Gene', '20299', (363, 366))	('glioma', 'Disease', 'MESH:D005910', (269, 275))	('IL-13Ra2', 'Gene', (224, 232))	('GSA', 'Chemical', '-', (265, 268))	('PBS', 'Chemical', '-', (405, 408))	('Glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('interleukin-13 receptor alpha 2', 'Gene', (233, 264))	('TGF-beta1', 'Gene', (504, 513))
16641	26542881	Furthermore, a significant radiosensitizing effect of Pt-ctpy in mice xenografted with glioblastoma SF763 cells was shown by delayed tumor growth and improved survival.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('survival', 'CPA', (159, 167))	('glioblastoma', 'Disease', (87, 99))	('Pt-ctpy', 'Var', (54, 61))	('delayed', 'NegReg', (125, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('tumor', 'Disease', (133, 138))	('Pt-ctpy', 'Chemical', '-', (54, 61))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('improved', 'PosReg', (150, 158))
16651	26542881	Here, we present an analysis of a second-generation G4-ligand Pt-ctpy that strongly enhances the sensitivity of human GBM and NSCLC cells to ionizing radiation both in vitro and in vivo.	('Pt-ctpy', 'Chemical', '-', (62, 69))	('enhances', 'PosReg', (84, 92))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('Pt-ctpy', 'Var', (62, 69))	('sensitivity', 'MPA', (97, 108))	('human', 'Species', '9606', (112, 117))	('NSCLC', 'Disease', (126, 131))
16661	26542881	GBM and NSCLC lines were found to be relatively radioresistant with a survival fraction at 2 Gy of 80.6% for SF763, 59.3% for SF767, 66.8% for A549 and 71.6% for H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (162, 167))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('SF763', 'Var', (109, 114))	('NSCLC', 'Disease', (8, 13))	('A549', 'CellLine', 'CVCL:0023', (143, 147))	('SF767', 'Var', (126, 131))
16673	26542881	In addition to its quadruplex-binding properties, Pt-ctpy is a monofunctional platinum complex and can form metal coordination adducts at the level of quadruplex DNA or, eventually, duplex DNA.	('quadruplex', 'Var', (151, 161))	('adducts', 'Interaction', (127, 134))	('metal', 'Chemical', 'MESH:D008670', (108, 113))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('Pt-ctpy', 'Chemical', '-', (50, 57))	('Pt-ctpy', 'Var', (50, 57))
16676	26542881	This indicates that the radiosensitizing effect of Pt-ctpy is due to specific properties of this compound and does not result from a classical DNA platination effect.	('radiosensitizing', 'MPA', (24, 40))	('Pt-ctpy', 'Chemical', '-', (51, 58))	('Pt-ctpy', 'Var', (51, 58))
16685	26542881	In particular, survival of mice treated with Pt-ctpy in combination with radiation was significantly longer (median: 148 days) compared with those of animals treated with radiation alone (52 days) or Pt-ctpy alone (24 days) (p = 0.032 and p = 0.043, respectively).	('longer', 'PosReg', (101, 107))	('Pt-ctpy', 'Chemical', '-', (45, 52))	('mice', 'Species', '10090', (27, 31))	('Pt-ctpy', 'Var', (45, 52))	('Pt-ctpy', 'Chemical', '-', (200, 207))	('survival', 'CPA', (15, 23))
16695	26542881	Low, non-cytotoxic concentrations of Pt-ctpy showed a strong radiosensitizing effect on GBM and NSCLC cells.	('NSCLC', 'Disease', (96, 101))	('Pt-ctpy', 'Var', (37, 44))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('radiosensitizing effect', 'CPA', (61, 84))	('Pt-ctpy', 'Chemical', '-', (37, 44))
16702	26542881	In conclusion, we show that Pt-ctpy, a G-quadruplex ligand of the terpyridine-metal family, is able to enhance the sensitivity to ionizing radiation of GBM and NSCLC cell lines in vitro.	('Pt-ctpy', 'Chemical', '-', (28, 35))	('terpyridine', 'Chemical', '-', (66, 77))	('enhance', 'PosReg', (103, 110))	('Pt-ctpy', 'Var', (28, 35))	('sensitivity to ionizing radiation', 'MPA', (115, 148))	('metal', 'Chemical', 'MESH:D008670', (78, 83))	('NSCLC', 'Disease', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
16711	26542881	Comparison of these data with the values obtained for the benchmark G4 ligand PhenDC3 (DeltaTm = 30  C, IC50 = 0.31 muM) indicates that Pt-ctpy exhibits high affinity for quadruplex conformation.	('Pt-ctpy', 'Var', (136, 143))	('quadruplex conformation', 'MPA', (171, 194))	('muM', 'Gene', (116, 119))	('Pt-ctpy', 'Chemical', '-', (136, 143))	('muM', 'Gene', '56925', (116, 119))
16748	33365061	The selected datasets were GSE2223, including 4 normal glioma samples and 27 GBM samples, GSE50161, including 13 normal samples and 34 GBM samples, and GSE4290, including 23 normal glioma samples and 81 GBM samples.	('glioma', 'Disease', (55, 61))	('GSE50161', 'Var', (90, 98))	('GSE4290', 'Chemical', '-', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('GSE2223', 'Chemical', '-', (27, 34))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioma', 'Disease', (181, 187))
16752	33365061	R software (version 3.5.1) was used to analyze the three datasets GSE2223, GSE50161 and GSE4290, as well as the TCGA and GTEX data.	('GSE2223', 'Var', (66, 73))	('GSE2223', 'Chemical', '-', (66, 73))	('GSE4290', 'Chemical', '-', (88, 95))	('GSE50161', 'Var', (75, 83))	('GTEX', 'Chemical', '-', (121, 125))	('GSE4290', 'Var', (88, 95))
16804	33365061	In GBM, MYC is mainly highly expressed, and it may therefore be speculated that high expression of MYC promotes the development of GBM through inhibition of SERPINA3, which requires further verification.	('SERPINA3', 'Gene', (157, 165))	('MYC', 'Gene', '4609', (8, 11))	('MYC', 'Gene', (8, 11))	('development', 'CPA', (116, 127))	('MYC', 'Gene', '4609', (99, 102))	('promotes', 'PosReg', (103, 111))	('SERPINA3', 'Gene', '12', (157, 165))	('MYC', 'Gene', (99, 102))	('inhibition', 'NegReg', (143, 153))	('high', 'Var', (80, 84))
16819	32573857	We also show that the loss of ASCL1 significantly reduces the proliferation of GBMs induced in the brain of a genetically relevant glioma mouse model, resulting in extended survival times.	('glioma', 'Disease', (131, 137))	('ASCL1', 'Gene', (30, 35))	('proliferation', 'CPA', (62, 75))	('mouse', 'Species', '10090', (138, 143))	('survival times', 'CPA', (173, 187))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('reduces', 'NegReg', (50, 57))	('extended', 'PosReg', (164, 172))	('loss', 'Var', (22, 26))
16820	32573857	RNA-seq analysis of mouse GBM tumors reveal that the loss of ASCL1 is associated with downregulation of cell cycle genes, illustrating an important role for ASCL1 in controlling the proliferation of GBM.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('downregulation', 'NegReg', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('GBM tumors', 'Disease', 'MESH:D005910', (26, 36))	('loss', 'Var', (53, 57))	('ASCL1', 'Gene', (61, 66))	('GBM tumors', 'Disease', (26, 36))	('cell cycle genes', 'Gene', (104, 120))	('mouse', 'Species', '10090', (20, 25))
16822	32573857	Loss of ASCL1 downregulates cell cycle genes and increase survival of glioma mouse model.	('increase', 'PosReg', (49, 57))	('glioma', 'Disease', (70, 76))	('cell', 'Protein', (28, 32))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('survival', 'CPA', (58, 66))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('downregulates', 'NegReg', (14, 27))	('ASCL1', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))	('mouse', 'Species', '10090', (77, 82))
16828	32573857	Despite displaying an aberrant array of mutations, GSCs are universally marked by coexpression of a combination of transcription factors, some of which include ASCL1, NFIA, NKX2.2, OLIG2, POU3F2, SALL2, SOX2, and ZEB1 (Glasgow et al., 2017; Lu et al., 2016; Rheinbay et al., 2013; Singh et al., 2017; Suva et al., 2014).	('POU3F2', 'Gene', (188, 194))	('ZEB1', 'Gene', '21417', (213, 217))	('SALL2', 'Gene', (196, 201))	('SALL2', 'Gene', '50524', (196, 201))	('NFIA', 'Gene', '18027', (167, 171))	('mutations', 'Var', (40, 49))	('NKX2.2', 'Gene', (173, 179))	('ZEB1', 'Gene', (213, 217))	('NFIA', 'Gene', (167, 171))	('NKX2.2', 'Gene', '18088', (173, 179))	('POU3F2', 'Gene', '18992', (188, 194))
16836	32573857	PDX-GBM (R738 and R548) were passaged orthotopically in the brains of NOD-SCID mice as previously described (Marian et al., 2010; Marin-Valencia et al., 2012).	('NOD', 'Gene', '1822', (70, 73))	('R738', 'Var', (9, 13))	('NOD', 'Gene', (70, 73))	('mice', 'Species', '10090', (79, 83))
16845	32573857	The following antibodies were used:  Two independent ASCL1 ChIP-seq experiments were performed using PDX-GBMs (R548 and R738) dissected from brains of NOD-SCID mice exhibiting symptoms of the presence of tumor.	('NOD', 'Gene', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('R738', 'Var', (120, 124))	('tumor', 'Disease', (204, 209))	('mice', 'Species', '10090', (160, 164))	('NOD', 'Gene', '1822', (151, 154))	('R548', 'Var', (111, 115))
16859	32573857	The number of DAPI+ tumor cells that were ASCL1+ along with each of the various markers were quantified using Image J on 20x immunofluorescence confocal images of both R548 and R738 PDX-GBMs.	('R738', 'Var', (177, 181))	('DAPI', 'Chemical', 'MESH:C007293', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('R548', 'Var', (168, 172))	('tumor', 'Disease', (20, 25))
16883	32573857	To functionally test ASCL1's role in gliomagenesis in vivo, we began by characterizing the temporal expression pattern of ASCL1 along with OLIG2, SOX2, and glial lineage markers in brain tumors induced in a mouse model carrying floxed alleles of the tumor suppressor genes Neurofibromin 1 (Nf1) and tumor protein 53 (Tp53) (Nf1 F/F ;Tp53 F/F) (Lin et al., 2004; Zhu et al., 2001).	('Tp53 F/F', 'Var', (333, 341))	('tumor', 'Disease', (187, 192))	('mouse', 'Species', '10090', (207, 212))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('tumor', 'Disease', (250, 255))	('Neurofibromin 1', 'Gene', '18015', (273, 288))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('Neurofibromin 1', 'Gene', (273, 288))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('brain tumors', 'Disease', 'MESH:D001932', (181, 193))	('brain tumors', 'Phenotype', 'HP:0030692', (181, 193))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('gliomagenesis', 'Disease', 'None', (37, 50))	('brain tumor', 'Phenotype', 'HP:0030692', (181, 192))	('gliomagenesis', 'Disease', (37, 50))	('tumor', 'Disease', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('brain tumors', 'Disease', (181, 193))
16884	32573857	NF1 and TP53 are two of the most highly mutated genes in human GBM (Brennan et al., 2013; Verhaak et al., 2010), and Cre-recombinase deletion of these two tumor suppressor genes (Nf1;Tp53 CKO) in neural progenitors or glial precursor cells have previously been shown to be fully penetrant in producing glioma tumors in the brains of mice (Alcantara Llaguno et al., 2009; Alcantara Llaguno et al., 2015; Zhu et al., 2005).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (309, 314))	('glioma tumors', 'Disease', (302, 315))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mice', 'Species', '10090', (333, 337))	('Tp53', 'Gene', (183, 187))	('deletion', 'Var', (133, 141))	('Nf1;Tp53', 'Gene', (179, 187))	('glioma tumors', 'Disease', 'MESH:D005910', (302, 315))	('tumor', 'Disease', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('glioma', 'Phenotype', 'HP:0009733', (302, 308))	('TP53', 'Gene', '7157', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('TP53', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('human', 'Species', '9606', (57, 62))
16887	32573857	Tamoxifen was then administered to pregnant dams at E14.5 to induce Nf1;Tp53 CKO in neural progenitors of embryos.	('Nf1', 'Gene', (68, 71))	('Tp53', 'Var', (72, 76))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))
16891	32573857	High magnifications revealed that ASCL1, OLIG2, and SOX2 are also expressed specifically within the YFP+ tumor cells (Figure 3m-r), which are highly irregular in shape, morphology, and density compared to normal YFP+ cells on the nontumor side (not shown).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('ASCL1', 'Gene', (34, 39))	('SOX2', 'Gene', (52, 56))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('YFP+', 'Var', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (105, 110))
16894	32573857	The lack of colocalization between YFP and GFAP was similar to that observed in tumors of another glioma mouse model in which PDGF stimulation was combined with deletion of another tumor suppressor, Pten (Lei et al., 2011), and implies that the majority of GFAP+ cells are reactive astrocytes that have infiltrated the YFP+ tumor bulk in our model.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GFAP', 'Gene', (257, 261))	('tumors', 'Disease', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('GFAP', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('glioma', 'Disease', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('PDGF', 'Gene', (126, 130))	('GFAP', 'Gene', '14580', (257, 261))	('tumor', 'Disease', (80, 85))	('Pten', 'Gene', (199, 203))	('Pten', 'Gene', '19211', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('GFAP', 'Gene', '14580', (43, 47))	('PDGF', 'Gene', '18595', (126, 130))	('tumor', 'Disease', (181, 186))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('tumor', 'Disease', (324, 329))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('deletion', 'Var', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('mouse', 'Species', '10090', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
16895	32573857	From P60-120, we found that 100% of Nf1;Tp53 CKO mice exhibited neurological symptoms and had tumors that evolved into an expanded mass with high mitotic index and microvascular proliferation resembling that of high-grade gliomas (Figure 4a,b).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('neurological symptoms', 'Disease', (64, 85))	('exhibited', 'Reg', (54, 63))	('neurological symptoms', 'Disease', 'MESH:D009422', (64, 85))	('mice', 'Species', '10090', (49, 53))	('gliomas', 'Disease', 'MESH:D005910', (222, 229))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('gliomas', 'Disease', (222, 229))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('gliomas', 'Phenotype', 'HP:0009733', (222, 229))	('Nf1;Tp53', 'Var', (36, 44))	('glioma', 'Phenotype', 'HP:0009733', (222, 228))
16902	32573857	To address this, we incorporated Ascl1 GFP knock-in (null) and Ascl1 Floxed alleles into the glioma mouse model to generate Glast CreERT2 ;Ascl1 GFP/F ;Nf1 F/F ;Tp53 F/F and Glast CreERT2 ;Ascl1 F/F ;Nf1 F/F ;Tp53 F/F mice, respectively, both of which when administered with tamoxifen at E14.5 will result in triple conditional knock-out of Ascl1 along with Nf1 and Tp53 (Ascl1;Nf1;Tp53 CKO).	('CreERT2', 'Gene', '26417', (130, 137))	('glioma', 'Disease', (93, 99))	('Glast', 'Gene', '20512', (124, 129))	('mouse', 'Species', '10090', (100, 105))	('CreERT2', 'Gene', (130, 137))	('Glast', 'Gene', (124, 129))	('CreERT2', 'Gene', '26417', (180, 187))	('knock-out', 'Var', (328, 337))	('Ascl1', 'Gene', (341, 346))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('tamoxifen', 'Chemical', 'MESH:D013629', (275, 284))	('mice', 'Species', '10090', (218, 222))	('Glast', 'Gene', '20512', (174, 179))	('CreERT2', 'Gene', (180, 187))	('Glast', 'Gene', (174, 179))
16904	32573857	In contrast, in vivo we found that Ascl1;Nf1;Tp53 CKO mice (hence forth referred to as Ascl1 CKO tumor mice, N = 39) still developed high-grade tumors that were phenotypically consistent with high-grade gliomas (Figure 5a).	('tumors', 'Disease', (144, 150))	('developed', 'PosReg', (123, 132))	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mice', 'Species', '10090', (103, 107))	('Ascl1', 'Var', (35, 40))	('CKO tumor', 'Disease', (93, 102))	('CKO tumor', 'Disease', 'MESH:D009369', (93, 102))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('gliomas', 'Disease', (203, 210))
16905	32573857	Furthermore, Ascl1 CKO tumor penetrance and location (Figure 5l,m) in the brain was similar to the Ascl1 HET (not shown) and Ascl1 WT tumors (Figure 4o,p).	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Ascl1', 'Var', (13, 18))	('WT tumors', 'Disease', 'MESH:C536751', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('HET', 'Gene', (105, 108))	('WT tumors', 'Disease', (131, 140))	('CKO tumor', 'Disease', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('HET', 'Gene', '224903', (105, 108))	('CKO tumor', 'Disease', 'MESH:D009369', (19, 28))
16907	32573857	As illustrated for a Glast CreERT2 ;Ascl1 GFP/F ;Nf1 F/F ;Tp53 F/F mouse, GFP driven by the endogenous Ascl1 locus marks precisely the tumor cells but ASCL1 was no longer detected (Figure 5b,c).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Tp53 F/F', 'Var', (58, 66))	('tumor', 'Disease', (135, 140))	('CreERT2', 'Gene', '26417', (27, 34))	('CreERT2', 'Gene', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mouse', 'Species', '10090', (67, 72))	('Glast', 'Gene', '20512', (21, 26))	('Glast', 'Gene', (21, 26))
16916	32573857	Overall, Ascl1 CKO tumors exhibited a decrease of about 30% Ki67+ cells compared to Ascl1 WT tumors (Figure 5p), which is consistent with our previous finding that numerous cell cycle and mitotic genes are targets of ASCL1.	('CKO tumors', 'Disease', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Ki67', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('decrease', 'NegReg', (38, 46))	('Ascl1', 'Var', (9, 14))	('WT tumors', 'Disease', 'MESH:C536751', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Ki67', 'Gene', '17345', (60, 64))	('WT tumors', 'Disease', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('CKO tumors', 'Disease', 'MESH:D009369', (15, 25))
16918	32573857	To determine if the loss of ASCL1 altered the molecular profiles of the mouse glioma tumors, we carefully isolated tumor bulk from various regions of the brain from Ascl1 WT (N = 5) and Ascl1 CKO (N = 5) tumor mice for RNA-seq analysis.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumor', 'Disease', (85, 90))	('ASCL1', 'Gene', (28, 33))	('loss', 'Var', (20, 24))	('mice', 'Species', '10090', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mouse', 'Species', '10090', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (115, 120))	('glioma tumors', 'Disease', (78, 91))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('glioma tumors', 'Disease', 'MESH:D005910', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
16927	32573857	In contrast, Sox genes were bidirectionally affected by the loss of ASCL1.	('ASCL1', 'Gene', (68, 73))	('affected', 'Reg', (44, 52))	('Sox', 'Gene', (13, 16))	('Sox', 'Gene', '104009', (13, 16))	('loss', 'Var', (60, 64))
16929	32573857	Heatmap and dendrogram analysis of all 1,054 ASCL1 putative targets (converted from a list of 1,106 genes from human GBMs, Table S4), revealed that there were as many genes being upregulated as there were genes being downregulated by the loss of ASCL1 (Figure 6h, Table S7).	('upregulated', 'PosReg', (179, 190))	('loss', 'Var', (238, 242))	('human', 'Species', '9606', (111, 116))	('ASCL1', 'Gene', (246, 251))
16942	32573857	Despite these findings, RNA-seq from a Nf1;Tp53 CKO mouse model of glioma where the tumors also lack ASCL1 revealed that although some Notch related genes (Dll3, Hes5, Hes6) were decreased, expression of many of the Wnt related genes seemed unaffected by the loss of ASCL1.	('decreased', 'NegReg', (179, 188))	('Hes5', 'Gene', '15208', (162, 166))	('mouse', 'Species', '10090', (52, 57))	('glioma where the tumors', 'Disease', (67, 90))	('Dll3', 'Gene', '13389', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('loss', 'Var', (259, 263))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('Hes6', 'Gene', (168, 172))	('ASCL1', 'Gene', (267, 272))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Hes6', 'Gene', '55927', (168, 172))	('Dll3', 'Gene', (156, 160))	('Hes5', 'Gene', (162, 166))	('glioma where the tumors', 'Disease', 'MESH:D005910', (67, 90))
16944	32573857	Interestingly, ChIP-seq for ASCL1 in PDX-GBMs and RNA-seq of mouse Ascl1 CKO tumors in our study revealed that cell cycle and mitotic genes are major targets of ASCL1 binding (Figure 2f,j), and these targets were most impacted by the loss of ASCL1 (Figure 6g,j).	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CKO tumors', 'Disease', (73, 83))	('mitotic genes', 'Gene', (126, 139))	('loss', 'Var', (234, 238))	('cell cycle', 'CPA', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ASCL1', 'Gene', (242, 247))	('mouse', 'Species', '10090', (61, 66))	('CKO tumors', 'Disease', 'MESH:D009369', (73, 83))	('binding', 'Interaction', (167, 174))
16947	32573857	Taken together, these findings demonstrate that a major role for ASCL1 in the Nf1;Tp53 CKO glioma mouse model is to drive tumor cell proliferation.	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('drive', 'PosReg', (116, 121))	('glioma', 'Disease', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Nf1;Tp53 CKO', 'Var', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Disease', (122, 127))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
16948	32573857	In particular, although overexpression of ASCL1 is predominantly known to promote cell cycle exit, cell fate specification, and neuronal differentiation, a prominent phenotype associated with Ascl1 mutants is a loss in the overall progenitor pool as a result of a decrease in proliferation and a disruption in the ASCL1/NOTCH balance, which is essential to maintain the progenitor pool (Borromeo et al., 2014; Casarosa, Fode, & Guillemot, 1999; Castro et al., 2011; Horton, Meredith, Richardson, & Johnson, 1999; Nakada, Hunsaker, Henke, & Johnson, 2004).	('cell cycle exit', 'CPA', (82, 97))	('progenitor pool', 'MPA', (231, 246))	('Ascl1', 'Gene', (192, 197))	('promote', 'PosReg', (74, 81))	('loss', 'NegReg', (211, 215))	('Johnson', 'Disease', 'MESH:C535882', (498, 505))	('Johnson', 'Disease', (498, 505))	('proliferation', 'CPA', (276, 289))	('decrease', 'NegReg', (264, 272))	('Johnson', 'Disease', 'MESH:C535882', (540, 547))	('Johnson', 'Disease', (540, 547))	('mutants', 'Var', (198, 205))	('ASCL1/NOTCH', 'MPA', (314, 325))	('Guillemot', 'Species', '13746', (428, 437))	('cell fate specification', 'CPA', (99, 122))	('disruption', 'Reg', (296, 306))	('neuronal differentiation', 'CPA', (128, 152))
16959	32573857	This downregulation suggests that the coexpression of these transcription factors is important for maintaining OPCs in a progenitor-like state, and the loss of just one of these factors does not completely abrogate tumor formation following deletion of Nf1 and Tp53 because OPCs are still generated, and are thus susceptible to being transformed into glioma.	('Tp53', 'Gene', (261, 265))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('glioma', 'Disease', 'MESH:D005910', (351, 357))	('glioma', 'Phenotype', 'HP:0009733', (351, 357))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('abrogate', 'NegReg', (206, 214))	('tumor', 'Disease', (215, 220))	('glioma', 'Disease', (351, 357))	('deletion', 'Var', (241, 249))	('Nf1', 'Gene', (253, 256))
16960	32573857	It is also possible that within the context of cancer, mutations to tumor suppressor and/or oncogenes may result in dysregulation of ASCL1 and the other transcription factors to be aberrantly coexpressed in neural progenitors or OPCs, thereby suppressing their differentiation and maintaining these cells in a constant state of proliferation, eventually leading to glioma formation.	('tumor', 'Disease', (68, 73))	('leading to', 'Reg', (354, 364))	('glioma', 'Disease', (365, 371))	('suppressing', 'NegReg', (243, 254))	('differentiation', 'CPA', (261, 276))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('dysregulation', 'MPA', (116, 129))	('result in', 'Reg', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('glioma', 'Disease', 'MESH:D005910', (365, 371))	('glioma', 'Phenotype', 'HP:0009733', (365, 371))	('ASCL1', 'Gene', (133, 138))	('maintaining', 'Reg', (281, 292))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
16963	32573857	Furthermore, despite utilizing different approaches and driver mutations to induce tumor formation, the loss of NFIA or OLIG2 was also accompanied by significant decreases in tumor cell proliferation resulting in an increase in survival for their respective mouse models (Glasgow et al., 2017; Lu et al., 2016).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('survival', 'CPA', (228, 236))	('tumor', 'Disease', (175, 180))	('mouse', 'Species', '10090', (258, 263))	('loss', 'Var', (104, 108))	('OLIG2', 'Gene', (120, 125))	('tumor', 'Disease', (83, 88))	('decreases', 'NegReg', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('NFIA', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('NFIA', 'Gene', '18027', (112, 116))	('increase', 'PosReg', (216, 224))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
16964	32573857	Together, these studies illustrate potential redundant roles for neurodevelopmental or glial transcription factors in driving glioma formation and progression in vivo in the brain, where the loss of one factor does not completely prevent tumor formation and progression possibly because of compensation by the remaining transcription factors.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('progression', 'CPA', (147, 158))	('loss', 'Var', (191, 195))	('tumor', 'Disease', (238, 243))	('glioma', 'Disease', (126, 132))
16965	32573857	Similar to the findings reported here, deletion of Nf1, Tp53, along with or without Pten at adult stages, produces glioma tumors in the brains of mice using multiple neural stem/progenitor cell type specific Cre drivers (Alcantara Llaguno et al., 2009; Alcantara Llaguno et al., 2015; Zhu et al., 2005).	('produces', 'Reg', (106, 114))	('Pten', 'Gene', (84, 88))	('glioma tumors', 'Disease', (115, 128))	('deletion', 'Var', (39, 47))	('glioma tumors', 'Disease', 'MESH:D005910', (115, 128))	('Pten', 'Gene', '19211', (84, 88))	('Nf1', 'Gene', (51, 54))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('Tp53', 'Gene', (56, 60))	('mice', 'Species', '10090', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
16973	32573857	In conclusion, the tumors induced embryonically through deletion of Nf1;Tp53 deletion are highly heterogenous based on RNA-seq analysis, which is similar to that seen for human GBMs (Patel et al., 2014; Sottoriva et al., 2013).	('deletion', 'Var', (56, 64))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('deletion', 'Var', (77, 85))	('Tp53', 'Gene', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('human', 'Species', '9606', (171, 176))	('Nf1;Tp53', 'Gene', (68, 76))
16975	32573857	Despite this heterogeneity, however, the loss of ASCL1 still significantly delays tumor progression and resulted in a significant increase in survival for mice with Ascl1 CKO tumors over those mice with Ascl1 WT tumors, illustrating an important role for ASCL1 in controlling the rate of glioma proliferation in vivo.	('WT tumors', 'Disease', (209, 218))	('survival', 'CPA', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (82, 87))	('WT tumors', 'Disease', 'MESH:C536751', (209, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('glioma proliferation', 'Disease', (288, 308))	('glioma proliferation', 'Disease', 'MESH:D005910', (288, 308))	('mice', 'Species', '10090', (193, 197))	('mice', 'Species', '10090', (155, 159))	('tumor', 'Disease', (175, 180))	('Ascl1', 'Gene', (165, 170))	('CKO tumors', 'Disease', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('increase', 'PosReg', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('glioma', 'Phenotype', 'HP:0009733', (288, 294))	('tumor', 'Disease', (212, 217))	('loss', 'Var', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('ASCL1', 'Gene', (49, 54))	('CKO tumors', 'Disease', 'MESH:D009369', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('delays', 'NegReg', (75, 81))
17045	32545241	For HA, the typical bands were found at about 3283 cm-1, 1044 cm-1, and 1614 cm-1 which were indicated to the hydrogen-bonded O-H stretching vibration, the C-O-C stretching vibration and the carbonyl group of the carboxylate (COO-) asymmetric stretching vibration, respectively.	('C-O-C stretching', 'MPA', (156, 172))	('HA', 'Chemical', 'MESH:D006820', (4, 6))	('1614 cm-1', 'Var', (72, 81))	('carboxylate', 'Chemical', '-', (213, 224))	('hydrogen-bonded O-H stretching', 'MPA', (110, 140))	('COO', 'Chemical', 'MESH:C041069', (226, 229))	('hydrogen', 'Chemical', 'MESH:D006859', (110, 118))
17066	32545241	The Figure 7 showed that after 1, 4, and 7 days of cell incubation, increased cell proliferation was demonstrated on the PCL/Gel/HA0.5 scaffold compared to the PCL/Gel/HA0.5xy and PCL/Gel and PCL/Gelxy scaffolds.	('HA', 'Chemical', 'MESH:D006820', (168, 170))	('PCL/Gel/HA0.5', 'Var', (121, 134))	('HA', 'Chemical', 'MESH:D006820', (129, 131))	('increased', 'PosReg', (68, 77))	('cell proliferation', 'CPA', (78, 96))
17102	32429463	In 2016, WHO consolidated tumor morphology, IDH mutation, and 1p19q co-deletion status into a new classification system for adult diffuse glioma.	('glioma', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('1p19q co-deletion', 'Var', (62, 79))	('IDH', 'Gene', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('IDH', 'Gene', '3417', (44, 47))
17122	32429463	For instance, miR-181a inhibited the levels of CD133 and subsequently suppressed GSCs formation and glioblastoma tumorigenesis via the Notch-2 pathway.	('miR-181a', 'Var', (14, 22))	('tumor', 'Disease', (113, 118))	('Notch-2', 'Gene', (135, 142))	('GSCs formation', 'CPA', (81, 95))	('inhibited', 'NegReg', (23, 32))	('GSCs', 'Chemical', '-', (81, 85))	('Notch-2', 'Gene', '4853', (135, 142))	('levels', 'MPA', (37, 43))	('glioblastoma', 'Disease', (100, 112))	('suppressed', 'NegReg', (70, 80))	('CD133', 'Gene', (47, 52))	('glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('miR-181a', 'Chemical', '-', (14, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CD133', 'Gene', '8842', (47, 52))
17132	32429463	Conversely, miR-154 increased CD133 expression by inhibiting phosphoribosyl pyrophosphate synthetase 1 (PRPS1) in CD133Pos GSCs, whilst miR-9 can activate the SHH signaling pathway by inhibiting protein patched homolog 1 (PTCH1), which enhanced the expression of CD133.	('miR-9', 'Var', (136, 141))	('CD133', 'Gene', (114, 119))	('PRPS1', 'Gene', '5631', (104, 109))	('CD133', 'Gene', (263, 268))	('CD133', 'Gene', '8842', (114, 119))	('CD133', 'Gene', '8842', (263, 268))	('miR-154', 'Gene', '406946', (12, 19))	('PTCH1', 'Gene', (222, 227))	('expression', 'MPA', (249, 259))	('increased', 'PosReg', (20, 29))	('GSCs', 'Chemical', '-', (123, 127))	('SHH', 'Gene', (159, 162))	('protein patched homolog 1', 'Gene', '5727', (195, 220))	('activate', 'PosReg', (146, 154))	('inhibiting', 'NegReg', (184, 194))	('miR-154', 'Gene', (12, 19))	('inhibiting', 'NegReg', (50, 60))	('phosphoribosyl pyrophosphate synthetase 1', 'Gene', '5631', (61, 102))	('CD133', 'Gene', (30, 35))	('CD133', 'Gene', '8842', (30, 35))	('enhanced', 'PosReg', (236, 244))	('protein patched homolog 1', 'Gene', (195, 220))	('expression', 'MPA', (36, 46))	('PTCH1', 'Gene', '5727', (222, 227))	('SHH', 'Gene', '6469', (159, 162))	('PRPS1', 'Gene', (104, 109))	('phosphoribosyl pyrophosphate synthetase 1', 'Gene', (61, 102))
17152	32429463	On the other hand, the migration and invasion of GSCs were considerably reduced by knockdown of the CD44 gene.	('reduced', 'NegReg', (72, 79))	('GSCs', 'Chemical', '-', (49, 53))	('CD44', 'Gene', '960', (100, 104))	('CD44', 'Gene', (100, 104))	('knockdown', 'Var', (83, 92))
17191	32429463	Similarly, the treatment with N-(p-coumaroyl) serotonin resulted in a noteworthy dose-dependent rise in the number of CD15 markers in GBM.	('CD15', 'Gene', '2526', (118, 122))	('CD15', 'Gene', (118, 122))	('N-(p-coumaroyl) serotonin', 'Var', (30, 55))	('rise', 'PosReg', (96, 100))	('N-(p-coumaroyl) serotonin', 'Chemical', 'MESH:C114774', (30, 55))	('number of', 'MPA', (108, 117))
17208	32429463	Ablation of CD70 in glioblastoma cells reduced genes correlated with tumor epithelial mesenchymal transition (EMT), such as SOX-2 and CD44, and inhibited the migration and growth of the tumor.	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glioblastoma', 'Disease', (20, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('genes', 'MPA', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('Ablation', 'Var', (0, 8))	('CD44', 'Gene', '960', (134, 138))	('inhibited', 'NegReg', (144, 153))	('CD44', 'Gene', (134, 138))	('reduced', 'NegReg', (39, 46))	('tumor', 'Disease', (69, 74))	('CD70', 'Gene', (12, 16))	('SOX-2', 'Gene', '6657', (124, 129))	('CD70', 'Gene', '970', (12, 16))	('SOX-2', 'Gene', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
17209	32429463	reported that in glioblastoma cells, HIF-2alpha upregulates and also causes the emergence of CD70 in CD70Neg cells, while silencing HIF-2alpha resulted in a reduction of CD70 expression.	('upregulates', 'PosReg', (48, 59))	('CD70', 'Gene', '970', (101, 105))	('CD70', 'Gene', '970', (93, 97))	('expression', 'MPA', (175, 185))	('CD70', 'Gene', (170, 174))	('CD70', 'Gene', (101, 105))	('HIF-2alpha', 'Gene', (132, 142))	('CD70', 'Gene', '970', (170, 174))	('glioblastoma', 'Disease', (17, 29))	('HIF-2alpha', 'Gene', (37, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (17, 29))	('emergence', 'MPA', (80, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (17, 29))	('HIF-2alpha', 'Gene', '2034', (37, 47))	('HIF-2alpha', 'Gene', '2034', (132, 142))	('causes', 'Reg', (69, 75))	('silencing', 'Var', (122, 131))	('CD70', 'Gene', (93, 97))
17210	32429463	Interestingly, knocking down HIF-1alpha did not considerably change CD70 expression in CD70Pos cells.	('CD70', 'Gene', (68, 72))	('HIF-1alpha', 'Gene', (29, 39))	('CD70', 'Gene', '970', (68, 72))	('expression', 'MPA', (73, 83))	('knocking', 'Var', (15, 23))	('CD70', 'Gene', '970', (87, 91))	('CD70', 'Gene', (87, 91))	('HIF-1alpha', 'Gene', '3091', (29, 39))
17227	32429463	S100A4 depletion lengthened the anti-VEGF treatment profile and hence reduced glioblastoma resistance to antiangiogenic therapy.	('glioblastoma', 'Disease', (78, 90))	('reduced', 'NegReg', (70, 77))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('lengthened', 'PosReg', (17, 27))	('VEGF', 'Gene', (37, 41))	('depletion', 'Var', (7, 16))	('S100A4', 'Gene', (0, 6))	('S100A4', 'Gene', '6275', (0, 6))	('VEGF', 'Gene', '7422', (37, 41))
17234	32429463	However, gliomas with low expression of ALDH1A3 were more likely to be the PN subtype, and suppression of ALDH1A3 inhibited PN GSCs' proliferation.	('low', 'NegReg', (22, 25))	('ALDH1A3', 'Gene', (40, 47))	('gliomas', 'Disease', (9, 16))	('GSCs', 'Chemical', '-', (127, 131))	("PN GSCs' proliferation", 'CPA', (124, 146))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('suppression', 'Var', (91, 102))	('ALDH1A3', 'Gene', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('inhibited', 'NegReg', (114, 123))
17243	32429463	They also found a higher mortality and a worst overall survival associated with overexpression of ALDH1A3.	('ALDH1A3', 'Gene', (98, 105))	('overexpression', 'Var', (80, 94))	('mortality', 'Disease', 'MESH:D003643', (25, 34))	('higher', 'PosReg', (18, 24))	('mortality', 'Disease', (25, 34))
17244	32429463	confirmed that ALDH1A3 knockdown in glioblastoma cells resulted in more sensitivity towards TMZ.	('ALDH1A3', 'Gene', (15, 22))	('more', 'PosReg', (67, 71))	('sensitivity towards TMZ', 'MPA', (72, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (36, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('knockdown', 'Var', (23, 32))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))	('glioblastoma', 'Disease', (36, 48))
17247	32429463	Similarly, ALDH1A3 has been reported to be downregulated in response to the combination of focal adhesion kinase (FAK) autophosphorylation inhibitor, Y15, and TMZ, indicating a synergistic contribution upon treating drug resistance.	('downregulated', 'NegReg', (43, 56))	('focal adhesion kinase', 'Gene', (91, 112))	('TMZ', 'Chemical', 'MESH:D000077204', (159, 162))	('FAK', 'Gene', (114, 117))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('Y15', 'Chemical', '-', (150, 153))	('focal adhesion kinase', 'Gene', '5747', (91, 112))	('ALDH1A3', 'Gene', (11, 18))	('FAK', 'Gene', '5747', (114, 117))	('TMZ', 'Var', (159, 162))	('Y15', 'Var', (150, 153))
17285	32429463	Other studies have shown that OCT-4 knockdown in embryonic carcinoma cells augmented Akt expression levels, whereas blocking of the Akt pathway enhanced the expression of OCT-4 in GSCs.	('expression', 'MPA', (157, 167))	('Akt', 'Gene', '207', (85, 88))	('enhanced', 'PosReg', (144, 152))	('OCT-4', 'Gene', (30, 35))	('Akt', 'Gene', (132, 135))	('embryonic carcinoma', 'Disease', 'MESH:D018236', (49, 68))	('OCT-4', 'Gene', '5460', (171, 176))	('OCT-4', 'Gene', (171, 176))	('knockdown', 'Var', (36, 45))	('OCT-4', 'Gene', '5460', (30, 35))	('Akt', 'Gene', (85, 88))	('embryonic carcinoma', 'Phenotype', 'HP:0002898', (49, 68))	('blocking', 'NegReg', (116, 124))	('GSCs', 'Chemical', '-', (180, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Akt', 'Gene', '207', (132, 135))	('embryonic carcinoma', 'Disease', (49, 68))	('augmented', 'PosReg', (75, 84))
17289	32429463	FAT1 knockdown in glioblastoma inhibited all EMT and stemness markers, including OCT-4.	('knockdown', 'Var', (5, 14))	('OCT-4', 'Gene', '5460', (81, 86))	('OCT-4', 'Gene', (81, 86))	('FAT1', 'Gene', '2195', (0, 4))	('glioblastoma', 'Disease', (18, 30))	('glioblastoma', 'Disease', 'MESH:D005909', (18, 30))	('inhibited', 'NegReg', (31, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (18, 30))	('FAT1', 'Gene', (0, 4))
17292	32429463	OCT-4Pos GSCs also showed a significant positive correlation with nucleolin, which was found to be involved in promoting tumor growth in GSCs.	('GSCs', 'Chemical', '-', (137, 141))	('OCT-4Pos', 'Chemical', '-', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('promoting', 'PosReg', (111, 120))	('tumor', 'Disease', (121, 126))	('nucleolin', 'Gene', (66, 75))	('OCT-4Pos', 'Var', (0, 8))	('GSCs', 'Chemical', '-', (9, 13))	('nucleolin', 'Gene', '4691', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
17293	32429463	Nucleolin was suggested as a potential therapeutic marker in OCT-4Pos GSCs, and therefore targeting this protein can perhaps diminish stemness and cell aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (152, 166))	('diminish', 'NegReg', (125, 133))	('OCT-4Pos', 'Chemical', '-', (61, 69))	('aggressiveness', 'Disease', 'MESH:D001523', (152, 166))	('Nucleolin', 'Gene', (0, 9))	('GSCs', 'Chemical', '-', (70, 74))	('OCT-4Pos', 'Disease', (61, 69))	('targeting', 'Var', (90, 99))	('Nucleolin', 'Gene', '4691', (0, 9))	('aggressiveness', 'Disease', (152, 166))
17309	32429463	They showed that cells with high expression of SOX-2 are more resistant to TMZ, assuming SOX-2 as one of the key proteins responsible for resistance to chemotherapy in GBM.	('resistant', 'MPA', (62, 71))	('SOX-2', 'Gene', (89, 94))	('TMZ', 'Chemical', 'MESH:D000077204', (75, 78))	('SOX-2', 'Gene', '6657', (47, 52))	('high expression', 'Var', (28, 43))	('SOX-2', 'Gene', '6657', (89, 94))	('SOX-2', 'Gene', (47, 52))
17329	32429463	In glioblastoma cells, Nestin regulates growth, stemness, and invasion through the alteration of HSC71 (gene HSPA8).	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('HSPA8', 'Gene', (109, 114))	('HSC71', 'Gene', '3312', (97, 102))	('regulates', 'Reg', (30, 39))	('Nestin', 'Gene', '10763', (23, 29))	('glioblastoma', 'Disease', (3, 15))	('HSPA8', 'Gene', '3312', (109, 114))	('stemness', 'CPA', (48, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('Nestin', 'Gene', (23, 29))	('growth', 'CPA', (40, 46))	('invasion', 'CPA', (62, 70))	('alteration', 'Var', (83, 93))	('HSC71', 'Gene', (97, 102))
17330	32429463	As such, inhibition of Nestin and/or HSC71 may be a beneficial molecular target therapy for glioblastoma.	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('HSC71', 'Gene', (37, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('HSC71', 'Gene', '3312', (37, 42))	('Nestin', 'Gene', '10763', (23, 29))	('Nestin', 'Gene', (23, 29))	('inhibition', 'Var', (9, 19))
17331	32429463	Many reports have showed that Nestin knockdown suppressed the proliferation, invasion, and migration of glioblastoma cells.	('suppressed', 'NegReg', (47, 57))	('proliferation', 'CPA', (62, 75))	('Nestin', 'Gene', '10763', (30, 36))	('knockdown', 'Var', (37, 46))	('invasion', 'CPA', (77, 85))	('glioblastoma', 'Disease', (104, 116))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('migration', 'CPA', (91, 100))	('Nestin', 'Gene', (30, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))
17332	32429463	Some studies suggested that Nestin expression is linked to a higher grade and worsens prognosis in gliomas.	('Nestin', 'Gene', (28, 34))	('linked', 'Reg', (49, 55))	('worsens', 'NegReg', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('Nestin', 'Gene', '10763', (28, 34))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('prognosis', 'CPA', (86, 95))	('expression', 'Var', (35, 45))
17338	32429463	Additionally, miR-423-5p through suppression of its target gene (ING-4) increased Nestin expression in GSCs and accordingly induced glioblastoma cells to exhibit greater resistance to TMZ.	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('expression', 'MPA', (89, 99))	('increased', 'PosReg', (72, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (184, 187))	('resistance', 'CPA', (170, 180))	('Nestin', 'Gene', '10763', (82, 88))	('miR-423-5p', 'Var', (14, 24))	('suppression', 'NegReg', (33, 44))	('miR-423-5p', 'Chemical', '-', (14, 24))	('GSCs', 'Chemical', '-', (103, 107))	('ING-4', 'Gene', '51147', (65, 70))	('induced', 'Reg', (124, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('Nestin', 'Gene', (82, 88))	('ING-4', 'Gene', (65, 70))
17339	32429463	Therefore, the prevention of miR-423-5p or miR-381 together with TMZ intervention may be a beneficial therapeutic approach for suppressing GSCs growth.	('miR-381', 'Gene', '494330', (43, 50))	('GSCs', 'Disease', (139, 143))	('suppressing', 'NegReg', (127, 138))	('miR-381', 'Gene', (43, 50))	('miR-423-5p', 'Chemical', '-', (29, 39))	('GSCs', 'Chemical', '-', (139, 143))	('miR-423-5p', 'Var', (29, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (65, 68))
17362	31687320	Modification of PEG chain on the pharmaceutical molecules could also improve the BBB penetrability by prolonging the circulation time in vivo which would increase the probability of the interactions between the drugs and BBB.	('circulation', 'MPA', (117, 128))	('PEG', 'Gene', (16, 19))	('BBB penetrability', 'CPA', (81, 98))	('PEG', 'Gene', '5047', (16, 19))	('Modification', 'Var', (0, 12))	('improve', 'PosReg', (69, 76))	('prolonging', 'NegReg', (102, 112))	('interactions', 'Interaction', (186, 198))	('increase', 'PosReg', (154, 162))
17379	31687320	Meanwhile, modification of the dendrimer carriers with the peptides significantly improved the BBB penetrability of DOX in a BBB model in vitro and enhanced its anti-glioma effect after traversing the BBB.	('DOX', 'Chemical', 'MESH:D004317', (116, 119))	('BBB', 'CPA', (95, 98))	('glioma', 'Disease', (166, 172))	('enhanced', 'PosReg', (148, 156))	('modification', 'Var', (11, 23))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('improved', 'PosReg', (82, 90))
17437	31687320	1H NMR (D2O, 400 MHz, ppm): delta 2.25-2.40 (-CH2CH2CONH-); delta 2.45-2.55 (-CH2CH2N<); delta 2.68-2.74 (-NCH2CH2CO-); delta 2.95-3.20 (-CONHCH2CH2- and -CH2CH2NH2); delta 3.32-3.75 (-CH2CH2O-); delta 6.79 (-COCH=CHCO-); delta 3.30 (-OCH3).	('N', 'Chemical', 'MESH:D009584', (84, 85))	('delta 2.45-2.55', 'Var', (60, 75))	('(-NCH2CH2CO-)', 'Chemical', 'MESH:C449943', (105, 118))	('1H', 'Chemical', 'MESH:D006859', (0, 2))	('(-CH2CH2O-)', 'Chemical', 'MESH:C103208', (183, 194))	('D2O', 'Chemical', 'MESH:D013481', (8, 11))	('delta', 'Var', (167, 172))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('N', 'Chemical', 'MESH:D009584', (140, 141))	('delta 2.68-2.74', 'Var', (89, 104))	('delta', 'Var', (196, 201))	('CONHCH2CH2', 'Chemical', 'MESH:C512684', (138, 148))	('CH2CH2NH2', 'Chemical', 'MESH:C076955', (155, 164))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('(-CH2CH2N<)', 'Chemical', 'MESH:C055635', (76, 87))	('(-CH2CH2CONH-)', 'Chemical', 'MESH:C087990', (44, 58))
17447	31687320	The DOX loaded different carrier forms were named P4PD, P4PED, P4PAD and P4PEAD, respectively.	('P4PED', 'Var', (56, 61))	('P4PED', 'Chemical', 'MESH:C033071', (56, 61))	('AD', 'Disease', 'MESH:D000544', (77, 79))	('AD', 'Disease', (77, 79))	('DOX', 'Chemical', 'MESH:D004317', (4, 7))	('PD', 'Disease', 'MESH:D010300', (52, 54))	('AD', 'Disease', 'MESH:D000544', (66, 68))	('AD', 'Disease', (66, 68))	('P4PEAD', 'Chemical', 'MESH:D010695', (73, 79))
17473	31687320	To evaluate the ability of DOX across the BBB after encapsulating into the carriers, free DOX, P4PD, P4PAD, P4PED and P4PEAD were added into the corresponding inserts of the BBB model in vitro with the DOX concentration of 20 muM and cultured at 37 C. Then a volume of 400 muL medium was taken out from the acceptor compartments at 30, 60, 90, 120, 180 min and 400 muL fresh medium was supplied immediately.	('muM', 'Gene', '56925', (226, 229))	('DOX', 'Chemical', 'MESH:D004317', (27, 30))	('P4PEAD', 'Chemical', 'MESH:D010695', (118, 124))	('P4PED', 'Var', (108, 113))	('DOX', 'Chemical', 'MESH:D004317', (202, 205))	('muM', 'Gene', (226, 229))	('DOX', 'Chemical', 'MESH:D004317', (90, 93))	('AD', 'Disease', 'MESH:D000544', (122, 124))	('AD', 'Disease', (122, 124))	('P4PED', 'Chemical', 'MESH:C033071', (108, 113))	('PD', 'Disease', 'MESH:D010300', (97, 99))	('AD', 'Disease', 'MESH:D000544', (104, 106))	('AD', 'Disease', (104, 106))
17497	31687320	Other five groups were treated with free DOX, P4PD, P4PAD, P4PED and P4PEAD via tail vein with a DOX dose of 5 mg/kg, respectively.	('AD', 'Disease', 'MESH:D000544', (55, 57))	('DOX', 'Chemical', 'MESH:D004317', (41, 44))	('AD', 'Disease', (55, 57))	('AD', 'Disease', 'MESH:D000544', (73, 75))	('P4PED', 'Chemical', 'MESH:C033071', (59, 64))	('PD', 'Disease', 'MESH:D010300', (48, 50))	('DOX', 'Chemical', 'MESH:D004317', (97, 100))	('P4PEAD', 'Chemical', 'MESH:D010695', (69, 75))	('P4PED', 'Var', (59, 64))	('AD', 'Disease', (73, 75))
17505	31687320	The peptide library was designed with the sequence of X1X2X3X4X5X6X7X8X9G in which each X represented any of the four different amino acid residues to improve the diversity of the library.	('X1X2X3X4X5X6X7X8X9G', 'Var', (54, 73))	('improve', 'PosReg', (151, 158))	('amino', 'Chemical', 'MESH:D000596', (128, 133))
17509	31687320	Sequence alignment showed that the most frequent amino acid residues in each position hit the high probability interaction between peptide and EGFR protein.	('EGFR', 'Gene', (143, 147))	('amino acid residues', 'Var', (49, 68))	('hit', 'Reg', (86, 89))	('interaction', 'Interaction', (111, 122))	('EGFR', 'Gene', '1956', (143, 147))	('peptide', 'Protein', (131, 138))	('amino', 'Chemical', 'MESH:D000596', (49, 54))
17510	31687320	We found that alkaline and acidic amino acids in the first two positions of N-terminal might enhance the affinity of peptide ligands to EGFR according to the multiple sequence alignment analysis (Figure S1).	('EGFR', 'Gene', '1956', (136, 140))	('affinity', 'Interaction', (105, 113))	('enhance', 'PosReg', (93, 100))	('peptide', 'Protein', (117, 124))	('amino', 'Chemical', 'MESH:D000596', (34, 39))	('alkaline', 'Var', (14, 22))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('EGFR', 'Gene', (136, 140))
17545	31687320	DLS analysis showed that the hydrodynamic diameter of the dendrimer-based carriers increased from ~5.78 nm for G4 PAMAM (P4) to ~11.63 nm for PEGylated PAMAM (P4P0 and ~16.80 nm for P4PEA (Figure 2b).	('PEG', 'Gene', '5047', (142, 145))	('increased', 'PosReg', (83, 92))	('PAMAM', 'Chemical', 'MESH:C522249', (152, 157))	('PAMAM', 'Chemical', 'MESH:C522249', (114, 119))	('hydrodynamic', 'MPA', (29, 41))	('P4PEA', 'Chemical', 'MESH:C526312', (182, 187))	('G4 PAMAM', 'Var', (111, 119))	('PEG', 'Gene', (142, 145))
17547	31687320	We measured the size of the particles in TEM images an found that the size distributions were determined to be 7.03 +- 1.04 nm for P4, 20.2 +- 3.63 nm for P4P and 26.07 +- 8.15 nm for P4PEA (Figure S6), in the similar range of the ones assessed by DLS.	('P4PEA', 'Var', (184, 189))	('P4PEA', 'Chemical', 'MESH:C526312', (184, 189))	('P4P', 'Var', (155, 158))
17549	31687320	Zeta potential measurement showed that the surface potential of P4, P4P and P4PEA was 21.0 +- 1.0 mV, 4.1 +- 0.3 mV, 6.5 +- 0.1 mV, respectively.	('P4P', 'Var', (68, 71))	('P4PEA', 'Var', (76, 81))	('P4PEA', 'Chemical', 'MESH:C526312', (76, 81))
17550	31687320	The modification of PEG chain reduced the positive charge greatly due to the shielding effect of the PEG, which would reduce the cytotoxicity and biotoxicity of the carriers.	('PEG', 'Gene', (101, 104))	('PEG', 'Gene', '5047', (101, 104))	('modification', 'Var', (4, 16))	('positive charge', 'MPA', (42, 57))	('reduced', 'NegReg', (30, 37))	('PEG', 'Gene', (20, 23))	('reduce', 'NegReg', (118, 124))	('cytotoxicity and biotoxicity', 'Disease', 'MESH:D064420', (129, 157))	('PEG', 'Gene', '5047', (20, 23))
17563	31687320	PEG modification significantly decreased the cytotoxicity of the dendrimer for HBMEC and U87-MG cells benefiting from the charge shielding effect of PEG (P4P, Figure 4c and d).	('PEG', 'Gene', '5047', (149, 152))	('U87-MG', 'CellLine', 'CVCL:0022', (89, 95))	('cytotoxicity of the dendrimer', 'Disease', 'MESH:D064420', (45, 74))	('decreased', 'NegReg', (31, 40))	('cytotoxicity of the dendrimer', 'Disease', (45, 74))	('modification', 'Var', (4, 16))	('PEG', 'Gene', (0, 3))	('HBMEC', 'CellLine', 'CVCL:0307', (79, 84))	('PEG', 'Gene', '5047', (0, 3))	('PEG', 'Gene', (149, 152))
17586	31687320	As expected, the fluorescent intensity of the cells was significantly higher in U87-MG than in HBMEC (Figure 5a), demonstrating the targeting effect of the peptide-functionalized dendrimers to the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('U87-MG', 'CellLine', 'CVCL:0022', (80, 86))	('fluorescent intensity', 'MPA', (17, 38))	('HBMEC', 'CellLine', 'CVCL:0307', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('U87-MG', 'Var', (80, 86))	('higher', 'PosReg', (70, 76))	('tumor', 'Disease', (197, 202))
17590	31687320	The cellular uptake of DOX in U87-MG was in the order of P4PEAD > DOX > P4PED > P4PAD > P4PD (Figure 5b), consistent with the overexpression of EGFR and the moderate expression of LRP1 in U87-MG cells.	('P4PED', 'Var', (72, 77))	('U87-MG', 'CellLine', 'CVCL:0022', (30, 36))	('AD', 'Disease', (83, 85))	('EGFR', 'Gene', (144, 148))	('U87-MG', 'CellLine', 'CVCL:0022', (188, 194))	('P4PEAD', 'Chemical', 'MESH:D010695', (57, 63))	('AD', 'Disease', 'MESH:D000544', (61, 63))	('overexpression', 'PosReg', (126, 140))	('AD', 'Disease', (61, 63))	('DOX', 'Chemical', 'MESH:D004317', (66, 69))	('LRP1', 'Gene', (180, 184))	('EGFR', 'Gene', '1956', (144, 148))	('PD', 'Disease', 'MESH:D010300', (90, 92))	('P4PED', 'Chemical', 'MESH:C033071', (72, 77))	('DOX', 'Chemical', 'MESH:D004317', (23, 26))	('AD', 'Disease', 'MESH:D000544', (83, 85))	('cellular uptake', 'MPA', (4, 19))	('LRP1', 'Gene', '4035', (180, 184))
17594	31687320	The strongest fluorescence intensity in these two cells after incubating with P4PEAD compared with the other DOX-loaded carriers also revealed the enhanced drug internalization mediated by the targeting effect of EP-1 and Ang2 peptide.	('enhanced', 'PosReg', (147, 155))	('P4PEAD', 'Var', (78, 84))	('fluorescence intensity', 'MPA', (14, 36))	('P4PEAD', 'Chemical', 'MESH:D010695', (78, 84))	('strongest', 'PosReg', (4, 13))	('drug internalization', 'MPA', (156, 176))	('DOX', 'Chemical', 'MESH:D004317', (109, 112))	('Ang2 peptide', 'Protein', (222, 234))	('EP-1', 'Protein', (213, 217))
17606	31687320	We found that only ~3.89% of the free DOX was transported through the BBB, while the transported DOX significantly increased after being encapsulated into the dendrimers (transport ratio of ~6.57% for P4PD, ~7.49% for P4PED, and ~10.25% for P4PAD).	('P4PED', 'Chemical', 'MESH:C033071', (218, 223))	('DOX', 'Chemical', 'MESH:D004317', (38, 41))	('increased', 'PosReg', (115, 124))	('PD', 'Disease', 'MESH:D010300', (203, 205))	('DOX', 'Chemical', 'MESH:D004317', (97, 100))	('P4PED', 'Var', (218, 223))	('AD', 'Disease', 'MESH:D000544', (244, 246))	('AD', 'Disease', (244, 246))
17615	31687320	These results were consistent with the flow cytometry analysis of the intracellular uptake of DOX by U87-MG cells which showed that the intracellular uptake of DOX by the tumor cells was higher in the dendrimer groups compared to free DOX group, and was higher when the cells were treated with peptide-functionalized dendrimers compared to the PEGylated dendrimer.	('PEG', 'Gene', '5047', (344, 347))	('intracellular uptake of DOX', 'MPA', (136, 163))	('dendrimer', 'Var', (201, 210))	('higher', 'PosReg', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('DOX', 'Chemical', 'MESH:D004317', (94, 97))	('higher', 'PosReg', (187, 193))	('DOX', 'Chemical', 'MESH:D004317', (160, 163))	('U87-MG', 'CellLine', 'CVCL:0022', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('DOX', 'Chemical', 'MESH:D004317', (235, 238))	('PEG', 'Gene', (344, 347))
17617	31687320	These results, taken together with the transport ratio of the DOX formulations across the BBB model, demonstrated that the modification of the dendrimers with Ang2 and EP-1 peptides enhanced the BBB penetrability and the glioma targeting efficacy synergistically.	('DOX', 'Chemical', 'MESH:D004317', (62, 65))	('glioma', 'Disease', (221, 227))	('modification', 'Var', (123, 135))	('enhanced', 'PosReg', (182, 190))	('glioma', 'Disease', 'MESH:D005910', (221, 227))	('glioma', 'Phenotype', 'HP:0009733', (221, 227))	('BBB penetrability', 'CPA', (195, 212))
17618	31687320	The possible mechanism of this dual-targeting effect was speculated as follows: 1) the modification of EP-1 and Ang2 peptides on dendrimer improved its targeting and accumulating effect to BBB, then the dendrimer-based carrier transported across the BBB by Ang2-LRP1 mediated transcytosis and the adsorption-mediated transcytosis.	('targeting', 'MPA', (152, 161))	('LRP1', 'Gene', (262, 266))	('adsorption-mediated transcytosis', 'CPA', (297, 329))	('transcytosis', 'CPA', (276, 288))	('improved', 'PosReg', (139, 147))	('accumulating effect', 'MPA', (166, 185))	('LRP1', 'Gene', '4035', (262, 266))	('modification', 'Var', (87, 99))
17624	31687320	We found that modification of the dendrimers with Ang2 peptide significantly improved the BBB penetrability of the dendrimer-based carriers by LRP1-mediated transcytosis.	('BBB penetrability of the', 'CPA', (90, 114))	('LRP1', 'Gene', '4035', (143, 147))	('Ang2', 'Gene', (50, 54))	('modification', 'Var', (14, 26))	('improved', 'PosReg', (77, 85))	('LRP1', 'Gene', (143, 147))
17630	31687320	We found that the group treated with dual-targeting dendrimer (P4PEAD) exhibited the longest survival time than any other groups, which indicated that the dual-functionalization of the dendrimer remarkably improve the BBB penetrating and glioma targeting effect of the drug delivery system (Figure 8b).	('dual-functionalization', 'Var', (155, 177))	('glioma', 'Disease', (238, 244))	('improve', 'PosReg', (206, 213))	('glioma', 'Disease', 'MESH:D005910', (238, 244))	('glioma', 'Phenotype', 'HP:0009733', (238, 244))	('P4PEAD', 'Var', (63, 69))	('P4PEAD', 'Chemical', 'MESH:D010695', (63, 69))	('BBB penetrating', 'CPA', (218, 233))
17632	31687320	Meanwhile, the overall survival time was 31 days for Ang2 modified dendrimer (P4PAD) and 27 days for EP-1 modified dendrimer (P4PED), which longer than the group treat with PEGylated dendrimer (PEPD, 24 days) and free DOX (19 days) (Figure 8b).	('PEG', 'Gene', (173, 176))	('PEG', 'Gene', '5047', (173, 176))	('PEPD', 'Gene', '5184', (194, 198))	('AD', 'Disease', 'MESH:D000544', (81, 83))	('P4PED', 'Chemical', 'MESH:C033071', (126, 131))	('AD', 'Disease', (81, 83))	('Ang2', 'Gene', (53, 57))	('modified', 'Var', (58, 66))	('DOX', 'Chemical', 'MESH:D004317', (218, 221))	('PEPD', 'Gene', (194, 198))
17633	31687320	These results demonstrated that the peptides modification synergistically improved the anti-glioma effect by improving BBB penetrability and glioma targeting.	('improved', 'PosReg', (74, 82))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('improving', 'PosReg', (109, 118))	('glioma', 'Disease', (92, 98))	('modification', 'Var', (45, 57))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('BBB penetrability', 'CPA', (119, 136))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('peptides modification', 'Var', (36, 57))	('glioma', 'Disease', (141, 147))
17653	31534165	Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression.	('high', 'Var', (15, 19))	('poor', 'NegReg', (56, 60))	('ATF4', 'Gene', '468', (20, 24))	('PERK', 'Gene', (104, 108))	('PERK', 'Gene', '9451', (104, 108))	('expression', 'MPA', (25, 35))	('overall survival', 'MPA', (61, 77))	('ATF4', 'Gene', (20, 24))
17657	31534165	Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence.	('GFAP', 'Gene', (166, 170))	('cell adherence', 'CPA', (183, 197))	('reduced', 'NegReg', (175, 182))	('expression', 'MPA', (130, 140))	('SOX2', 'Gene', '6657', (125, 129))	('SOX2', 'Gene', (125, 129))	('GFAP', 'Gene', '2670', (166, 170))	('PERK', 'Gene', '9451', (10, 14))	('serum-induced differentiation', 'CPA', (49, 78))	('upregulation', 'PosReg', (150, 162))	('inactivation', 'Var', (15, 27))	('PERK', 'Gene', (10, 14))
17662	31534165	Oncogenic driver mutations have been identified in GBM that affect retinoblastoma, p53 and receptor tyrosine kinase signaling, but targeting these pathways has not yet resulted in effective therapy.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('retinoblastoma', 'Disease', 'MESH:D012175', (67, 81))	('retinoblastoma', 'Disease', (67, 81))	('receptor tyrosine kinase signaling', 'MPA', (91, 125))	('mutations', 'Var', (17, 26))	('affect', 'Reg', (60, 66))	('GBM', 'Gene', (51, 54))	('retinoblastoma', 'Phenotype', 'HP:0009919', (67, 81))
17672	31534165	IRE1alpha oligomerization and auto-phosphorylation results in activation of its endoribonuclease activity and subsequent splicing of the X-box binding protein 1 (XBP1) mRNA yielding the transcription factor XBP1s.	('oligomerization', 'Var', (10, 25))	('XBP1', 'Gene', '7494', (207, 211))	('IRE1alpha', 'Gene', (0, 9))	('endoribonuclease', 'Enzyme', (80, 96))	('IRE1alpha', 'Gene', '2081', (0, 9))	('X-box binding protein 1', 'Gene', (137, 160))	('X-box binding protein 1', 'Gene', '7494', (137, 160))	('activity', 'MPA', (97, 105))	('XBP1', 'Gene', (162, 166))	('XBP1', 'Gene', (207, 211))	('splicing', 'MPA', (121, 129))	('XBP1', 'Gene', '7494', (162, 166))	('activation', 'PosReg', (62, 72))	('auto-phosphorylation', 'Var', (30, 50))
17691	31534165	A dose-dependent reduction of cell viability was seen after 24 h treatment that became more pronounced after 48 h, particularly for MES GG6 and GG16 (Fig.	('GG16', 'Var', (144, 148))	('MES', 'Chemical', '-', (132, 135))	('reduction', 'NegReg', (17, 26))	('cell viability', 'CPA', (30, 44))
17715	31534165	PERK inhibition suppressed Tg-induced cytotoxicity that was associated with decreased cleavage of caspase-3 and PARP (Fig.	('PARP', 'Gene', '1302', (112, 116))	('suppressed', 'NegReg', (16, 26))	('PERK', 'Gene', (0, 4))	('PARP', 'Gene', (112, 116))	('inhibition', 'Var', (5, 15))	('PERK', 'Gene', '9451', (0, 4))	('caspase-3', 'Gene', (98, 107))	('decreased', 'NegReg', (76, 85))	('cytotoxicity', 'Disease', (38, 50))	('Tg', 'Chemical', 'MESH:D019284', (27, 29))	('cleavage', 'MPA', (86, 94))	('caspase-3', 'Gene', '836', (98, 107))	('cytotoxicity', 'Disease', 'MESH:D064420', (38, 50))
17724	31534165	Tg resulted in a two- to fourfold reduction in neurosphere formation ability in GG6, GG14, and GG16, whereas in GSC23 no significant effects were seen (Fig.	('GG16', 'Var', (95, 99))	('GG14', 'Var', (85, 89))	('Tg', 'Chemical', 'MESH:D019284', (0, 2))	('GG6', 'Var', (80, 83))	('reduction', 'NegReg', (34, 43))	('neurosphere formation ability', 'CPA', (47, 76))
17749	31534165	Interestingly, absence of PERK resulted in impaired cell adhesion compared with rapid adherence normally seen after serum addition as observed by microscopy (Fig.	('PERK', 'Gene', '9451', (26, 30))	('impaired cell adhesion', 'Phenotype', 'HP:0008352', (43, 65))	('cell adhesion', 'CPA', (52, 65))	('absence', 'Var', (15, 22))	('impaired', 'NegReg', (43, 51))	('PERK', 'Gene', (26, 30))
17753	31534165	Evaluation of UPR biomarker expression in primary GBM samples on TMA revealed that high levels of ATF4 is associated with poor prognosis in treatment naive patients.	('patients', 'Species', '9606', (156, 164))	('high levels', 'Var', (83, 94))	('ATF4', 'Gene', (98, 102))	('TMA', 'Chemical', '-', (65, 68))	('ATF4', 'Gene', '468', (98, 102))
17754	31534165	This suggests that low activity of the PERK/eIF2alpha/ATF4 branch is beneficial for prognosis.	('eIF2alpha', 'Gene', '83939', (44, 53))	('ATF4', 'Gene', (54, 58))	('low', 'Var', (19, 22))	('activity', 'MPA', (23, 31))	('PERK', 'Gene', (39, 43))	('ATF4', 'Gene', '468', (54, 58))	('PERK', 'Gene', '9451', (39, 43))	('eIF2alpha', 'Gene', (44, 53))
17760	31534165	ATF4 has been implicated in promoting angiogenesis, invasion and temozolomide resistance, which may explain poor prognoses in high ATF4 expressing GBM patients.	('ATF4', 'Gene', (131, 135))	('ATF4', 'Gene', '468', (0, 4))	('ATF4', 'Gene', '468', (131, 135))	('patients', 'Species', '9606', (151, 159))	('temozolomide', 'Chemical', 'MESH:D000077204', (65, 77))	('high', 'Var', (126, 130))	('invasion', 'CPA', (52, 60))	('ATF4', 'Gene', (0, 4))	('temozolomide resistance', 'MPA', (65, 88))	('angiogenesis', 'CPA', (38, 50))	('promoting', 'PosReg', (28, 37))
17799	31534165	The patient-derived GBM neurospheres GG6, GG14, GG16, and GSC23 were cultured in neural stem cell medium (NSM) as previously described, GG6 and GG16 representing MES GBM, GG14 and GSC23, PN GBM.	('patient', 'Species', '9606', (4, 11))	('MES', 'Chemical', '-', (162, 165))	('GG16', 'Gene', (144, 148))	('PN', 'Chemical', '-', (187, 189))	('GG6', 'Var', (136, 139))
17816	31534165	Representative PERK and ATF4 knockouts (ko) were selected together with control transfected GG16 cells for further use.	('ATF4', 'Gene', '468', (24, 28))	('knockouts', 'Var', (29, 38))	('PERK', 'Gene', (15, 19))	('ATF4', 'Gene', (24, 28))	('PERK', 'Gene', '9451', (15, 19))
17831	30643430	In particular, chloroquine has been reported to be a possible neurorestorative agent in animal models of Parkinson's disease and has been used in rheumatology, treatment of amebic liver abscess, and management of systemic lupus erythematosus, due to its immunomodulatory effects.	('liver abscess', 'Phenotype', 'HP:0100523', (180, 193))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (213, 241))	('rat', 'Species', '10116', (72, 75))	('chloroquine', 'Var', (15, 26))	('abscess', 'Phenotype', 'HP:0025615', (186, 193))	("Parkinson's disease", 'Disease', (105, 124))	('amebic liver abscess', 'Disease', (173, 193))	("Parkinson's disease", 'Disease', 'MESH:D010300', (105, 124))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (213, 241))	('systemic lupus erythematosus', 'Disease', (213, 241))	('chloroquine', 'Chemical', 'MESH:D002738', (15, 26))	('amebic liver abscess', 'Disease', 'MESH:D008101', (173, 193))
17856	30643430	At the therapeutic level, unradiolabeled octreotide has an application as an antisecretory agent to palliate the symptoms of bowel obstruction in patients with advanced gastrointestinal (GI), gynecological, or pelvic cancer and for the amelioration of carcinoid symptoms.	('carcinoid symptoms', 'Disease', (252, 270))	('rat', 'Species', '10116', (242, 245))	('advanced gastrointestinal', 'Disease', (160, 185))	('pelvic cancer', 'Disease', (210, 223))	('unradiolabeled', 'Var', (26, 40))	('patients', 'Species', '9606', (146, 154))	('bowel obstruction', 'Phenotype', 'HP:0005214', (125, 142))	('octreotide', 'Chemical', 'MESH:D015282', (41, 51))	('bowel obstruction', 'Disease', 'MESH:D015212', (125, 142))	('carcinoid', 'Phenotype', 'HP:0100570', (252, 261))	('palliate', 'NegReg', (100, 108))	('pelvic cancer', 'Disease', 'MESH:D010386', (210, 223))	('gynecological', 'Disease', (192, 205))	('carcinoid symptoms', 'Disease', 'MESH:D002276', (252, 270))	('bowel obstruction', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('advanced gastrointestinal', 'Disease', 'MESH:D005767', (160, 185))
17870	30643430	In this acidic compartment, chloroquine inhibits the biocrystallization of hemozoin, thereby leading to the accumulation of either toxic heme monomers or toxic chloroquine-bound heme complexes.	('leading to', 'Reg', (93, 103))	('chloroquine-bound', 'MPA', (160, 177))	('accumulation', 'PosReg', (108, 120))	('chloroquine', 'Chemical', 'MESH:D002738', (160, 171))	('heme', 'Chemical', 'MESH:D006418', (137, 141))	('chloroquine', 'Chemical', 'MESH:D002738', (28, 39))	('biocrystallization', 'MPA', (53, 71))	('inhibits', 'NegReg', (40, 48))	('heme', 'Chemical', 'MESH:D006418', (178, 182))	('chloroquine', 'Var', (28, 39))
17911	30643430	In DLD1 colon cancer cells, combined exposure to 10 microM 5-fluorouracil (a conventional chemotherapeutic agent) and 100 microM chloroquine resulted in cytostatic synergy by influencing different cell-cycle-inhibitory molecules exemplified by p53 and p27Kip1 (positive regulation) and cyclin D1 and CDK2 (negative regulation), suggesting a role for chloroquine as an adjunct in cancer therapeutics.	('colon cancer', 'Phenotype', 'HP:0003003', (8, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (59, 73))	('chloroquine', 'Chemical', 'MESH:D002738', (129, 140))	('cyclin D1', 'Gene', (286, 295))	('p27Kip1', 'Gene', (252, 259))	('p27Kip1', 'Gene', '1027', (252, 259))	('5-fluorouracil', 'Var', (59, 73))	('cyclin D1', 'Gene', '595', (286, 295))	('p53', 'Protein', (244, 247))	('cancer', 'Disease', (379, 385))	('colon cancer', 'Disease', 'MESH:D015179', (8, 20))	('cytostatic synergy', 'MPA', (153, 171))	('cell-cycle-inhibitory molecules', 'MPA', (197, 228))	('chloroquine', 'Chemical', 'MESH:D002738', (350, 361))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('CDK2', 'Gene', '1017', (300, 304))	('cancer', 'Disease', (14, 20))	('influencing', 'Reg', (175, 186))	('positive regulation', 'PosReg', (261, 280))	('colon cancer', 'Disease', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('CDK2', 'Gene', (300, 304))	('cancer', 'Disease', 'MESH:D009369', (379, 385))
17915	30643430	Additionally, in the pancreatic cancer cells Panc1 and MiaPaCa2, chloroquine exhibited cytostatic effects (induction of G2/M phase arrest), while it decreased the levels of antiapoptotic proteins and enhanced the growth-suppressive properties of TRAIL in xenografts.	('Panc1', 'CellLine', 'CVCL:0480', (45, 50))	('enhanced', 'PosReg', (200, 208))	('pancreatic cancer', 'Disease', (21, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (21, 38))	('chloroquine', 'Chemical', 'MESH:D002738', (65, 76))	('TRAIL', 'Gene', '8743', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('chloroquine', 'Var', (65, 76))	('decreased', 'NegReg', (149, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (21, 38))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (55, 63))	('cytostatic effects', 'MPA', (87, 105))	('TRAIL', 'Gene', (246, 251))	('levels of antiapoptotic proteins', 'MPA', (163, 195))
17920	30643430	In addition, autophagy was evoked in response to chemotherapeutic agents to enable escape from tumor dormancy, and pharmacological blockage of this response with chloroquine resulted in the prevention of tumor relapse in vitro, as evidenced by experiments in Neu-overexpressing MMC cells during treatment with adriamycin.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('prevention', 'NegReg', (190, 200))	('blockage', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('escape', 'CPA', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (204, 209))	('chloroquine', 'Chemical', 'MESH:D002738', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('adriamycin', 'Chemical', 'MESH:D004317', (310, 320))	('autophagy', 'CPA', (13, 22))	('tumor', 'Disease', (95, 100))
17924	30643430	In human PC3 and DU145 prostate cancer cells, concomitant treatment with the Akt inhibitor AZD5363 and chloroquine unleashed the apoptosis-triggering effects of AZD5363.	('Akt', 'Gene', '207', (77, 80))	('PC3', 'Gene', (9, 12))	('human', 'Species', '9606', (3, 8))	('Akt', 'Gene', (77, 80))	('prostate cancer', 'Disease', (23, 38))	('AZD5363', 'Chemical', 'MESH:C575618', (91, 98))	('chloroquine', 'Chemical', 'MESH:D002738', (103, 114))	('AZD5363', 'Var', (91, 98))	('PC3', 'Gene', '3853', (9, 12))	('DU145', 'CellLine', 'CVCL:0105', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('AZD5363', 'Chemical', 'MESH:C575618', (161, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))
17925	30643430	Significantly, chloroquine and AZD5363 synergistically promoted tumor shrinkage in xenografts involving the aforementioned prostate cancer cells.	('AZD5363', 'Var', (31, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('tumor', 'Disease', (64, 69))	('prostate cancer', 'Disease', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('promoted', 'PosReg', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))	('chloroquine', 'Chemical', 'MESH:D002738', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('AZD5363', 'Chemical', 'MESH:C575618', (31, 38))
17938	30643430	Entrectinib inhibits a neural RTK (ALK), which is etiopathologically linked to neuroblastoma and mutated in 8% of cases of sporadic neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (79, 92))	('neuroblastoma', 'Disease', (132, 145))	('mutated', 'Var', (97, 104))	('Entrectinib', 'Chemical', 'MESH:C000607349', (0, 11))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (79, 92))	('inhibits', 'NegReg', (12, 20))	('sporadic neuroblastoma', 'Disease', (123, 145))	('neuroblastoma', 'Disease', (79, 92))	('neural RTK', 'Pathway', (23, 33))	('sporadic neuroblastoma', 'Disease', 'MESH:D009447', (123, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))
17939	30643430	In fact, NB1amp cells that harbor an amplified ALK gene are sensitive to entrectinib-induced apoptosis.	('sensitive', 'Reg', (60, 69))	('entrectinib', 'Chemical', 'MESH:C000607349', (73, 84))	('amplified', 'Var', (37, 46))	('ALK gene', 'Gene', (47, 55))
17941	30643430	Intriguingly, a Beclin 1-independent autophagic response has been identified as being involved in drug resistance in these cells, and treatment of SHSY5YF1174L with chloroquine may restore their sensitivity to entrectinib.	('drug resistance', 'Phenotype', 'HP:0020174', (98, 113))	('autophagic response', 'CPA', (37, 56))	('chloroquine', 'Chemical', 'MESH:D002738', (165, 176))	('sensitivity to entrectinib', 'MPA', (195, 221))	('SHSY5YF1174L', 'CellLine', 'CVCL:0019', (147, 159))	('restore', 'PosReg', (181, 188))	('involved', 'Reg', (86, 94))	('entrectinib', 'Chemical', 'MESH:C000607349', (210, 221))	('SHSY5YF1174L', 'Var', (147, 159))
17942	30643430	Therefore, if entrectinib is approved as an antineuroblastoma agent and launched in the market, chloroquine could be repositioned in oncology for use in combination with entrectinib for the treatment of neuroblastomas that carry mutations associated with entrectinib resistance (as identified by molecular screening).	('entrectinib', 'Chemical', 'MESH:C000607349', (170, 181))	('antineuroblastoma', 'Disease', (44, 61))	('oncology', 'Phenotype', 'HP:0002664', (133, 141))	('antineuroblastoma', 'Disease', 'None', (44, 61))	('neuroblastoma', 'Phenotype', 'HP:0003006', (48, 61))	('mutations', 'Var', (229, 238))	('chloroquine', 'Chemical', 'MESH:D002738', (96, 107))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('neuroblastomas', 'Phenotype', 'HP:0003006', (203, 217))	('entrectinib', 'Chemical', 'MESH:C000607349', (255, 266))	('neuroblastomas', 'Disease', 'MESH:D009447', (203, 217))	('entrectinib', 'Chemical', 'MESH:C000607349', (14, 25))	('neuroblastomas', 'Disease', (203, 217))
17948	30643430	Chloroquine exhibited cytotoxic effects both under conditions of normoxia and hypoxia independent of wild-type or mutant BRAF expression in various melanoma cell lines.	('BRAF', 'Gene', (121, 125))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('hypoxia', 'Disease', (78, 85))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('mutant', 'Var', (114, 120))	('cytotoxic effects', 'CPA', (22, 39))	('BRAF', 'Gene', '673', (121, 125))	('Chloroquine', 'Chemical', 'MESH:D002738', (0, 11))
17950	30643430	The pharmacological inhibition of autophagy via exposure to chloroquine or via targeting autophagy-associated molecules (eg, Beclin 1 and ATG5) has more recently been found to stimulate the expression of the chemokine CCL5 via the PP2A-JNK-c-Jun pathway.	('CCL5', 'Gene', '6352', (218, 222))	('PP2A-JNK-c-Jun pathway', 'Pathway', (231, 253))	('autophagy', 'CPA', (34, 43))	('chloroquine', 'Chemical', 'MESH:D002738', (60, 71))	('ATG5', 'Gene', '9474', (138, 142))	('Beclin 1', 'Gene', (125, 133))	('inhibition', 'Var', (20, 30))	('ATG5', 'Gene', (138, 142))	('chemokine', 'Gene', (208, 217))	('stimulate', 'PosReg', (176, 185))	('CCL5', 'Gene', (218, 222))	('expression', 'MPA', (190, 200))
17966	30643430	In 4T1 and 67NR mouse mammary tumor cells, chloroquine increased sensitivity to the mTOR inhibitor rapamycin and to the PI3K inhibitor LY294002, even in the absence of Beclin 1 and ATG12.	('chloroquine', 'Chemical', 'MESH:D002738', (43, 54))	('increased', 'PosReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('LY294002', 'Var', (135, 143))	('ATG12', 'Gene', (181, 186))	('sensitivity', 'MPA', (65, 76))	('rapamycin', 'Chemical', 'MESH:D020123', (99, 108))	('4T1', 'CellLine', 'CVCL:0125', (3, 6))	('ATG12', 'Gene', '67526', (181, 186))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('LY294002', 'Chemical', 'MESH:C085911', (135, 143))
17967	30643430	These data suggest that chloroquine suppresses tumor-cell growth of mammalian cells by engaging diverge signaling pathways other than autophagy pathways.	('diverge signaling pathways', 'Pathway', (96, 122))	('chloroquine', 'Chemical', 'MESH:D002738', (24, 35))	('suppresses', 'NegReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('engaging', 'PosReg', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('chloroquine', 'Var', (24, 35))	('mammalian', 'Species', '9606', (68, 77))	('tumor', 'Disease', (47, 52))
17975	30643430	The prevention of DNA repair could force cancer cells to undergo apoptotic death.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('prevention', 'Var', (4, 14))	('apoptotic death', 'CPA', (65, 80))	('force', 'Reg', (35, 40))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
17982	30643430	In addition, chloroquine prevented the spread of EO771 mouse mammary tumor cells to the lungs in Par-4+/+ mice, but not in Par-4-deficient mice.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('chloroquine', 'Chemical', 'MESH:D002738', (13, 24))	('mice', 'Species', '10090', (106, 110))	('tumor', 'Disease', (69, 74))	('prevented', 'NegReg', (25, 34))	('mouse', 'Species', '10090', (55, 60))	('mice', 'Species', '10090', (139, 143))	('spread', 'CPA', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('EO771', 'Var', (49, 54))	('Par-4+/+', 'Var', (97, 105))
17989	30643430	The fact that chloroquine counteracts angiogenesis has further been validated using the in vivo angiogenesis-screening chicken chorioallantoic membrane model, and chloroquine also decreased microvascular density in malignant pleural effusion (MPE) xenograft models.	('chicken', 'Species', '9031', (119, 126))	('chloroquine', 'Chemical', 'MESH:D002738', (14, 25))	('chloroquine', 'Chemical', 'MESH:D002738', (163, 174))	('decreased', 'NegReg', (180, 189))	('malignant pleural effusion', 'Disease', 'MESH:D016066', (215, 241))	('pleural effusion', 'Phenotype', 'HP:0002202', (225, 241))	('chloroquine', 'Var', (163, 174))	('malignant pleural effusion', 'Disease', (215, 241))	('microvascular density', 'CPA', (190, 211))
17998	30643430	According to AutoDock Vina, octreotide may bind to APC2 at two positions with affinity DeltaG=-9.1 kcal/mol and DeltaG=-7.2 kcal/mol, respectively.	('APC2', 'Gene', (51, 55))	('APC2', 'Gene', '10297', (51, 55))	('bind', 'Interaction', (43, 47))	('octreotide', 'Chemical', 'MESH:D015282', (28, 38))	('DeltaG=-9.1', 'Var', (87, 98))
18014	30643430	Interestingly, as shown in Table S2, the binding site for octreotide on GSK-3beta includes Y216 (1O9U.pdb).	('octreotide', 'Chemical', 'MESH:D015282', (58, 68))	('GSK-3beta', 'Gene', '2932', (72, 81))	('Y216', 'Var', (91, 95))	('GSK-3beta', 'Gene', (72, 81))
18061	30643430	However, a series of safety issues arise regarding the use of chloroquine in oncology, due to the fact that it interferes with the homeostatic process of autophagy, which is pivotal for certain tissue, such as the myocardium and neuronal tissue.	('chloroquine', 'Chemical', 'MESH:D002738', (62, 73))	('interferes', 'NegReg', (111, 121))	('oncology', 'Phenotype', 'HP:0002664', (77, 85))	('chloroquine', 'Var', (62, 73))	('homeostatic process of autophagy', 'CPA', (131, 163))
18095	30643430	In addition, the completion of several ongoing clinical studies addressing the exploitability of chloroquine in oncology (eg, NCT01446016 and NCT02333890) and the publication of their results is much awaited.	('NCT02333890', 'Var', (142, 153))	('NCT01446016', 'Var', (126, 137))	('oncology', 'Phenotype', 'HP:0002664', (112, 120))	('chloroquine', 'Chemical', 'MESH:D002738', (97, 108))
18111	30399449	The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly metastatic and resistant to therapy.	('proliferation', 'CPA', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('self-renewal', 'CPA', (65, 77))	('CD133high', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('rat', 'Species', '10116', (86, 89))
18117	30399449	PROM1 mutations are harbored in the populations suffering from retinitis pigmentosa, macular degeneration and cone-rod retinal dystrophy.	('retinitis pigmentosa', 'Disease', (63, 83))	('retinal dystrophy', 'Disease', (119, 136))	('retinitis pigmentosa', 'Disease', 'MESH:D012174', (63, 83))	('retinal dystrophy', 'Disease', 'MESH:D058499', (119, 136))	('rod retinal dystrophy', 'Phenotype', 'HP:0000510', (115, 136))	('macular degeneration', 'Phenotype', 'HP:0000608', (85, 105))	('PROM1', 'Gene', (0, 5))	('rat', 'Species', '10116', (99, 102))	('PROM1', 'Gene', '8842', (0, 5))	('macular degeneration', 'Disease', (85, 105))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (119, 136))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (63, 83))	('cone-rod retinal dystrophy', 'Phenotype', 'HP:0000548', (110, 136))	('retinitis', 'Phenotype', 'HP:0032118', (63, 72))	('mutations', 'Var', (6, 15))
18121	30399449	This is because cancer cells that express high levels of CD133 are more metastatic and resistant to chemotherapy and radiation therapy.	('more', 'PosReg', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('metastatic', 'CPA', (72, 82))	('high levels', 'Var', (42, 53))	('cancer', 'Disease', (16, 22))	('CD133', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
18122	30399449	Given that CD133+ cells are capable of self-renewal, proliferation and differentiation into different types of cells, known as stem cell properties, CD133+ cancer cells are cancer stem cells (CSCs).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (173, 179))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CD133+', 'Var', (149, 155))
18138	30399449	A major body of evidence has demonstrated that the isolated CD133+ cancer cells from patients are capable of forming cancers in immune-comprised xenograft mice, implicating the involvement of CSCs in cancer initiation.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer initiation', 'Disease', 'MESH:D009369', (200, 217))	('CD133+', 'Var', (60, 66))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer initiation', 'Disease', (200, 217))	('rat', 'Species', '10116', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mice', 'Species', '10090', (155, 159))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (117, 123))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancer', 'Disease', (200, 206))	('cancers', 'Disease', (117, 124))
18140	30399449	It suggested that CD133+ colon cancer cells are the colon cancer initiating cells.	('colon cancer', 'Disease', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (25, 37))	('colon cancer', 'Disease', 'MESH:D015179', (25, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('CD133+', 'Var', (18, 24))	('colon cancer', 'Disease', (25, 37))
18143	30399449	In addition to recapitulating the parental heterogeneous cancer phenotype, the isolated CD133+ ovarian tumor cells have a higher tumor-forming ability in vivo as compared to the CD133- ovarian tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (57, 63))	('ovarian tumor', 'Phenotype', 'HP:0100615', (95, 108))	('ovarian tumor', 'Disease', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (129, 134))	('ovarian tumor', 'Disease', 'MESH:D010051', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (193, 198))	('CD133+', 'Var', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('higher', 'PosReg', (122, 128))	('ovarian tumor', 'Disease', (95, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ovarian tumor', 'Disease', 'MESH:D010051', (95, 108))	('ovarian tumor', 'Phenotype', 'HP:0100615', (185, 198))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
18145	30399449	It clearly showed that CD133 is sufficient to initiate tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CD133', 'Var', (23, 28))
18149	30399449	In several pancreatic cancer cell lines as well as human PDAC patient xenografts, FACS sorted CD133+ population was DCLK1high and acetylated alpha-tubulinhigh.	('PDAC', 'Disease', (57, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (11, 28))	('PDAC', 'Disease', 'MESH:D021441', (57, 61))	('alpha-tubulin', 'Gene', (141, 154))	('pancreatic cancer', 'Disease', (11, 28))	('DCLK1high', 'Var', (116, 125))	('patient', 'Species', '9606', (62, 69))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('human', 'Species', '9606', (51, 56))	('acetyl', 'Chemical', 'MESH:C011632', (130, 136))	('alpha-tubulin', 'Gene', '10376', (141, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
18151	30399449	In head and neck cancer initiating cells (HNCIC), knockdown of CD133 reduced the stemness gene expressions of OCT4 and NANOG, enhanced epithelial differentiation and promoted apoptosis.	('OCT4', 'Gene', (110, 114))	('NANOG', 'Gene', '79923', (119, 124))	('enhanced', 'PosReg', (126, 134))	('reduced', 'NegReg', (69, 76))	('apoptosis', 'CPA', (175, 184))	('knockdown', 'Var', (50, 59))	('NANOG', 'Gene', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('epithelial differentiation', 'CPA', (135, 161))	('cancer', 'Disease', (17, 23))	('stemness gene', 'Disease', (81, 94))	('stemness gene', 'Disease', 'MESH:D058495', (81, 94))	('promoted', 'PosReg', (166, 174))	('CD133', 'Gene', (63, 68))	('OCT4', 'Gene', '5460', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
18152	30399449	In addition, these effects were also observed in the tumor tissues from the shCD133 derived xenograft mice, indicating that CD133 initiates tumor formation via upregulation of cell stemness and downregulation of cell differentiation as well as cell death.	('cell stemness', 'CPA', (176, 189))	('mice', 'Species', '10090', (102, 106))	('downregulation', 'NegReg', (194, 208))	('upregulation', 'PosReg', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cell death', 'CPA', (244, 254))	('tumor', 'Disease', (53, 58))	('CD133', 'Var', (124, 129))	('cell differentiation', 'CPA', (212, 232))	('tumor', 'Disease', (140, 145))
18154	30399449	Primary heterogeneous glioblastoma can be derived from either CD133+ or CD133- CSCs.	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('CD133+', 'Var', (62, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('CD133-', 'Var', (72, 78))
18159	30399449	Blockade of Notch through its gene silencing or a gamma secretase inhibitor suppressed the glioblastoma tumor formation in the xenograted mice.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('rat', 'Species', '10116', (132, 135))	('gene silencing', 'Var', (30, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('mice', 'Species', '10090', (138, 142))	('suppressed', 'NegReg', (76, 86))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (91, 109))	('glioblastoma tumor', 'Disease', (91, 109))
18160	30399449	In addition, this Notch inhibition decreased several CSC markers including CD133, nestin, Bmi1 and OLIG2.	('Notch', 'Var', (18, 23))	('Bmi1', 'Gene', '648', (90, 94))	('OLIG2', 'Gene', (99, 104))	('nestin', 'Gene', '10763', (82, 88))	('decreased', 'NegReg', (35, 44))	('CD133', 'Gene', (75, 80))	('CSC', 'Disease', (53, 56))	('OLIG2', 'Gene', '10215', (99, 104))	('nestin', 'Gene', (82, 88))	('Bmi1', 'Gene', (90, 94))
18161	30399449	In a xenograft mouse model, the size of tumor derived from the high CD133+ HEK293 cells is dramatically larger than that from the low CD133+ HEK293 cells, suggesting that a role of CD133 in regulating cell growth during cancer development.	('high CD133+ HEK293', 'Var', (63, 81))	('HEK293', 'CellLine', 'CVCL:0045', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HEK293', 'CellLine', 'CVCL:0045', (141, 147))	('tumor', 'Disease', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancer', 'Disease', (220, 226))	('larger', 'PosReg', (104, 110))
18168	30399449	Knockout of DCLK1 specifically in the pancreas reduced KrasG12D-induced PanIN formations and the size of the formed PanIN lesions.	('DCLK1', 'Gene', (12, 17))	('PanIN', 'Disease', (116, 121))	('PanIN', 'Disease', 'MESH:D018290', (72, 77))	('KrasG12D-induced', 'Var', (55, 71))	('PanIN', 'Disease', (72, 77))	('PanIN', 'Disease', 'MESH:D018290', (116, 121))	('Knockout', 'Var', (0, 8))	('reduced', 'NegReg', (47, 54))
18174	30399449	Furthermore, inhibition of STAT3 by short hairpin RNA or pharmacological compounds, Stattic and LLL12 in this population decreased cancer cell metabolic activity, CD133 protein level and gene expressions that are associated with cell proliferation including cyclin D1, survivin, Bcl-2, and Notch.	('cancer', 'Disease', (131, 137))	('CD133 protein level', 'MPA', (163, 182))	('Bcl-2', 'Gene', (279, 284))	('Bcl-2', 'Gene', '596', (279, 284))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('decreased', 'NegReg', (121, 130))	('gene expressions', 'MPA', (187, 203))	('cyclin D1', 'Gene', '595', (258, 267))	('rat', 'Species', '10116', (241, 244))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cyclin D1', 'Gene', (258, 267))
18175	30399449	The STAT3 inhibition also led to a smaller size of the CD133+/ALDH+-generated xenograft tumors.	('rat', 'Species', '10116', (72, 75))	('inhibition', 'NegReg', (10, 20))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('CD133+/ALDH+-generated', 'Var', (55, 77))	('smaller', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
18181	30399449	In addition, overexpressed CD133 promotes the attachment of ovarian adenocarcinoma cells including Kuramochi, OVCA429 and Skov3IP cells to mesothelial cells in vitro and the mesothelium in ex vivo.	('promotes', 'PosReg', (33, 41))	('attachment of ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (46, 82))	('CD133', 'Gene', (27, 32))	('attachment of ovarian adenocarcinoma', 'Disease', (46, 82))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (60, 82))	('overexpressed', 'Var', (13, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
18183	30399449	CD133+ cancer cells selected from cultured human pancreatic cancer cell lines KP-2 and SUIT-2 showed elevated anchorage-independent growth as compared to the CD133-population in the same cell lines, implicating that CD133 promotes cancer cell transformation, invasiveness, and metastasis.	('promotes', 'PosReg', (222, 230))	('elevated', 'PosReg', (101, 109))	('CD133', 'Var', (216, 221))	('metastasis', 'CPA', (277, 287))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (231, 237))	('cancer', 'Disease', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('pancreatic cancer', 'Disease', (49, 66))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('invasiveness', 'CPA', (259, 271))	('cancer', 'Disease', (60, 66))	('anchorage-independent growth', 'CPA', (110, 138))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (43, 48))
18184	30399449	In addition, CXCR4 was highly expressed in these CD133+ isolated cells and knockdown of CXCR4 by small interfering RNA diminished CD133-mediated cell migration and invasion.	('small interfering', 'Var', (97, 114))	('diminished', 'NegReg', (119, 129))	('rat', 'Species', '10116', (153, 156))
18185	30399449	Similarly, as compared to the CD133+/CXCR4- cells isolated from a highly metastatic pancreatic cancer cell line L3.6pl, CD133+/CXCR4+ cells from the same parental cells were able to intravasate into the portal vein in a xenograft mouse model.	('mouse', 'Species', '10090', (230, 235))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('CD133+/CXCR4+', 'Var', (120, 133))	('pancreatic cancer', 'Disease', (84, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('intravasate into the portal vein', 'MPA', (182, 214))
18187	30399449	Silencing of CD133 in Capan1M9 cells that have high levels of endogenous CD133 inhibits Capan1M9-induced lung and liver metastases in mice possibly through downregulation of genes that modulate epithelial-mesenchymal transition (EMT) process such as Slug and N-Cadherin.	('Capan1M9-induced', 'Gene', (88, 104))	('mice', 'Species', '10090', (134, 138))	('downregulation', 'NegReg', (156, 170))	('CD133', 'Gene', (73, 78))	('Slug', 'Gene', (250, 254))	('inhibits', 'NegReg', (79, 87))	('Capan1M9', 'CellLine', 'CVCL:0A59', (88, 96))	('liver metastases', 'Disease', (114, 130))	('Capan1M9', 'CellLine', 'CVCL:0A59', (22, 30))	('Slug', 'Gene', '20583', (250, 254))	('liver metastases', 'Disease', 'MESH:D009362', (114, 130))	('Silencing', 'Var', (0, 9))	('CD133', 'Gene', (13, 18))
18189	30399449	It also has been shown that ectopically expressed CD133 induced EMT and more invasive cells of MIA PaCa-2 through activation of NF-kappaB.	('activation', 'PosReg', (114, 124))	('invasive cells of MIA PaCa-2', 'CPA', (77, 105))	('NF-kappaB', 'Protein', (128, 137))	('ectopically expressed', 'Var', (28, 49))	('induced', 'PosReg', (56, 63))	('CD133', 'Gene', (50, 55))	('more', 'PosReg', (72, 76))	('EMT', 'CPA', (64, 67))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))
18190	30399449	Furthermore, either silencing of PROM1 by shRNA technique or inhibition of NF-kappaB activation by introduction of an IKKbeta mutant or by a pharmacological BAY 11-7085 treatment, all of them abolished CD133 mediated invasiveness of MIA PaCa-2 cells.	('silencing', 'NegReg', (20, 29))	('abolished', 'NegReg', (192, 201))	('PROM1', 'Gene', (33, 38))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (157, 168))	('inhibition', 'NegReg', (61, 71))	('IKKbeta', 'Gene', '1147', (118, 125))	('IKKbeta', 'Gene', (118, 125))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (233, 243))	('PROM1', 'Gene', '8842', (33, 38))	('activation', 'PosReg', (85, 95))	('NF-kappaB', 'Protein', (75, 84))	('CD133 mediated invasiveness of MIA PaCa-2 cells', 'CPA', (202, 249))	('mutant', 'Var', (126, 132))
18195	30399449	Treating AsPC-1 cells with the EGFR inhibitor Gefitinib reversed the effect on cancer cell migration induced by ectopically expressed CD133.	('rat', 'Species', '10116', (94, 97))	('EGFR', 'Gene', '1956', (31, 35))	('ectopically expressed', 'Var', (112, 133))	('AsPC-1', 'CellLine', 'CVCL:0152', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('EGFR', 'Gene', (31, 35))	('Gefitinib', 'Chemical', 'MESH:C419708', (46, 55))	('CD133', 'Gene', (134, 139))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
18197	30399449	Of note, it has been shown that upon using the lineage tracing technique to track endogenous CD133+ cells in a transgenic mouse model during the development of colon cancer metastasis, CD133 is expressed in the colon cancer epithelium.	('colon cancer', 'Disease', 'MESH:D015179', (160, 172))	('colon cancer metastasis', 'Disease', (160, 183))	('colon cancer', 'Disease', (211, 223))	('colon cancer metastasis', 'Disease', 'MESH:D015179', (160, 183))	('CD133', 'Var', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('mouse', 'Species', '10090', (122, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (211, 223))	('colon cancer', 'Disease', 'MESH:D015179', (211, 223))
18217	30399449	Among them, colorectal cancer is the best reported cancer type for the presence of the CD133+/CD44+ population in the metastatic site liver at an early stage of the disease.	('colorectal cancer', 'Disease', (12, 29))	('rectal cancer', 'Phenotype', 'HP:0100743', (16, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CD133+/CD44+', 'Var', (87, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
18222	30399449	Overexpression of CD133 in a head and neck squamous cell carcinoma (HNSCC) cell line rendered the cells insensitive to 5-FU-or cisplatin-induced cell death.	('CD133', 'Gene', (18, 23))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (38, 66))	('neck squamous cell carcinoma', 'Disease', (38, 66))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (29, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))
18223	30399449	Furthermore, the CD133+ HNSCCs were arrested at the G0/G1 phase of the cell cycle in response to 5-FU and cisplatin treatment.	('CD133+', 'Var', (17, 23))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('HNSCCs', 'Disease', (24, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('HNSCCs', 'Disease', 'MESH:C535575', (24, 30))
18224	30399449	Similarly, ectopic expression of CD133 in rat C6 glioma cells increased the drug resistance of camptothecin and doxorubicin via upregulation of p-glycoprotein 1 (multidrug resistance protein 1/MDR1) transcription and ABC transporter activity.	('increased', 'PosReg', (62, 71))	('activity', 'MPA', (233, 241))	('upregulation', 'PosReg', (128, 140))	('transcription', 'MPA', (199, 212))	('CD133', 'Gene', (33, 38))	('MDR1', 'Gene', '24646', (193, 197))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('MDR1', 'Gene', (193, 197))	('p-glycoprotein 1', 'Gene', (144, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('ectopic expression', 'Var', (11, 29))	('glioma', 'Disease', (49, 55))	('multidrug resistance protein 1', 'Gene', '24646', (162, 192))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('ABC', 'Enzyme', (217, 220))	('drug resistance', 'Phenotype', 'HP:0020174', (167, 182))	('multidrug resistance protein 1', 'Gene', (162, 192))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('C6', 'CellLine', 'CVCL:X905', (46, 48))	('camptothecin', 'Chemical', 'MESH:D002166', (95, 107))	('p-glycoprotein 1', 'Gene', '24646', (144, 160))	('rat', 'Species', '10116', (42, 45))
18226	30399449	In cultured human gastric cancer cells, knockdown of CD133 rendered cells more sensitive to 5-FU induced cell death.	('gastric cancer', 'Disease', (18, 32))	('more', 'PosReg', (74, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('CD133', 'Gene', (53, 58))	('knockdown', 'Var', (40, 49))	('sensitive to 5-FU induced', 'MPA', (79, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('human', 'Species', '9606', (12, 17))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
18228	30399449	Blockade of this pathway via the PI3K/Akt inhibitor LY294002 in CD133-expressed gastric cancer cells has the same effect as shCD133-expressed cells in response to 5-FU treatment.	('gastric cancer', 'Disease', (80, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('LY294002', 'Var', (52, 60))	('PI3', 'Gene', (33, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('5-FU', 'Chemical', 'MESH:D005472', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('LY294002', 'Chemical', 'MESH:C085911', (52, 60))	('PI3', 'Gene', '5266', (33, 36))
18230	30399449	Colorectal cancer cells that are CD133high/CD44high survived better than CD133low/CD44low cancer cells after exposure to a high dose of gamma irradiation.	('survived', 'CPA', (52, 60))	('better', 'PosReg', (61, 67))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('rectal cancer', 'Phenotype', 'HP:0100743', (4, 17))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('Colorectal cancer', 'Disease', (0, 17))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (90, 96))	('CD133high/CD44high', 'Var', (33, 51))
18231	30399449	In addition, Akt expression was higher in the CD133high/CD44high cells as compared to the CD133low/CD44low cancer cells.	('CD133high/CD44high', 'Var', (46, 64))	('higher', 'PosReg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('Akt', 'Pathway', (13, 16))
18234	30399449	Given that CD133 plays a pivotal role in regulating cancer metastasis and therapeutic resistance and that both of cancer metastasis and drug resistance are the major contributors to cancer death, targeting CD133 in cancer patients who have metastatic disease would be the best strategy to bring down the death toll of cancer.	('cancer', 'Disease', (318, 324))	('cancer metastasis', 'Disease', (52, 69))	('patients', 'Species', '9606', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (215, 221))	('cancer metastasis', 'Disease', (114, 131))	('cancer', 'Disease', (182, 188))	('cancer death', 'Disease', 'MESH:D003643', (182, 194))	('cancer metastasis', 'Disease', 'MESH:D009362', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('CD133', 'Gene', (206, 211))	('drug resistance', 'Phenotype', 'HP:0020174', (136, 151))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer metastasis', 'Disease', 'MESH:D009362', (114, 131))	('cancer death', 'Disease', (182, 194))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('targeting', 'Var', (196, 205))	('rat', 'Species', '10116', (279, 282))	('cancer', 'Disease', (114, 120))
18242	30399449	The in vitro effect of CD133-MMAF conjugates was verified in Hep3B xenografted SCID mice that anti-CD133-MMAF treatment delayed tumor growth in vivo.	('SCID', 'Gene', (79, 83))	('anti-CD133-MMAF', 'Var', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('delayed', 'NegReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('SCID', 'Gene', '19090', (79, 83))	('Hep3B', 'CellLine', 'CVCL:0326', (61, 66))	('mice', 'Species', '10090', (84, 88))
18243	30399449	Another invention includes to conjugate anti-CD133 monoclonal antibody to nanoparticles that were loaded with anti-cancer drug paclitaxel.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('anti-CD133', 'Var', (40, 50))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
18248	30399449	CART-CD133 treatment has been tested in CD133high glioblastoma stem cells in vitro and in an orthotopic tumor model in vivo.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CART-CD133', 'Gene', (0, 10))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('CD133high', 'Var', (40, 49))	('CART-CD133', 'Gene', '8842', (0, 10))	('tumor', 'Disease', (104, 109))	('glioblastoma', 'Disease', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
18261	30399449	It would be of most importance to evaluate if the blockade of CD133 alternatively results in selections for other cancer stem cell markers that could compensate the loss of CD133, and what the final outcome of cancer metastasis as well as drug resistance is in animal models capitulating human cancers.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('loss', 'Var', (165, 169))	('blockade', 'Var', (50, 58))	('human', 'Species', '9606', (288, 293))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancer metastasis', 'Disease', (210, 227))	('cancer', 'Disease', (294, 300))	('cancers', 'Disease', (294, 301))	('results in', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('CD133', 'Gene', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('CD133', 'Gene', (173, 178))	('cancer metastasis', 'Disease', 'MESH:D009362', (210, 227))	('drug resistance', 'Phenotype', 'HP:0020174', (239, 254))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (114, 120))
18263	29987920	Aberrant methylation and silencing of the SPINT2 gene in high-grade gliomas Hepatocyte growth factor activator inhibitor type 2 (HAI-2), encoded by the SPINT2 gene, is a membrane-anchored protein that inhibits proteases involved in the activation of hepatocyte growth factor (HGF), a ligand of MET receptor.	('methylation', 'Var', (9, 20))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('SPINT2', 'Gene', (152, 158))	('Aberrant', 'Var', (0, 8))	('SPINT2', 'Gene', '10653', (152, 158))	('inhibits', 'NegReg', (201, 209))	('proteases', 'Enzyme', (210, 219))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (68, 75))	('SPINT2', 'Gene', (42, 48))	('Hepatocyte growth factor activator inhibitor type 2', 'Gene', '10653', (76, 127))	('SPINT2', 'Gene', '10653', (42, 48))	('silencing', 'NegReg', (25, 34))
18264	29987920	Epigenetic silencing of the SPINT2 gene has been reported in a human glioblastoma cell line (U87) and glioblastoma-derived cancer stem cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (63, 68))	('glioblastoma', 'Disease', (102, 114))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('SPINT2', 'Gene', (28, 34))	('cancer', 'Disease', (123, 129))	('Epigenetic silencing', 'Var', (0, 20))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
18267	29987920	Most glioblastoma lines (7/8) showed methylation of the SPINT2 gene with a significantly reduced level of SPINT2 mRNA compared to cultured astrocytes and normal brain tissues.	('glioblastoma', 'Disease', (5, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (5, 17))	('methylation', 'Var', (37, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (5, 17))	('level', 'MPA', (97, 102))	('reduced', 'NegReg', (89, 96))	('SPINT2 mRNA', 'MPA', (106, 117))	('SPINT2', 'Gene', (56, 62))
18268	29987920	However, all glioblastoma lines expressed mRNA for HGF activator (HGFAC), a target protease of HAI-2/SPINT2.	('HGF activator', 'Gene', '3083', (51, 64))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('HGF activator', 'Gene', (51, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('HGFAC', 'Gene', (66, 71))	('mRNA', 'Var', (42, 46))	('HGFAC', 'Gene', '3083', (66, 71))
18272	29987920	In summary, aberrant methylation of the SPINT2 gene is frequently observed in high-grade gliomas and might confer MET signaling in the glioma cells.	('observed', 'Reg', (66, 74))	('aberrant methylation', 'Var', (12, 32))	('glioma', 'Disease', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('confer', 'Reg', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('SPINT2', 'Gene', (40, 46))	('methylation', 'Var', (21, 32))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('MET signaling', 'MPA', (114, 127))	('glioma', 'Disease', (89, 95))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('glioma', 'Disease', 'MESH:D005910', (135, 141))
18282	29987920	U251, YKG1, T98G, A172, and KS1 were obtained from the Riken Cell Bank (Tsukuba, Japan).	('KS1', 'Gene', '84911', (28, 31))	('T98G', 'Var', (12, 16))	('KS1', 'Gene', (28, 31))
18312	29987920	The results of both MSP (Figure 1D) and bisulfite sequencing (Figure 1E) were consistent with the SPINT2 expression status observed by RT-PCR analysis, suggesting that HAI-2/SPINT2 is epigenetically downregulated in glioblastoma cell lines by hypermethylation of the SPINT2 gene.	('SPINT2', 'Gene', (267, 273))	('downregulated', 'NegReg', (199, 212))	('bisulfite', 'Chemical', 'MESH:C042345', (40, 49))	('glioblastoma', 'Disease', (216, 228))	('glioblastoma', 'Disease', 'MESH:D005909', (216, 228))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('hypermethylation', 'Var', (243, 259))	('HAI-2/SPINT2', 'Var', (168, 180))
18317	29987920	The forced SPINT2 expression alleviated the mortality, as observed in the Kaplan-Meier survival curves of the implanted mice, although the difference was not statistically significant as determined with a log-rank test (Figure 2C).	('mice', 'Species', '10090', (120, 124))	('alleviated', 'NegReg', (29, 39))	('mortality', 'CPA', (44, 53))	('SPINT2', 'Gene', (11, 17))	('expression', 'Var', (18, 28))
18321	29987920	Whereas methylation of the SPINT2 gene has been reported in cultured glioblastoma cells, its incidence in human glioma tissues in vivo is unknown.	('human', 'Species', '9606', (106, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('reported', 'Reg', (48, 56))	('glioma', 'Disease', (112, 118))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('SPINT2', 'Gene', (27, 33))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('methylation', 'Var', (8, 19))
18325	29987920	Methylation of the SPINT2 gene was observed in 33.3% (2/6), 71.4% (10/14), and 74.3% (26/35) of grade II, grade III, and grade IV tumors, respectively (Table 1).	('Methylation', 'Var', (0, 11))	('SPINT2', 'Gene', (19, 25))	('IV tumors', 'Disease', 'MESH:D009369', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('IV tumors', 'Disease', (127, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('observed', 'Reg', (35, 43))
18331	29987920	However, most cases of MGMT-methylated high-grade gliomas showed SPINT2 methylation (14/16) (Table 2).	('gliomas', 'Disease', (50, 57))	('SPINT2 methylation', 'Var', (65, 83))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('MGMT', 'Gene', '4255', (23, 27))	('MGMT', 'Gene', (23, 27))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
18339	29987920	In accordance with previous reports using U87 cells,14, 15 most glioblastoma cell lines showed methylation of the SPINT2 gene, and that reversion of SPINT2 expression in glioblastoma cell lines (U87, U251, and T98G) suppressed the growth rate in vitro.	('SPINT2', 'Gene', (114, 120))	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('methylation', 'Var', (95, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('reversion', 'Var', (136, 145))	('growth rate in vitro', 'CPA', (231, 251))	('suppressed', 'NegReg', (216, 226))	('glioblastoma', 'Disease', (170, 182))	('SPINT2', 'Gene', (149, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (170, 182))
18346	29987920	The analyses confirmed the high incidence of SPINT2 methylation in high-grade gliomas (grades III and IV).	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('gliomas', 'Disease', (78, 85))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('methylation', 'Var', (52, 63))	('SPINT2', 'Gene', (45, 51))
18351	29987920	Alternatively, the expression level of the target proteases of HAI-2/SPINT2, such as HGFA, in glioma cells with SPINT2 methylation could be an important determinant in the patient's prognosis.	('HGFA', 'Gene', (85, 89))	('glioma', 'Disease', (94, 100))	('HAI-2/SPINT2', 'Gene', (63, 75))	('patient', 'Species', '9606', (172, 179))	('methylation', 'Var', (119, 130))	('expression level', 'MPA', (19, 35))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))
18362	29864158	Furthermore, high DSE expression was associated with advanced tumor grade and poor survival.	('high', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
18363	29864158	We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells.	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('DS chain formation', 'MPA', (102, 120))	('glioblastoma', 'Disease', (124, 136))	('DSE', 'Var', (69, 72))	('DS', 'Chemical', 'MESH:D003871', (102, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('mediated', 'Reg', (93, 101))	('DS', 'Chemical', 'MESH:D003871', (69, 71))	('DS', 'Chemical', 'MESH:D003871', (14, 16))	('DSE', 'MPA', (14, 17))	('glioblastoma', 'Disease', (40, 52))
18375	29864158	The aberrant expression of extracellular matrix (ECM) proteins and an abnormal glycan composition in the tumor microenvironment are hallmarks of all types of cancer.	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('glycan', 'Chemical', 'MESH:D011134', (79, 85))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('extracellular', 'Protein', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('glycan composition', 'MPA', (79, 97))
18386	29864158	Moreover, a recent study revealed that cleaving CS chains increases the availability of temozolomide and its effectiveness on glioma cells.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('increases', 'PosReg', (58, 67))	('CS', 'Chemical', 'MESH:D002809', (48, 50))	('CS chains', 'Protein', (48, 57))	('cleaving', 'Var', (39, 47))	('effectiveness', 'MPA', (109, 122))	('availability of temozolomide', 'MPA', (72, 100))	('glioma', 'Disease', (126, 132))	('temozolomide', 'Chemical', 'MESH:D000077204', (88, 100))
18391	29864158	Overexpression of DS epimerase 1 in squamous cell carcinoma increases levels of DS chains in cancer tissue, which can mediate hepatocyte growth factor (HGF) signaling.	('HGF', 'Gene', '3082', (152, 155))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('levels of DS chains', 'MPA', (70, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 59))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Disease', (36, 59))	('HGF', 'Gene', (152, 155))	('DS', 'Chemical', 'MESH:D003871', (80, 82))	('increases', 'PosReg', (60, 69))	('DS', 'Chemical', 'MESH:D003871', (18, 20))
18393	29864158	These findings point to the oncogenic function of aberrant CS/DS chains in many types of tumor cells.	('CS', 'Chemical', 'MESH:D002809', (59, 61))	('CS/DS chains', 'Protein', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('DS', 'Chemical', 'MESH:D003871', (62, 64))	('aberrant', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
18399	29864158	Two pLKO.1/DSE-shRNA plasmids (DSE sh1, 5'- CAGAAAGAACTACCCATAGAT -3'; DSE sh2, 5'- CAGAAAGAACTACCCATAGAT -3') and nontargeting pLKO.1 plasmids were purchased from National RNAi Core Facility (Academia Sinica, Taipei, Taiwan).	('Academia Sinica', 'Disease', 'None', (193, 208))	('Academia Sinica', 'Disease', (193, 208))	('DSE sh2', 'Var', (71, 78))
18429	29864158	Furthermore, a search of the REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) database revealed that high expression of DSE is associated with worse overall survival in glioma patients (n = 329), whereas DSEL expression does not correlate with patient outcomes (S1 Fig).	('DSE', 'Gene', (129, 132))	('patient', 'Species', '9606', (253, 260))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('BRAin Neoplasia', 'Phenotype', 'HP:0030692', (54, 69))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('worse', 'NegReg', (152, 157))	('patient', 'Species', '9606', (185, 192))	('Neoplasia DaTa', 'Disease', (60, 74))	('Neoplasia', 'Phenotype', 'HP:0002664', (60, 69))	('DSEL', 'Gene', '92126', (213, 217))	('overall survival', 'MPA', (158, 174))	('DSEL', 'Gene', (213, 217))	('patients', 'Species', '9606', (185, 193))	('high expression', 'Var', (110, 125))	('Neoplasia DaTa', 'Disease', 'MESH:D009369', (60, 74))	('glioma', 'Disease', (178, 184))
18434	29864158	Furthermore, high DSE expression in glioma tissue was associated with the worst histologic grade (Table 1).	('high', 'Var', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('glioma', 'Disease', (36, 42))	('glioma', 'Disease', 'MESH:D005910', (36, 42))
18438	29864158	We knocked down DSE in U118 cells and overexpressed it in GL261 cells to investigate the functions of DSE in DS formation.	('DS', 'Chemical', 'MESH:D003871', (16, 18))	('DS', 'Chemical', 'MESH:D003871', (109, 111))	('knocked', 'Var', (3, 10))	('DS', 'Chemical', 'MESH:D003871', (102, 104))	('DSE', 'Gene', (16, 19))
18439	29864158	In addition, we found that DSE knockdown reduced the binding of the DS-binding protein to proteoglycans in the U118 cells (Fig 2B), whereas overexpression of DSE enhanced the DS-binding protein signals in the GL261 cells (Fig 2C).	('reduced', 'NegReg', (41, 48))	('proteoglycans', 'Protein', (90, 103))	('glycan', 'Chemical', 'MESH:D011134', (96, 102))	('DSE', 'Gene', (27, 30))	('DS', 'Chemical', 'MESH:D003871', (68, 70))	('DS', 'Chemical', 'MESH:D003871', (158, 160))	('DS-binding protein', 'Protein', (68, 86))	('DS-binding protein signals', 'MPA', (175, 201))	('enhanced', 'PosReg', (162, 170))	('DS', 'Chemical', 'MESH:D003871', (175, 177))	('DS', 'Chemical', 'MESH:D003871', (27, 29))	('binding', 'Interaction', (53, 60))	('knockdown', 'Var', (31, 40))
18440	29864158	Furthermore, the DS ELISA assay showed that DSE knockdown decreased DS in cell lysates, whereas DSE overexpression increased DS quantity in cell lysate (Fig 2D).	('DS quantity', 'MPA', (125, 136))	('increased', 'PosReg', (115, 124))	('decreased', 'NegReg', (58, 67))	('DS in cell lysates', 'MPA', (68, 86))	('DS', 'Chemical', 'MESH:D003871', (68, 70))	('DS', 'Chemical', 'MESH:D003871', (44, 46))	('DS', 'Chemical', 'MESH:D003871', (17, 19))	('DSE', 'Gene', (44, 47))	('DS', 'Chemical', 'MESH:D003871', (96, 98))	('DS', 'Chemical', 'MESH:D003871', (125, 127))	('knockdown', 'Var', (48, 57))
18445	29864158	These data indicate that DSE can modulate the cell viability, colony formation, cell migration and invasion, and in vivo tumor growth of glioma cells.	('colony formation', 'CPA', (62, 78))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('tumor', 'Disease', (121, 126))	('DSE', 'Var', (25, 28))	('modulate', 'Reg', (33, 41))	('cell migration', 'CPA', (80, 94))	('invasion', 'CPA', (99, 107))	('glioma', 'Disease', (137, 143))	('cell viability', 'CPA', (46, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
18446	29864158	Aberrations in the ErbB pathway are the most common causes of alterations in human gliomas, and CS/DS hybrid chains have the ability to interact with several growth factors.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('ErbB', 'Gene', (19, 23))	('ErbB', 'Gene', '1956', (19, 23))	('Aberrations', 'Var', (0, 11))	('DS', 'Chemical', 'MESH:D003871', (99, 101))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('interact', 'Interaction', (136, 144))	('CS', 'Chemical', 'MESH:D002809', (96, 98))	('human', 'Species', '9606', (77, 82))
18449	29864158	We found that DSE knockdown in U118 cells selectively suppressed HB-EGF-triggered downstream ERK and AKT activation, whereas no obvious differences were observed following NRG1 and EGF treatment (Fig 4A and S5 Fig).	('AKT', 'Pathway', (101, 104))	('knockdown', 'Var', (18, 27))	('NRG1', 'Gene', '3084', (172, 176))	('suppressed', 'NegReg', (54, 64))	('activation', 'PosReg', (105, 115))	('HB-EGF-triggered', 'Gene', (65, 81))	('NRG1', 'Gene', (172, 176))
18461	29864158	DSE knockdown suppresses malignant phenotypes, whereas DSE overexpression enhances glioma cell malignancy, both in vitro and in vivo.	('overexpression enhances', 'PosReg', (59, 82))	('DSE', 'Gene', (55, 58))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('glioma cell malignancy', 'Disease', (83, 105))	('malignant phenotypes', 'CPA', (25, 45))	('glioma cell malignancy', 'Phenotype', 'HP:0012174', (83, 105))	('knockdown', 'Var', (4, 13))	('glioma cell malignancy', 'Disease', 'MESH:D005910', (83, 105))	('suppresses', 'NegReg', (14, 24))
18470	29864158	CS/DS hybrid chains have greater structural flexibility than pure CS chains, and have greater affinity for various heparin-binding growth factors.	('heparin', 'Chemical', 'MESH:D006493', (115, 122))	('CS', 'Chemical', 'MESH:D002809', (66, 68))	('structural flexibility', 'MPA', (33, 55))	('affinity', 'Interaction', (94, 102))	('greater', 'PosReg', (25, 32))	('heparin-binding', 'Protein', (115, 130))	('CS/DS hybrid', 'Var', (0, 12))	('DS', 'Chemical', 'MESH:D003871', (3, 5))	('CS', 'Chemical', 'MESH:D002809', (0, 2))
18474	29864158	It has been proposed that DSE promotes DS formation, resulting in enhanced HGF binding to the cell surface and the activation of downstream signaling in esophagus cancer cells.	('DS', 'Chemical', 'MESH:D003871', (39, 41))	('activation', 'PosReg', (115, 125))	('DSE', 'Var', (26, 29))	('HGF', 'Gene', '3082', (75, 78))	('DS', 'Chemical', 'MESH:D003871', (26, 28))	('esophagus cancer', 'Disease', (153, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('enhanced', 'PosReg', (66, 74))	('esophagus cancer', 'Disease', 'MESH:D004938', (153, 169))	('HGF', 'Gene', (75, 78))	('downstream signaling', 'MPA', (129, 149))
18476	29864158	Importantly, we report for the first time that DSE selectively regulates HB-EGF-induced signaling, but not EGF and NRG1, implying that changes to DS could modulate the activity of HB-EGF or its affinity for EGFR/ErbB2 receptors.	('activity', 'MPA', (168, 176))	('changes', 'Var', (135, 142))	('affinity', 'Interaction', (194, 202))	('NRG1', 'Gene', '3084', (115, 119))	('DS', 'Chemical', 'MESH:D003871', (47, 49))	('HB-EGF-induced signaling', 'MPA', (73, 97))	('EGFR/ErbB2', 'Protein', (207, 217))	('regulates', 'Reg', (63, 72))	('HB-EGF', 'Protein', (180, 186))	('NRG1', 'Gene', (115, 119))	('DS', 'Chemical', 'MESH:D003871', (146, 148))	('modulate', 'Reg', (155, 163))
18485	29864158	The present study demonstrates a pathophysiologic role of DSE in glioblastoma cells, and elucidates the biological functions of aberrant CS/DS expression in glioma progression.	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('DS', 'Chemical', 'MESH:D003871', (140, 142))	('aberrant', 'Var', (128, 136))	('glioblastoma', 'Disease', (65, 77))	('DS', 'Chemical', 'MESH:D003871', (58, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (65, 77))	('glioma', 'Disease', (157, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('CS', 'Chemical', 'MESH:D002809', (137, 139))
18504	27557493	We show that BBR induces autophagy and impairs the glycolytic capacity.	('induces', 'Reg', (17, 24))	('impairs', 'NegReg', (39, 46))	('BBR', 'Var', (13, 16))	('autophagy', 'CPA', (25, 34))	('BBR', 'Chemical', 'MESH:D001599', (13, 16))	('glycolytic capacity', 'CPA', (51, 70))
18516	27557493	Taken together, these results supports that BBR reduces cell viability by inducing Cytochrome C mediated apoptotic cell death.	('BBR', 'Var', (44, 47))	('Cytochrome C', 'Gene', (83, 95))	('BBR', 'Chemical', 'MESH:D001599', (44, 47))	('Cytochrome C', 'Gene', '54205', (83, 95))	('cell viability', 'CPA', (56, 70))	('inducing', 'PosReg', (74, 82))	('reduces', 'NegReg', (48, 55))
18531	27557493	Corresponding results were found for LDH, further strengthening that BBR reduced the glycolytic activity (Figure 4B).	('reduced', 'NegReg', (73, 80))	('BBR', 'Var', (69, 72))	('BBR', 'Chemical', 'MESH:D001599', (69, 72))	('glycolytic activity', 'MPA', (85, 104))
18539	27557493	Taken together, these results demonstrate that BBR attenuates glycolysis dependent energy production and induced mitochondrial dysfunction.	('induced', 'Reg', (105, 112))	('BBR', 'Var', (47, 50))	('BBR', 'Chemical', 'MESH:D001599', (47, 50))	('attenuates', 'NegReg', (51, 61))	('glycolysis dependent energy production', 'MPA', (62, 100))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (113, 138))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (113, 138))	('mitochondrial dysfunction', 'Disease', (113, 138))
18551	27557493	Previous studies has shown that activation of mTOR impairs autophagy and pharmacological mTOR inhibitors induce autophagy in most model systems.	('mTOR', 'Gene', '2475', (89, 93))	('autophagy', 'CPA', (59, 68))	('mTOR', 'Gene', '2475', (46, 50))	('mTOR', 'Gene', (46, 50))	('impairs', 'NegReg', (51, 58))	('induce', 'Reg', (105, 111))	('activation', 'Var', (32, 42))	('autophagy', 'CPA', (112, 121))	('mTOR', 'Gene', (89, 93))
18556	27557493	This was followed by increased levels of Beclin-1, which is directly dependent on phosphorylation at Ser93 or Ser96 by AMPK.	('levels', 'MPA', (31, 37))	('AMPK', 'Gene', '5563', (119, 123))	('increased', 'PosReg', (21, 30))	('Ser93', 'Chemical', '-', (101, 106))	('Beclin-1', 'Gene', (41, 49))	('AMPK', 'Gene', (119, 123))	('Beclin-1', 'Gene', '8678', (41, 49))	('Ser96', 'Chemical', '-', (110, 115))	('Ser93', 'Var', (101, 106))	('Ser96', 'Var', (110, 115))
18560	27557493	As shown in Figure 6C, knockdown of Beclin-1 prevented BBR-induced autophagy flux compared with the siRNA control group.	('autophagy flux', 'CPA', (67, 81))	('knockdown', 'Var', (23, 32))	('prevented', 'NegReg', (45, 54))	('BBR-induced', 'Disease', (55, 66))	('BBR', 'Chemical', 'MESH:D001599', (55, 58))	('Beclin-1', 'Gene', (36, 44))	('Beclin-1', 'Gene', '8678', (36, 44))
18582	27557493	Berberine chloride (BBR), Bafilomycin A1 (Baf), chloroquine (CQ), AMPK inhibitor Compound C (Comp C) and Dimethyl sulfoxide (DMSO) were obtained from Sigma-Aldrich, USA (PHR1502, B1793, C6628, P5499, D2650).	('PHR1502', 'Chemical', '-', (170, 177))	('AMPK', 'Gene', '5563', (66, 70))	('C6628', 'Var', (186, 191))	('BBR', 'Chemical', 'MESH:D001599', (20, 23))	('D2650', 'Var', (200, 205))	('Baf', 'Gene', (26, 29))	('Berberine chloride', 'Chemical', '-', (0, 18))	('Bafilomycin A1', 'Gene', '8815', (26, 40))	('Baf', 'Gene', (42, 45))	('B1793', 'Var', (179, 184))	('Baf', 'Gene', '8815', (26, 29))	('AMPK', 'Gene', (66, 70))	('DMSO', 'Chemical', 'MESH:D004121', (125, 129))	('Baf', 'Gene', '8815', (42, 45))	('P5499', 'Var', (193, 198))	('Bafilomycin A1', 'Gene', (26, 40))	('chloroquine', 'Chemical', 'MESH:D002738', (48, 59))	('Dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (105, 123))	('CQ', 'Chemical', 'MESH:D002738', (61, 63))	('PHR1502', 'Var', (170, 177))
18599	27557493	The mitochondrial membrane potential was analyzed using an Olympus BX61 fluorescence microscope and fluorescence intensity ratio of JC-1 aggregates to JC-1 monomers (ratio of 590:530 nm emission intensity).	('JC-1', 'Gene', (132, 136))	('aggregates', 'Var', (137, 147))	('JC-1', 'Chemical', 'MESH:C068624', (151, 155))	('JC-1', 'Chemical', 'MESH:C068624', (132, 136))
18678	26223282	MGMT methylation status significantly influenced OS in the reference group (methylated: 25.2 months vs. non-methylated: 15.4 months; p = 0.04), whereas this, in no way, influenced survival for the study group (p = 0.129).	('MGMT', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('OS', 'Chemical', '-', (49, 51))	('influenced', 'Reg', (169, 179))	('influenced', 'Reg', (38, 48))	('MGMT', 'Gene', '4255', (0, 4))
18680	26223282	However, delaying radiotherapy had a significant protective effect on death rates, with a Hazard ratio of 0.95 (95 % CI: 0.90-1.00; p = 0.044) (Table 5).	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('delaying', 'Var', (9, 17))
18692	26223282	These unexpected findings might be explained by the fact that postoperative radiotherapy is typically initiated more immediately for advanced tumours, thus contributing to the larger number of patients in the sample with KPS <= 70.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('patients', 'Species', '9606', (193, 201))	('tumours', 'Disease', (142, 149))	('KPS <= 70', 'Var', (221, 230))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))
18709	25849940	Here, we show that intravenously injected spores of C. novyi-NT led to dramatic tumor destructions and significant survival increases in implanted, intracranial syngeneic F98 and human xenograft 060919 rat GBM models.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('C. novyi-NT', 'Species', '386415', (52, 63))	('human', 'Species', '9606', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('increases', 'PosReg', (124, 133))	('tumor', 'Disease', (80, 85))	('survival', 'CPA', (115, 123))	('rat', 'Species', '10116', (202, 205))	('C. novyi-NT', 'Var', (52, 63))
18728	25849940	Previous studies showed that a single dose of C. novyi-NT spores injected intravenously in syngeneic tumor-bearing animals often led to localized tumor necrosis and oncolysis, leading to cures in up to one-third of treated animals, without excessive toxicity.	('C. novyi-NT', 'Var', (46, 57))	('toxicity', 'Disease', 'MESH:D064420', (250, 258))	('toxicity', 'Disease', (250, 258))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('C. novyi-NT', 'Species', '386415', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (146, 151))	('localized tumor necrosis', 'Disease', 'MESH:D009336', (136, 160))	('cures', 'CPA', (187, 192))	('oncolysis', 'CPA', (165, 174))	('led to', 'Reg', (129, 135))	('localized tumor necrosis', 'Disease', (136, 160))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
18751	25849940	In the syngeneic F98 GBM model, the combination of Lip-DXR and C. novyi-NT increased the survival modestly compared to C. novyi-NT alone (Fig.	('C. novyi-NT', 'Species', '386415', (119, 130))	('C. novyi-NT', 'Var', (63, 74))	('Lip-DXR', 'Var', (51, 58))	('increased', 'PosReg', (75, 84))	('C. novyi-NT', 'Species', '386415', (63, 74))
18752	25849940	Tumors treated with C. novyi-NT spores plus Lip-DXR had improved tumor clearance, as exemplified by the lower number of viable tumor cells, particularly in the periphery (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (127, 132))	('improved', 'PosReg', (56, 64))	('C. novyi-NT', 'Var', (20, 31))	('lower', 'NegReg', (104, 109))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('C. novyi-NT', 'Species', '386415', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
18777	25849940	In our study, the majority of rats treated with C. novyi-NT developed lethargy and signs of increased intracranial pressure due to local inflammation-driven edema that were medically manageable with the use of steroids and antibiotics, but the dangers of treating rats with intracranial tumors were evident.	('rats', 'Species', '10116', (30, 34))	('edema', 'Disease', 'MESH:D004487', (157, 162))	('increased', 'PosReg', (92, 101))	('lethargy', 'Disease', 'MESH:D053609', (70, 78))	('intracranial tumors', 'Disease', (274, 293))	('edema', 'Disease', (157, 162))	('intracranial tumors', 'Disease', 'MESH:D001932', (274, 293))	('inflammation', 'Disease', 'MESH:D007249', (137, 149))	('rats', 'Species', '10116', (264, 268))	('intracranial pressure', 'MPA', (102, 123))	('increased intracranial pressure', 'Phenotype', 'HP:0002516', (92, 123))	('inflammation', 'Disease', (137, 149))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('C. novyi-NT', 'Species', '386415', (48, 59))	('steroids', 'Chemical', 'MESH:D013256', (210, 218))	('lethargy', 'Disease', (70, 78))	('lethargy', 'Phenotype', 'HP:0001254', (70, 78))	('edema', 'Phenotype', 'HP:0000969', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('C. novyi-NT', 'Var', (48, 59))
18781	25849940	Intravenous administration of C. novyi-NT enhances the effect of chemotherapy, particularly of hypoxia-enhancing agents, and radiation.	('hypoxia', 'Disease', (95, 102))	('C. novyi-NT', 'Var', (30, 41))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('C. novyi-NT', 'Species', '386415', (30, 41))	('enhances', 'PosReg', (42, 50))	('effect', 'MPA', (55, 61))	('rat', 'Species', '10116', (20, 23))
18782	25849940	Consistent with those data, treatment with C. novyi-NT and liposomal doxorubicin resulted in a slightly increased survival benefit due to enhanced cytotoxicity.	('C. novyi-NT', 'Var', (43, 54))	('survival benefit', 'CPA', (114, 130))	('increased', 'PosReg', (104, 113))	('cytotoxicity', 'Disease', (147, 159))	('C. novyi-NT', 'Species', '386415', (43, 54))	('enhanced', 'PosReg', (138, 146))	('cytotoxicity', 'Disease', 'MESH:D064420', (147, 159))	('doxorubicin', 'Chemical', 'MESH:D004317', (69, 80))
18784	25849940	It has been demonstrated that long-term response to C. novyi-NT involves an immunologic T-cell based recognition that likely includes tumor antigens.	('C. novyi-NT', 'Species', '386415', (52, 63))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('C. novyi-NT', 'Var', (52, 63))	('tumor', 'Disease', (134, 139))
18793	25849940	The tumors were allowed to grow until day 25 (060919) or 15 (F98), when 3x108C.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('060919', 'Var', (46, 52))
18863	25569113	Would inhibition of tenascin-C expression be sufficient to prevent tumor onset and/or counteract tumor progression?	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tenascin-C', 'Protein', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (97, 102))	('prevent', 'NegReg', (59, 66))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', (67, 72))
18903	25569113	Here, we will focus on the antibody F16 since it had reached the most advanced application in clinical trials for cancer therapy and new results have been reported recently (see also Catania et al., this issue of Cell Adhesion & Migration).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('F16', 'Var', (36, 39))	('cancer', 'Disease', (114, 120))
18904	25569113	A fully humanized antibody F16 that specifically recognizes the domain A1 of tenascin-C (generated by alternative splicing) has been developed by the company Philogen.	('human', 'Species', '9606', (8, 13))	('tenascin-C', 'Gene', (77, 87))	('domain A1', 'Var', (64, 73))
18940	25569113	Using the SELEX technology on tenascin-C expressing U251 glioblastoma cells or on purified tenascin-C the aptamer "TTA1" was generated that showed high specificity and selectivity for human tenascin-C. Further modifications improved biodistribution and led to the design of radionuclide labeled 99mTc-TTA1.	('improved', 'PosReg', (224, 232))	('glioblastoma', 'Disease', (57, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('modifications', 'Var', (210, 223))	('U251', 'CellLine', 'CVCL:0021', (52, 56))	('biodistribution', 'MPA', (233, 248))	('Tc', 'Chemical', 'MESH:D013667', (298, 300))	('radionuclide', 'Chemical', 'MESH:D011868', (274, 286))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('human', 'Species', '9606', (184, 189))
18941	25569113	Upon intravenous injection into tumor bearing nude mice 99mTc-TTA1 specifically had accumulated in the GBM xenograft tumor, as well as in tumors induced by human colon, breast and rhabdomyosarcoma cells.	('tumor', 'Disease', (138, 143))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (180, 196))	('99mTc-TTA1', 'Var', (56, 66))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (180, 196))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('nude mice', 'Species', '10090', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', (32, 37))	('Tc', 'Chemical', 'MESH:D013667', (59, 61))	('rhabdomyosarcoma', 'Disease', (180, 196))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('accumulated', 'PosReg', (84, 95))	('tumors', 'Disease', (138, 144))	('human', 'Species', '9606', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
18961	25569113	The vaccine is composed of a recombinant protein (e.g., C-domain of tenascin-C) fused to bacterial thioredoxin.	('thioredoxin', 'Gene', '7295', (99, 110))	('tenascin-C', 'Gene', (68, 78))	('C-domain', 'Var', (56, 64))	('thioredoxin', 'Gene', (99, 110))
18963	25569113	Vaccination of mice and rabbits against the C-domain of tenascin-C induced high serum titers of specific antibodies to the target but its effect in preclinical cancer models is not yet reported.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('C-domain', 'Var', (44, 52))	('tenascin-C', 'Gene', (56, 66))	('serum titers', 'MPA', (80, 92))	('rabbits', 'Species', '9986', (24, 31))	('high serum titers', 'Phenotype', 'HP:0010702', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mice', 'Species', '10090', (15, 19))
18977	25569113	These novel approaches in particular aptamers or therapeutic vaccination might be superior over conventional chemotherapy since their production is easier and cheaper, and targeting of multiple tumor antigens at once is possible.	('aptamers', 'Var', (37, 45))	('multiple tumor', 'Disease', (185, 199))	('multiple tumor', 'Disease', 'MESH:D009369', (185, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))
18978	25569113	Currently, tumor specific drug delivery using monoclonal antibodies against tenascin-C represents the most advanced approach.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('monoclonal antibodies', 'Var', (46, 67))	('tumor', 'Disease', (11, 16))	('tenascin-C', 'Gene', (76, 86))	('Cu', 'Chemical', 'MESH:D003300', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
18983	25569113	It is conceivable that tumor ECM is affected by radiotherapy since radiotherapy can induce inflammation and fibrosis, 2 conditions where ECM is largely remodeled.	('ECM', 'Gene', (137, 140))	('inflammation', 'Disease', 'MESH:D007249', (91, 103))	('inflammation', 'Disease', (91, 103))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('radiotherapy', 'Var', (67, 79))	('fibrosis', 'Disease', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('induce', 'Reg', (84, 90))	('fibrosis', 'Disease', 'MESH:D005355', (108, 116))	('ECM', 'Gene', '22915', (29, 32))	('tumor', 'Disease', (23, 28))	('ECM', 'Gene', (29, 32))	('ECM', 'Gene', '22915', (137, 140))
18986	25569113	The major effect of radiation therapy is the induction of tumor cell death triggered by DNA damage (DNA double strand breaks) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('DNA', 'Var', (88, 91))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
19026	25569113	Radiotherapy induces inflammation, fibrosis and hypoxia which altogether represent conditions in multiple pathologies where tenascin-C is highly expressed and has proven to play a critical role in disease severity.	('induces', 'Reg', (13, 20))	('Radiotherapy', 'Var', (0, 12))	('fibrosis', 'Disease', 'MESH:D005355', (35, 43))	('fibrosis', 'Disease', (35, 43))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('inflammation', 'Disease', 'MESH:D007249', (21, 33))	('inflammation', 'Disease', (21, 33))	('hypoxia', 'Disease', (48, 55))
19060	25569113	Recently it was shown that adhesion to fibronectin promotes DNA damage recognition and chemosensitization to cisplatin via the potentiation of the DNA damage signaling response (DDR) in human colon cancer cells and tumor derived myofibroblasts.	('DNA damage recognition', 'MPA', (60, 82))	('fibronectin', 'Gene', (39, 50))	('fibronectin', 'Gene', '2335', (39, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (192, 204))	('potentiation', 'PosReg', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (215, 220))	('colon cancer', 'Disease', 'MESH:D015179', (192, 204))	('DNA', 'MPA', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('promotes', 'PosReg', (51, 59))	('human', 'Species', '9606', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colon cancer', 'Disease', (192, 204))	('adhesion', 'Var', (27, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
19066	25569113	This possibility is indeed supported by the observation that adhesion of T98G GBM cells onto a fibronectin/tenascin-C substratum caused downregulation of gammaH2AX among several other molecules involved in DNA repair (e.g., several MCMs) in comparison to a fibronectin substratum.	('fibronectin', 'Gene', (257, 268))	('fibronectin', 'Gene', '2335', (95, 106))	('downregulation', 'NegReg', (136, 150))	('gammaH2AX', 'Protein', (154, 163))	('fibronectin', 'Gene', (95, 106))	('fibronectin', 'Gene', '2335', (257, 268))	('T98G', 'Var', (73, 77))
19067	25569113	In consequence cells with damaged DNA that escape cell death upon cisplatin treatment might be more prone to accumulate mutations when grown in a tenascin-C rich microenvironment.	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('accumulate', 'MPA', (109, 119))	('mutations', 'Var', (120, 129))
19069	25569113	It had been demonstrated that DKK1 levels are increased by cisplatin in HNSCC and GBM presumably due to its p53 binding element in its promoter.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('increased', 'PosReg', (46, 55))	('DKK1', 'Gene', '22943', (30, 34))	('cisplatin', 'Var', (59, 68))	('DKK1', 'Gene', (30, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
19078	25349993	Stable overexpression of PODX in LN-229 and U-118 MG human GBM cells increased the soluble/intracellular beta-cat level, TOPflash luciferase reporter activity, the mRNA levels of beta-cat signaling target genes, matrix metalloproteinase 9 (MMP9) expression/activity, and cell invasion and proliferation, which was abolished by selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 and selective beta-cat signaling inhibitor CCT031374.	('beta-cat', 'Gene', (105, 113))	('U-118 MG', 'CellLine', 'CVCL:0633', (44, 52))	('increased', 'PosReg', (69, 78))	('beta-cat', 'Gene', '1499', (414, 422))	('PD169316', 'Var', (391, 399))	('cell invasion', 'CPA', (271, 284))	('beta-cat', 'Gene', (414, 422))	('PODX', 'Gene', '5420', (25, 29))	('CCT031374', 'Chemical', '-', (443, 452))	('PD169316', 'Chemical', 'MESH:C408604', (391, 399))	('activity', 'MPA', (150, 158))	('LN-229', 'CellLine', 'CVCL:0393', (33, 39))	('expression', 'Species', '29278', (11, 21))	('matrix metalloproteinase 9', 'Gene', (212, 238))	('PODX', 'Gene', (25, 29))	('human', 'Species', '9606', (53, 58))	('expression/activity', 'MPA', (246, 265))	('mRNA levels', 'MPA', (164, 175))	('beta-cat', 'Gene', '1499', (179, 187))	('p38 mitogen-activated protein kinase', 'Gene', (337, 373))	('matrix metalloproteinase 9', 'Gene', '4318', (212, 238))	('MMP9', 'Gene', (240, 244))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (337, 373))	('MMP9', 'Gene', '4318', (240, 244))	('beta-cat', 'Gene', '1499', (105, 113))	('beta-cat', 'Gene', (179, 187))	('expression', 'Species', '29278', (246, 256))	('LN-229', 'Var', (33, 39))
19080	25349993	In addition, overexpression of PODX induced p38 MAPK activity and inactivating phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at serine 389 in LN-229 and U-118 MG cells, which was abolished by PD169316, but not CCT031374; knockdown of PODX decreased p38 MAPK activity and inactivating phosphorylation of GSK-3beta at serine 389 in both cell lines, which was not significantly affected by overexpression of constitutively active beta-cat.	('inactivating phosphorylation', 'MPA', (287, 315))	('serine', 'Chemical', 'MESH:D012694', (332, 338))	('p38', 'Gene', (44, 47))	('PODX', 'Gene', (31, 35))	('GSK-3beta', 'Gene', '2932', (130, 139))	('PODX', 'Gene', '5420', (250, 254))	('p38', 'Gene', (265, 268))	('decreased', 'NegReg', (255, 264))	('GSK-3beta', 'Gene', (130, 139))	('beta-cat', 'Gene', '1499', (443, 451))	('GSK-3beta', 'Gene', '2932', (319, 328))	('U-118 MG', 'CellLine', 'CVCL:0633', (169, 177))	('serine', 'Chemical', 'MESH:D012694', (144, 150))	('p38', 'Gene', '1432', (44, 47))	('PODX', 'Gene', (250, 254))	('PD169316', 'Chemical', 'MESH:C408604', (208, 216))	('CCT031374', 'Chemical', '-', (226, 235))	('glycogen synthase kinase-3beta', 'Gene', (98, 128))	('beta-cat', 'Gene', (443, 451))	('activity', 'MPA', (53, 61))	('activity', 'MPA', (274, 282))	('p38', 'Gene', '1432', (265, 268))	('expression', 'Species', '29278', (407, 417))	('GSK-3beta', 'Gene', (319, 328))	('LN-229', 'CellLine', 'CVCL:0393', (158, 164))	('expression', 'Species', '29278', (17, 27))	('PODX', 'Gene', '5420', (31, 35))	('knockdown', 'Var', (237, 246))	('glycogen synthase kinase-3beta', 'Gene', '2932', (98, 128))
19103	25349993	Human PODX shRNA plasmid (RHS3979-98487921) was purchased from Open Biosystems (Huntsville, AL, USA).	('PODX', 'Gene', '5420', (6, 10))	('PODX', 'Gene', (6, 10))	('Human', 'Species', '9606', (0, 5))	('RHS3979-98487921', 'Var', (26, 42))
19104	25349993	Human beta-cat cDNA clone (SC107921) was purchased from from Origene (Beijing, China) and the beta-cat cDNA sequence lacking those encoding 151 amino-terminal residues was subcloned into pcDNA 3.1 to generate a constitutively active (DeltaN151) beta-cat expression vector.	('Human', 'Species', '9606', (0, 5))	('expression', 'Species', '29278', (254, 264))	('DeltaN151', 'Var', (234, 243))	('beta-cat', 'Gene', '1499', (94, 102))	('beta-cat', 'Gene', '1499', (245, 253))	('beta-cat', 'Gene', (6, 14))	('beta-cat', 'Gene', '1499', (6, 14))	('DeltaN151', 'DELETION', 'None', (234, 243))	('beta-cat', 'Gene', (94, 102))	('beta-cat', 'Gene', (245, 253))
19113	25349993	Puromycin, G418, and selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 were purchased from Sigma-Aldrich (St. Louis, MO, USA).	('p38 mitogen-activated protein kinase', 'Gene', '1432', (31, 67))	('Puromycin', 'Chemical', 'MESH:D011691', (0, 9))	('G418', 'Chemical', 'MESH:C010680', (11, 15))	('PD169316', 'Chemical', 'MESH:C408604', (85, 93))	('p38 mitogen-activated protein kinase', 'Gene', (31, 67))	('PD169316', 'Var', (85, 93))
19114	25349993	The PODX and the constitutively active (DeltaN151) beta-cat expression vectors were respectively transfected into LN-229 and U-118 MG cells using Lipofectamine 2000 transfection reagent (Life Technologies) according to the manufacturer's instructions.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (146, 164))	('beta-cat', 'Gene', '1499', (51, 59))	('DeltaN151', 'Var', (40, 49))	('PODX', 'Gene', '5420', (4, 8))	('expression vectors', 'Species', '29278', (60, 78))	('DeltaN151', 'DELETION', 'None', (40, 49))	('PODX', 'Gene', (4, 8))	('beta-cat', 'Gene', (51, 59))	('LN-229', 'CellLine', 'CVCL:0393', (114, 120))	('U-118 MG', 'CellLine', 'CVCL:0633', (125, 133))
19126	25349993	The primers used are as follows: for beta-cat (primers designed to measure both wild type beta-cat and constitutively active DeltaN151 beta-cat mRNA levels), 5'- GATCATGCTAGCATGGCAATTCCTGAG-3' (forward) and 5'- AAGATCGGTACCTCAGTTATCTACAGG-3' (reverse); for c-Myc, 5'-GGACGACGAGACCTTCATCAA-3' (forward) and 5'-CCAGCTTCTCTGAGACGAGCTT-3' (reverse); for c-Jun, 5'-CAAAGTTTGGATTGCATCAAGTG-3' (forward) and 5'-TAACATTATAAATGGTCACAGCACATG-3' (reverse); for MMP9, 5'-GTTCCCGGAGTGAGTTGA-3' (forward) and 5'-TTTACATGGCACTGCAAAGC-3' (reverse); for GAPDH, 5'-GACTCATGACCACAGTCCATGC-3' (forward) and 5'-AGAGGCAGGGATGATGTTCTG-3' (reverse).	('c-Myc', 'Gene', '4609', (257, 262))	('beta-cat', 'Gene', (135, 143))	('MMP9', 'Gene', '4318', (450, 454))	('beta-cat', 'Gene', (37, 45))	('c-Myc', 'Gene', (257, 262))	('beta-cat', 'Gene', '1499', (135, 143))	('c-Jun', 'Gene', '3725', (350, 355))	('DeltaN151', 'DELETION', 'None', (125, 134))	('beta-cat', 'Gene', '1499', (90, 98))	('beta-cat', 'Gene', '1499', (37, 45))	('GAPDH', 'Gene', '2597', (537, 542))	('GAPDH', 'Gene', (537, 542))	('DeltaN151', 'Var', (125, 134))	('c-Jun', 'Gene', (350, 355))	('beta-cat', 'Gene', (90, 98))	('MMP9', 'Gene', (450, 454))
19141	25349993	We stably overexpressed PODX in LN-229 and U-118 MG human GBM cells by stable transfection, and on the other hand stably transduced the cells with lentiviral shRNA to knock down PODX.	('U-118 MG', 'CellLine', 'CVCL:0633', (43, 51))	('knock', 'Var', (167, 172))	('PODX', 'Gene', '5420', (24, 28))	('PODX', 'Gene', (24, 28))	('PODX', 'Gene', '5420', (178, 182))	('PODX', 'Gene', (178, 182))	('human', 'Species', '9606', (52, 57))	('LN-229', 'CellLine', 'CVCL:0393', (32, 38))
19143	25349993	A constitutively active beta-cat mutant, which lacks 151 amino-terminal residues (DeltaN151), was stably overexpressed in cells expressing PODX-shRNA.	('lacks', 'NegReg', (47, 52))	('PODX', 'Gene', (139, 143))	('DeltaN151', 'DELETION', 'None', (82, 91))	('beta-cat', 'Gene', (24, 32))	('PODX', 'Gene', '5420', (139, 143))	('beta-cat', 'Gene', '1499', (24, 32))	('DeltaN151', 'Var', (82, 91))
19144	25349993	In addition, as our pilot study had suggested that PODX could regulate the soluble beta-cat level in GBM cells by a p38 MAPK-dependent mechanism (data not shown), we included a selective p38 MAPK inhibitor PD169316 in all experiments in this study.	('PD169316', 'Var', (206, 214))	('p38', 'Gene', (187, 190))	('PODX', 'Gene', '5420', (51, 55))	('p38', 'Gene', '1432', (116, 119))	('PODX', 'Gene', (51, 55))	('regulate', 'Reg', (62, 70))	('beta-cat', 'Gene', (83, 91))	('p38', 'Gene', (116, 119))	('PD169316', 'Chemical', 'MESH:C408604', (206, 214))	('p38', 'Gene', '1432', (187, 190))	('beta-cat', 'Gene', '1499', (83, 91))
19147	25349993	On the other hand, knockdown of PODX decreased the soluble beta-cat level by over 60% in both cell lines.	('PODX', 'Gene', (32, 36))	('beta-cat', 'Gene', '1499', (59, 67))	('knockdown', 'Var', (19, 28))	('decreased the soluble beta-cat level', 'Phenotype', 'HP:0031426', (37, 73))	('beta-cat', 'Gene', (59, 67))	('PODX', 'Gene', '5420', (32, 36))	('decreased', 'NegReg', (37, 46))
19148	25349993	1 also shows that the constitutively active (DeltaN151) form of beta-cat was overexpressed in the cells.	('beta-cat', 'Gene', '1499', (64, 72))	('DeltaN151', 'DELETION', 'None', (45, 54))	('beta-cat', 'Gene', (64, 72))	('DeltaN151', 'Var', (45, 54))
19149	25349993	It is apparent that CCT031374 and DeltaN151 beta-cat showed no significant effect on the protein level of PODX (Fig.	('beta-cat', 'Gene', (44, 52))	('PODX', 'Gene', '5420', (106, 110))	('DeltaN151', 'Var', (34, 43))	('PODX', 'Gene', (106, 110))	('beta-cat', 'Gene', '1499', (44, 52))	('CCT031374', 'Chemical', '-', (20, 29))	('CCT031374', 'Var', (20, 29))	('DeltaN151', 'DELETION', 'None', (34, 43))	('protein level', 'MPA', (89, 102))
19154	25349993	On the other hand, knockdown of PODX decreased the luciferase activity of TOPflash by approximately 70% in both cell lines, which was completely reversed by overexpression of DeltaN151 beta-cat.	('PODX', 'Gene', (32, 36))	('expression', 'Species', '29278', (161, 171))	('activity', 'MPA', (62, 70))	('DeltaN151', 'Var', (175, 184))	('knockdown', 'Var', (19, 28))	('DeltaN151', 'DELETION', 'None', (175, 184))	('beta-cat', 'Gene', '1499', (185, 193))	('beta-cat', 'Gene', (185, 193))	('PODX', 'Gene', '5420', (32, 36))	('luciferase', 'Enzyme', (51, 61))	('decreased', 'NegReg', (37, 46))
19155	25349993	Little change was observed with FOPflash, a negative control reporter with mutated Tcf binding elements (Fig.	('mutated', 'Var', (75, 82))	('Tcf', 'Gene', '3172', (83, 86))	('Tcf', 'Gene', (83, 86))
19156	25349993	3, real-time RT-PCR showed that overexpression or knockdown of PODX did not significantly affect beta-cat mRNA levels in LN-229 and U-118 MG cells.	('beta-cat', 'Gene', '1499', (97, 105))	('knockdown', 'Var', (50, 59))	('PODX', 'Gene', '5420', (63, 67))	('LN-229', 'CellLine', 'CVCL:0393', (121, 127))	('PODX', 'Gene', (63, 67))	('beta-cat', 'Gene', (97, 105))	('expression', 'Species', '29278', (36, 46))	('U-118 MG', 'CellLine', 'CVCL:0633', (132, 140))
19158	25349993	Knockdown of PODX decreased the mRNA levels of c-Myc and c-Jun by over 60% in both cell lines, which was completely reversed by overexpression of DeltaN151 beta-cat (Fig.	('c-Jun', 'Gene', '3725', (57, 62))	('DeltaN151', 'DELETION', 'None', (146, 155))	('beta-cat', 'Gene', '1499', (156, 164))	('PODX', 'Gene', '5420', (13, 17))	('PODX', 'Gene', (13, 17))	('decreased', 'NegReg', (18, 27))	('c-Myc', 'Gene', '4609', (47, 52))	('DeltaN151', 'Var', (146, 155))	('expression', 'Species', '29278', (132, 142))	('c-Jun', 'Gene', (57, 62))	('c-Myc', 'Gene', (47, 52))	('beta-cat', 'Gene', (156, 164))
19160	25349993	In addition, real-time RT-PCR with primers specifically designed to measure both wild type beta-cat and DeltaN151 beta-cat mRNA levels showed that stable transfection of DeltaN151 beta-cat markedly increased the detected beta-cat mRNA level, which was in agreement with the strong DeltaN151 beta-cat protein expression in Fig.	('beta-cat', 'Gene', (221, 229))	('beta-cat', 'Gene', (91, 99))	('expression', 'Species', '29278', (308, 318))	('DeltaN151', 'DELETION', 'None', (104, 113))	('beta-cat', 'Gene', '1499', (114, 122))	('beta-cat', 'Gene', (291, 299))	('beta-cat', 'Gene', '1499', (221, 229))	('DeltaN151', 'Var', (281, 290))	('DeltaN151', 'DELETION', 'None', (170, 179))	('beta-cat', 'Gene', '1499', (180, 188))	('increased', 'PosReg', (198, 207))	('beta-cat', 'Gene', '1499', (91, 99))	('DeltaN151', 'DELETION', 'None', (281, 290))	('beta-cat', 'Gene', '1499', (291, 299))	('DeltaN151', 'Var', (170, 179))	('beta-cat', 'Gene', (114, 122))	('DeltaN151', 'Var', (104, 113))	('beta-cat', 'Gene', (180, 188))
19163	25349993	On the other hand, knockdown of PODX decreased cell invasion by approximately 50% in both cell lines, which was completely reversed by overexpression of DeltaN151 beta-cat (Fig.	('PODX', 'Gene', (32, 36))	('DeltaN151', 'DELETION', 'None', (153, 162))	('beta-cat', 'Gene', '1499', (163, 171))	('knockdown', 'Var', (19, 28))	('expression', 'Species', '29278', (139, 149))	('PODX', 'Gene', '5420', (32, 36))	('beta-cat', 'Gene', (163, 171))	('decreased', 'NegReg', (37, 46))	('DeltaN151', 'Var', (153, 162))	('cell invasion', 'CPA', (47, 60))
19167	25349993	Knockdown of PODX decreased MMP9 expression by approximately 60% in both cell lines, which was completely reversed by overexpression of DeltaN151 beta-cat (Fig.	('PODX', 'Gene', '5420', (13, 17))	('PODX', 'Gene', (13, 17))	('DeltaN151', 'Var', (136, 145))	('decreased', 'NegReg', (18, 27))	('MMP9', 'Gene', (28, 32))	('MMP9', 'Gene', '4318', (28, 32))	('beta-cat', 'Gene', '1499', (146, 154))	('expression', 'Species', '29278', (33, 43))	('DeltaN151', 'DELETION', 'None', (136, 145))	('expression', 'MPA', (33, 43))	('beta-cat', 'Gene', (146, 154))	('expression', 'Species', '29278', (122, 132))
19170	25349993	Compared with the controls, overexpression of PODX significantly increased cell proliferation in LN-229 and U-118 MG cells after 30 hours of culture, which was abolished by PD169316 and CCT031374 (Fig.	('PODX', 'Gene', (46, 50))	('increased', 'PosReg', (65, 74))	('CCT031374', 'Chemical', '-', (186, 195))	('CCT031374', 'Var', (186, 195))	('PD169316', 'Chemical', 'MESH:C408604', (173, 181))	('PD169316', 'Var', (173, 181))	('expression', 'Species', '29278', (32, 42))	('U-118 MG', 'CellLine', 'CVCL:0633', (108, 116))	('PODX', 'Gene', '5420', (46, 50))	('LN-229', 'CellLine', 'CVCL:0393', (97, 103))	('cell proliferation', 'CPA', (75, 93))
19171	25349993	On the other hand, knockdown of PODX significantly inhibited cell proliferation in both cell lines, which was completely reversed by overexpression of DeltaN151 beta-cat (Fig.	('PODX', 'Gene', (32, 36))	('DeltaN151', 'DELETION', 'None', (151, 160))	('beta-cat', 'Gene', (161, 169))	('knockdown', 'Var', (19, 28))	('expression', 'Species', '29278', (137, 147))	('DeltaN151', 'Var', (151, 160))	('beta-cat', 'Gene', '1499', (161, 169))	('PODX', 'Gene', '5420', (32, 36))	('inhibited', 'NegReg', (51, 60))	('cell proliferation', 'CPA', (61, 79))
19174	25349993	As evidenced by increased expression of phosphorylated ATF2, overexpression of PODX respectively induced p38 MAPK activity by 3.6 and 3.1 folds in LN-229 and U-118 MG cells, which was abolished by PD169316, but not CCT031374 (Fig.	('expression', 'MPA', (26, 36))	('ATF2', 'Gene', (55, 59))	('activity', 'MPA', (114, 122))	('ATF2', 'Gene', '1386', (55, 59))	('PD169316', 'Chemical', 'MESH:C408604', (197, 205))	('PD169316', 'Var', (197, 205))	('CCT031374', 'Chemical', '-', (215, 224))	('U-118 MG', 'CellLine', 'CVCL:0633', (158, 166))	('LN-229', 'CellLine', 'CVCL:0393', (147, 153))	('expression', 'Species', '29278', (65, 75))	('increased', 'PosReg', (16, 25))	('PODX', 'Gene', (79, 83))	('p38', 'Gene', (105, 108))	('PODX', 'Gene', '5420', (79, 83))	('expression', 'Species', '29278', (26, 36))	('p38', 'Gene', '1432', (105, 108))
19175	25349993	On the other hand, knockdown of PODX decreased p38 MAPK activity by approximately 70% in both cell lines, which was not significantly affected by overexpression of DeltaN151 beta-cat (Fig.	('PODX', 'Gene', (32, 36))	('activity', 'MPA', (56, 64))	('beta-cat', 'Gene', (174, 182))	('p38', 'Gene', '1432', (47, 50))	('knockdown', 'Var', (19, 28))	('DeltaN151', 'DELETION', 'None', (164, 173))	('DeltaN151', 'Var', (164, 173))	('beta-cat', 'Gene', '1499', (174, 182))	('PODX', 'Gene', '5420', (32, 36))	('p38', 'Gene', (47, 50))	('decreased', 'NegReg', (37, 46))	('expression', 'Species', '29278', (150, 160))
19178	25349993	Phosphorylation of GSK-3beta at serine 389 by p38 enhances inactivation of GSK-3beta and results in subsequent stabilization and accumulation of soluble beta-cat.	('enhances', 'PosReg', (50, 58))	('beta-cat', 'Gene', (153, 161))	('serine 389', 'Var', (32, 42))	('serine', 'Chemical', 'MESH:D012694', (32, 38))	('p38', 'Gene', (46, 49))	('accumulation', 'PosReg', (129, 141))	('beta-cat', 'Gene', '1499', (153, 161))	('Phosphorylation', 'MPA', (0, 15))	('GSK-3beta', 'Gene', '2932', (19, 28))	('GSK-3beta', 'Gene', (19, 28))	('GSK-3beta', 'Gene', '2932', (75, 84))	('GSK-3beta', 'Gene', (75, 84))	('stabilization', 'MPA', (111, 124))	('p38', 'Gene', '1432', (46, 49))	('inactivation', 'MPA', (59, 71))
19180	25349993	9, while the total GSK-3beta was not significantly changed, overexpression of PODX respectively increased the level of phosphorylated GSK-3beta (serine 389) by 3.2 and 3.0 folds in LN-229 and U-118 MG cells, which was abolished by PD169316, but not CCT031374.	('CCT031374', 'Chemical', '-', (249, 258))	('increased', 'PosReg', (96, 105))	('PODX', 'Gene', (78, 82))	('PODX', 'Gene', '5420', (78, 82))	('level of phosphorylated', 'MPA', (110, 133))	('U-118 MG', 'CellLine', 'CVCL:0633', (192, 200))	('PD169316', 'Chemical', 'MESH:C408604', (231, 239))	('PD169316', 'Var', (231, 239))	('LN-229', 'CellLine', 'CVCL:0393', (181, 187))	('GSK-3beta', 'Gene', '2932', (19, 28))	('GSK-3beta', 'Gene', (19, 28))	('serine', 'Chemical', 'MESH:D012694', (145, 151))	('GSK-3beta', 'Gene', '2932', (134, 143))	('GSK-3beta', 'Gene', (134, 143))	('expression', 'Species', '29278', (64, 74))
19181	25349993	On the other hand, knockdown of PODX decreased phosphorylation of GSK-3beta at serine 389 by approximately 60% in both cell lines, which was not significantly affected by overexpression of DeltaN151 beta-cat (Fig.	('PODX', 'Gene', (32, 36))	('GSK-3beta', 'Gene', '2932', (66, 75))	('GSK-3beta', 'Gene', (66, 75))	('knockdown', 'Var', (19, 28))	('phosphorylation', 'MPA', (47, 62))	('DeltaN151', 'Var', (189, 198))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('beta-cat', 'Gene', '1499', (199, 207))	('beta-cat', 'Gene', (199, 207))	('PODX', 'Gene', '5420', (32, 36))	('DeltaN151', 'DELETION', 'None', (189, 198))	('decreased', 'NegReg', (37, 46))	('expression', 'Species', '29278', (175, 185))
19200	25349993	This was corroborated by the finding that knockdown of PODX significantly inhibited GBM dell invasion, which was completely reversed by overexpression of a constitutively active beta-cat mutant.	('expression', 'Species', '29278', (140, 150))	('inhibited', 'NegReg', (74, 83))	('beta-cat', 'Gene', (178, 186))	('GBM dell invasion', 'CPA', (84, 101))	('PODX', 'Gene', '5420', (55, 59))	('PODX', 'Gene', (55, 59))	('beta-cat', 'Gene', '1499', (178, 186))	('knockdown', 'Var', (42, 51))
19205	25349993	This was confirmed by the finding that direct activation of beta-cat signaling by overexpressing a constitutively active beta-cat mutant completely reversed the inhibitory effects of PODX-knockdown on MMP9 expression.	('beta-cat', 'Gene', (60, 68))	('beta-cat', 'Gene', '1499', (121, 129))	('beta-cat', 'Gene', (121, 129))	('expression', 'Species', '29278', (206, 216))	('MMP9', 'Gene', (201, 205))	('activation', 'PosReg', (46, 56))	('expression', 'MPA', (206, 216))	('MMP9', 'Gene', '4318', (201, 205))	('beta-cat', 'Gene', '1499', (60, 68))	('PODX', 'Gene', '5420', (183, 187))	('PODX', 'Gene', (183, 187))	('mutant', 'Var', (130, 136))
19218	24319635	Mutations in glioblastoma oncosuppressive pathways pave the way for oncomodulatory activity of cytomegalovirus Over the last decade, cytomegalovirus (CMV) has been suggested to promote the development of glioblastoma multiforme (GBM).	('glioblastoma multiforme', 'Disease', (204, 227))	('glioblastoma oncosuppressive', 'Disease', (13, 41))	('promote', 'PosReg', (177, 184))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (204, 227))	('glioblastoma oncosuppressive', 'Disease', 'MESH:D005909', (13, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('Mutations', 'Var', (0, 9))
19219	24319635	This finding provides further insights into the mechanisms whereby CMV exacerbates the malignancy of GBM.	('malignancy', 'Disease', 'MESH:D009369', (87, 97))	('exacerbates', 'PosReg', (71, 82))	('GBM', 'Disease', (101, 104))	('malignancy', 'Disease', (87, 97))	('CMV', 'Var', (67, 70))
19227	24319635	Oncomodulation is a process whereby CMV may infect cancer cells, hence affecting their functions, without being directly involved in malignant transformation.	('affecting', 'Reg', (71, 80))	('functions', 'MPA', (87, 96))	('infect cancer', 'Disease', (44, 57))	('infect cancer', 'Disease', 'MESH:D009369', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CMV', 'Var', (36, 39))	('Oncomodulation', 'Disease', (0, 14))
19228	24319635	In this setting, neoplastic cells provide the molecular and genetic milieu whereby disturbances in tumor suppressors, transcription factors, and signal transduction pathways allow CMV to exert an oncomodulatory effect.	('tumor', 'Disease', (99, 104))	('CMV', 'Disease', (180, 183))	('oncomodulatory effect', 'MPA', (196, 217))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('disturbances', 'Var', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
19231	24319635	More recently, 2 distinct mouse models of oncosuppressor mutations commonly associated with glioma were employed to determine the effect of perinatal MCMV infection on tumor progression and overall survival.	('MCMV infection on tumor', 'Disease', (150, 173))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('MCMV infection on tumor', 'Disease', 'MESH:D009369', (150, 173))	('glioma', 'Disease', (92, 98))	('associated', 'Reg', (76, 86))	('mutations', 'Var', (57, 66))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('mouse', 'Species', '10090', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
19233	24319635	Mut3 mice spontaneously develop high-grade astrocytomas with near-to-complete penetrance by adulthood.	('develop', 'PosReg', (24, 31))	('astrocytomas', 'Disease', (43, 55))	('Mut3', 'Var', (0, 4))	('mice', 'Species', '10090', (5, 9))	('astrocytomas', 'Disease', 'MESH:D001254', (43, 55))
19243	24319635	Genomics analyses of human GBM samples revealed that the murine models that we employed bear mutations that affect the core signal transduction pathways most commonly mutated in the course of GBM.	('murine', 'Species', '10090', (57, 63))	('mutations', 'Var', (93, 102))	('human', 'Species', '9606', (21, 26))	('core signal transduction pathways', 'Pathway', (119, 152))	('mutated', 'Var', (167, 174))	('GBM', 'Disease', (192, 195))
19244	24319635	The genes coding for phosphatase and tensin homolog (PTEN) and neurofibromin 1 (NF1) are mutated or deleted in 36% and 18% of GBM cases, respectively, and play an essential role as negative regulators of the signal transduction pathway involving receptor tyrosine kinases (RTKs), RAS, and phosphoinositide-3-kinase (PI3K), which is hyperactivated (hence delivering mitogenic and antiapoptotic signals) in 88% of GBM patients.	('NF1', 'Gene', (80, 83))	('deleted', 'Var', (100, 107))	('neurofibromin 1', 'Gene', (63, 78))	('NF1', 'Gene', '4763', (80, 83))	('RAS', 'Enzyme', (280, 283))	('signal transduction pathway', 'Pathway', (208, 235))	('phosphoinositide-3-kinase', 'Enzyme', (289, 314))	('PTEN', 'Gene', (53, 57))	('phosphatase', 'Gene', (21, 32))	('hyperactivated', 'PosReg', (332, 346))	('neurofibromin 1', 'Gene', '4763', (63, 78))	('patients', 'Species', '9606', (416, 424))	('PTEN', 'Gene', '5728', (53, 57))
19278	24312904	Sections were prepared as described previously and immunostained for Nestin (1 : 1000, Chemicon, Temecula, CA, USA), Vimentin (1 : 500, DAKO, Glostrup, Denmark), and Ki-67 (MIB-1, 1 : 500, Dako).	('1 : 500', 'Var', (127, 134))	('1 : 1000', 'Var', (77, 85))	('Vimentin', 'Gene', (117, 125))	('Nestin', 'Gene', (69, 75))	('MIB-1, 1', 'Gene', '307594', (173, 181))	('Nestin', 'Gene', '25491', (69, 75))	('Vimentin', 'Gene', '81818', (117, 125))
19366	23108208	In addition, metabolic ratios were calculated from the cNA, which is important to ensure metabolic ratio abnormality from the intratumoral and the peritumoral regions.	('abnormality', 'Var', (105, 116))	('metabolic', 'MPA', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (131, 136))	('metabolic ratio', 'MPA', (89, 104))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
19397	23108208	For the peritumoral region only, among all the techniques applied the optimal cut-off values that were able to differentiate GBMs from intracranial metastases are NAA/Cr = 1.50, Cho/Cr = 1.40 and Cho/NAA = 1.10, and rCBV = 1.70 (Fig.	('Cr', 'Chemical', 'MESH:D003401', (182, 184))	('rCBV', 'Chemical', '-', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('NAA/Cr', 'Var', (163, 169))	('intracranial metastases', 'Disease', (135, 158))	('intracranial metastases', 'Disease', 'MESH:D009362', (135, 158))	('Cho', 'Chemical', 'MESH:D002794', (178, 181))	('NAA', 'Chemical', 'MESH:C000179', (163, 166))	('GBMs', 'Disease', (125, 129))	('Cho', 'Chemical', 'MESH:D002794', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('NAA', 'Chemical', 'MESH:C000179', (200, 203))	('Cr', 'Chemical', 'MESH:D003401', (167, 169))
19514	33114182	In most cases, tumor cells carrying mutations in genes which belong to pathways targeted by the drug, gain selective advantage.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (15, 20))	('gain', 'PosReg', (102, 106))
19542	33114182	This may suggest that, despite the high diversity of mutations, the transcriptional programs of cancer cells converged on some specific signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (53, 62))
19547	33114182	Several mechanisms of such de novo adaptation of tumors to the therapy are already well described: regulation of chemotherapeutic drug concentration in the cell, suppression of apoptotic pathways, modification of target proteins, or activation of alternative signaling cascades.	('modification', 'Var', (197, 209))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('suppression', 'NegReg', (162, 173))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('alternative signaling cascades', 'Pathway', (247, 277))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('apoptotic pathways', 'Pathway', (177, 195))	('target proteins', 'Protein', (213, 228))	('proteins', 'Protein', (220, 228))
19554	33114182	Thus, in the course of tumor progression and subsequent therapy, additional mutations may occur providing the resistance of tumor cells to the drugs.	('mutations', 'Var', (76, 85))	('resistance', 'MPA', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (124, 129))	('occur', 'Reg', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
19555	33114182	Among chemotherapy-induced mutations, mutations in genes of the EGFR-dependent signaling pathway (EGFR, HER2, RAS) targeted by the drugs are common.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (27, 36))	('RAS', 'Gene', (110, 113))	('chemotherapy-induced', 'Disease', (6, 26))	('HER2', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (98, 102))	('HER2', 'Gene', '2064', (104, 108))
19556	33114182	Some of the most common examples are mutations in the BRCA1 and BRCA2 tumor suppressor genes.	('BRCA2', 'Gene', '675', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('mutations', 'Var', (37, 46))	('BRCA1', 'Gene', '672', (54, 59))	('BRCA2', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('BRCA1', 'Gene', (54, 59))
19557	33114182	Mutations in these genes lead not only to the enhanced probability of genomic instability but also to a greater sensitivity of tumor cells to DNA-damaging agents of the platinum group and inhibitors of poly(ADP-ribose) polymerase.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sensitivity', 'MPA', (112, 123))	('tumor', 'Disease', (127, 132))	('poly(ADP-ribose) polymerase', 'Gene', '142', (202, 229))	('platinum', 'Chemical', 'MESH:D010984', (169, 177))	('poly(ADP-ribose) polymerase', 'Gene', (202, 229))	('genomic instability', 'MPA', (70, 89))	('Mutations', 'Var', (0, 9))	('enhanced', 'PosReg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
19558	33114182	Mutations in the TP53 gene induced by chemotherapy can lead to an acquisition of resistance to the drugs used.	('lead to', 'Reg', (55, 62))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (17, 21))	('acquisition of resistance to the drugs used', 'MPA', (66, 109))	('TP53', 'Gene', (17, 21))
19559	33114182	In addition to genetic aberrations, epigenetic changes may occur in tumor cells in response to therapy, for example, the silencing of key tumor suppressor genes mediates by DNA hypermethylation, histone modifications, and chromatin remodeling.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (138, 143))	('histone', 'Var', (195, 202))	('chromatin remodeling', 'CPA', (222, 242))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('DNA hypermethylation', 'Var', (173, 193))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('silencing', 'NegReg', (121, 130))
19571	33114182	Knockdown of ZEB1 in breast cancer, non-small cell lung carcinoma, and osteosarcoma cell lines leads to an increase in the sensitivity to radiotherapy while its ectopic expression in cell models of breast cancer decreases the sensitivity.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (36, 65))	('ZEB1', 'Gene', (13, 17))	('non-small cell lung carcinoma', 'Disease', (36, 65))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (40, 65))	('breast cancer', 'Disease', (198, 211))	('sensitivity to radiotherapy', 'MPA', (123, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('increase', 'PosReg', (107, 115))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (36, 65))	('breast cancer', 'Disease', (21, 34))	('ZEB1', 'Gene', '6935', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('ectopic expression', 'Var', (161, 179))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('decreases', 'NegReg', (212, 221))	('osteosarcoma', 'Disease', (71, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))
19598	33114182	For example, cisplatin causes replicative stress, which activates the phosphokinases ATR, CHK1, and WEE1, thereby preventing further course of the cell cycle and leading to the arrest of tumor cells in the S phase.	('activates', 'PosReg', (56, 65))	('WEE1', 'Gene', '7465', (100, 104))	('preventing', 'NegReg', (114, 124))	('ATR', 'Gene', '545', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('arrest of tumor', 'Disease', 'MESH:D006323', (177, 192))	('ATR', 'Gene', (85, 88))	('phosphokinases', 'Enzyme', (70, 84))	('cisplatin', 'Var', (13, 22))	('CHK1', 'Gene', (90, 94))	('arrest of tumor', 'Disease', (177, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('leading to', 'Reg', (162, 172))	('WEE1', 'Gene', (100, 104))	('course of the cell cycle', 'CPA', (133, 157))	('CHK1', 'Gene', '1111', (90, 94))
19621	33114182	For example, cisplatin leads to a decrease in the level of miR-199a-5p in hepatocellular carcinoma cells, which, as a result, stimulates the activation of autophagy and promotes the proliferation of tumor cells.	('tumor', 'Disease', (199, 204))	('promotes', 'PosReg', (169, 177))	('proliferation', 'CPA', (182, 195))	('stimulates', 'PosReg', (126, 136))	('autophagy', 'CPA', (155, 164))	('decrease', 'NegReg', (34, 42))	('cisplatin', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('hepatocellular carcinoma', 'Disease', (74, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('level', 'MPA', (50, 55))	('activation', 'PosReg', (141, 151))
19654	33114182	Components of the spliceosome; PGE2; survivin; MDR1, HMGB1; several microRNAs (miR-21, miR-155, and miR-194-5p, and lincRNA-VLDLR have been proposed as the main participants that trigger the acquisition of therapy resistance by tumor cells (Figure 2).	('HMGB1', 'Gene', '3146', (53, 58))	('lincRNA-VLDLR', 'Gene', '401491', (116, 129))	('miR-194-5p', 'Var', (100, 110))	('therapy resistance', 'CPA', (206, 224))	('lincRNA-VLDLR', 'Gene', (116, 129))	('MDR1', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('miR-155', 'Gene', '406947', (87, 94))	('participants', 'Species', '9606', (161, 173))	('MDR1', 'Gene', '5243', (47, 51))	('miR-21', 'Gene', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('PGE2', 'Chemical', 'MESH:D015232', (31, 35))	('miR-155', 'Gene', (87, 94))	('tumor', 'Disease', (228, 233))	('HMGB1', 'Gene', (53, 58))	('miR-21', 'Gene', '406991', (79, 85))
19672	33114182	Communication between CAFs and tumor cells promotes the formation of a therapy-resistant phenotype in the latter.	('CAFs', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('promotes', 'PosReg', (43, 51))	('Communication', 'Var', (0, 13))	('tumor', 'Disease', (31, 36))	('CAFs', 'Gene', '6899', (22, 26))	('formation', 'MPA', (56, 65))	('therapy-resistant phenotype', 'MPA', (71, 98))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
19675	33114182	After entering recipient tumor cells, miRNA-106b or miR-522 reduce cancer cells' sensitivity to the chemotherapy by targeting antiproliferative and pro-apoptotic protein TP53INP1 and arachidonate lipoxygenase (ALOX15), leading to a decrease in the accumulation of lipid peroxides in cells and inhibition of ferroptosis.	('TP53INP1 and arachidonate lipoxygenase', 'Gene', '94241', (170, 208))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('inhibition', 'NegReg', (293, 303))	('lipid peroxides', 'Chemical', 'MESH:D008054', (264, 279))	('reduce', 'NegReg', (60, 66))	('tumor', 'Disease', (25, 30))	('ferroptosis', 'CPA', (307, 318))	('miRNA-106b', 'Var', (38, 48))	('-106b', 'Chemical', '-', (43, 48))	('ALOX15', 'Gene', '246', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('miR-522', 'Gene', (52, 59))	('decrease', 'NegReg', (232, 240))	('accumulation of lipid peroxides', 'MPA', (248, 279))	('miR-522', 'Gene', '574495', (52, 59))	('cancer', 'Disease', (67, 73))	('ALOX15', 'Gene', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('sensitivity to the chemotherapy', 'MPA', (81, 112))
19677	33114182	Similarly, miR-92a-3p activates the Wnt/beta-catenin pathway and directly inhibits pro-apoptotic proteins FBXW7 and MOAP1.	('MOAP1', 'Gene', (116, 121))	('FBXW7', 'Gene', '55294', (106, 111))	('FBXW7', 'Gene', (106, 111))	('beta-catenin', 'Gene', (40, 52))	('activates', 'PosReg', (22, 31))	('inhibits', 'NegReg', (74, 82))	('beta-catenin', 'Gene', '1499', (40, 52))	('miR-92a-3p', 'Chemical', '-', (11, 21))	('pro-apoptotic proteins', 'MPA', (83, 105))	('MOAP1', 'Gene', '64112', (116, 121))	('miR-92a-3p', 'Var', (11, 21))
19692	33114182	A similar mechanism has been demonstrated for gastric cancer: TGF-beta1 secreted by MSCs activates SMAD2/3 and thereby induces the expression of lncRNA MACC1-AS1 in tumor cells, which promotes fatty acid oxidation-dependent stemness and chemoresistance through antagonizing miR-145- 5p.	('induces', 'Reg', (119, 126))	('SMAD2/3', 'Gene', '4087;4088', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('gastric cancer', 'Disease', (46, 60))	('miR-145', 'Gene', '406937', (274, 281))	('AS1', 'Gene', '5729', (158, 161))	('antagonizing', 'Var', (261, 273))	('fatty acid', 'Chemical', 'MESH:D005227', (193, 203))	('MACC1', 'Gene', (152, 157))	('TGF-beta1', 'Gene', (62, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('miR-145', 'Gene', (274, 281))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('promotes', 'PosReg', (184, 192))	('tumor', 'Disease', (165, 170))	('TGF-beta1', 'Gene', '7040', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('expression', 'MPA', (131, 141))	('AS1', 'Gene', (158, 161))	('activates', 'PosReg', (89, 98))	('SMAD2/3', 'Gene', (99, 106))	('fatty', 'CPA', (193, 198))	('chemoresistance', 'CPA', (237, 252))	('MACC1', 'Gene', '346389', (152, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))
19718	32117235	Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway.	('inhibition', 'NegReg', (29, 39))	('Dinaciclib', 'Chemical', 'MESH:C553669', (65, 75))	('TRP catabolism', 'MPA', (47, 61))	('TRP', 'Chemical', 'MESH:D014364', (47, 50))	('Dinaciclib', 'Var', (65, 75))
19723	32117235	IDO1 activity inhibits T-cell activation and proliferation and even mediates regulatory T-cell recruitment to the tumor microenvironment, provoking local immune tolerance.	('provoking', 'PosReg', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('local', 'CPA', (148, 153))	('IDO1', 'Gene', (0, 4))	('inhibits', 'NegReg', (14, 22))	('regulatory T-cell recruitment', 'CPA', (77, 106))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('T-cell activation', 'CPA', (23, 40))	('tumor', 'Disease', (114, 119))	('mediates', 'Reg', (68, 76))	('activity', 'Var', (5, 13))
19728	32117235	Current trials are evaluating the efficacy of IDO1 inhibitors in combination with chemotherapy, radiotherapy, and other immunotherapies including cytotoxic T-lymphocyte-associated protein 4 blockade.	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (146, 189))	('IDO1', 'Gene', (46, 50))	('inhibitors', 'Var', (51, 61))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (146, 189))
19729	32117235	The latter is based on the observation of an enhanced lytic ability of tumor-antigen-specific T cells upon IDO1 inhibition and decreased numbers of local immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells.	('inhibition', 'Var', (112, 122))	('decreased', 'NegReg', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('IDO1', 'Gene', (107, 111))	('enhanced', 'PosReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('lytic ability', 'CPA', (54, 67))	('tumor', 'Disease', (71, 76))
19785	32117235	Even at high concentrations, Dinaciclib impaired cellular viability/integrity only marginally (Supplementary Figure 1C).	('Dinaciclib', 'Chemical', 'MESH:C553669', (29, 39))	('cellular viability/integrity', 'CPA', (49, 77))	('Dinaciclib', 'Var', (29, 39))	('impaired', 'NegReg', (40, 48))
19786	32117235	TMZ is an oral alkylating agent that methylates DNA at the O6 position of guanine causing cell cycle arrest at G2/M.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('arrest', 'Disease', 'MESH:D006323', (101, 107))	('methylates', 'Var', (37, 47))	('guanine', 'Chemical', 'MESH:D006147', (74, 81))	('arrest', 'Disease', (101, 107))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
19788	32117235	Here, TMZ downregulated IDO1 in three of five GBM cell lines but led to increased expression in HROG52 and HROG63:a paired GBM cell line established from the very same patient (primary lesion and upon relapse) (Figure 4).	('GBM', 'Disease', 'MESH:D005909', (123, 126))	('increased', 'PosReg', (72, 81))	('expression', 'MPA', (82, 92))	('IDO1', 'Gene', (24, 28))	('downregulated', 'NegReg', (10, 23))	('HROG52', 'Gene', (96, 102))	('patient', 'Species', '9606', (168, 175))	('GBM', 'Disease', (46, 49))	('TMZ', 'Var', (6, 9))	('GBM', 'Disease', 'MESH:D005909', (46, 49))	('HROG63', 'Gene', (107, 113))	('GBM', 'Disease', (123, 126))	('TMZ', 'Chemical', 'MESH:D000077204', (6, 9))
19797	32117235	By adding Dinaciclib to cytostatic drugs, this effect was abrogated, even in the presence of IFNgamma (Figure 6 and data not shown).	('IFNgamma', 'Gene', '3458', (93, 101))	('abrogated', 'NegReg', (58, 67))	('Dinaciclib', 'Chemical', 'MESH:C553669', (10, 20))	('Dinaciclib', 'Var', (10, 20))	('IFNgamma', 'Gene', (93, 101))
19808	32117235	Our data revealed IDO1 induction by TMZ, which is reversible by Dinaciclib.	('TMZ', 'Chemical', 'MESH:D000077204', (36, 39))	('IDO1', 'Gene', (18, 22))	('induction', 'Reg', (23, 32))	('Dinaciclib', 'Chemical', 'MESH:C553669', (64, 74))	('TMZ', 'Var', (36, 39))
19813	32117235	Stimulation with either IFNgamma or a combination of TMZ resulted in greatly enhanced TRP depletion and increased KYN levels, although to varying degrees in the different cell lines (Figure 8A).	('KYN levels', 'MPA', (114, 124))	('enhanced', 'PosReg', (77, 85))	('TRP depletion', 'MPA', (86, 99))	('TMZ', 'Var', (53, 56))	('increased', 'PosReg', (104, 113))	('TMZ', 'Chemical', 'MESH:D000077204', (53, 56))	('IFNgamma', 'Gene', (24, 32))	('TRP', 'Chemical', 'MESH:D014364', (86, 89))	('IFNgamma', 'Gene', '3458', (24, 32))	('KYN', 'Chemical', 'MESH:D007737', (114, 117))
19819	32117235	The finding that high IDO1 expression is associated with shorter survival in cancer patients made IDO1 a promising target either by specific inhibitors or indirectly by immunomodulation.	('patients', 'Species', '9606', (84, 92))	('cancer', 'Disease', (77, 83))	('high', 'Var', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('expression', 'MPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('survival', 'MPA', (65, 73))	('IDO1', 'Gene', (22, 26))	('shorter', 'NegReg', (57, 64))
19820	32117235	A recent study described dramatically suppressed tumor growth upon IDO1 knockdown by increasing the number of CD4+ and CD8+ T cells in murine GBM models.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('GBM', 'Disease', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('increasing', 'PosReg', (85, 95))	('suppressed', 'NegReg', (38, 48))	('tumor', 'Disease', (49, 54))	('GBM', 'Disease', 'MESH:D005909', (142, 145))	('knockdown', 'Var', (72, 81))	('murine', 'Species', '10090', (135, 141))	('IDO1', 'Gene', (67, 71))
19860	32117235	Lastly, specific KP inhibition may increase the efficacy of standard drugs by restoring immune function and thus improve patients' outcome.	('increase', 'PosReg', (35, 43))	('restoring', 'PosReg', (78, 87))	('specific', 'Var', (8, 16))	('immune function', 'MPA', (88, 103))	('efficacy', 'MPA', (48, 56))	('patients', 'Species', '9606', (121, 129))	('improve', 'PosReg', (113, 120))
19950	31768815	adhesion to the brain vasculature, extravasation, and outgrowth in a brain-specific environment that supplies oxygen and nutrients, while clamping the external carotid artery is expected to further reduce metastases to other organs.	('reduce', 'NegReg', (198, 204))	('outgrowth', 'CPA', (54, 63))	('metastases', 'Disease', (205, 215))	('extravasation', 'CPA', (35, 48))	('clamping', 'Var', (138, 146))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('oxygen', 'Chemical', 'MESH:D010100', (110, 116))	('adhesion', 'Var', (0, 8))
19965	31768815	of PET scans of patients with metastatic renal cell carcinoma given 89Zr-bevacizumab suggested that bevacizumab accumulates in metastatic brain lesions but not in normal brain parenchyma, though it was uncertain whether there was enough accumulated bevacizumab to provide efficacy.	('metastatic brain lesions', 'CPA', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('89Zr-bevacizumab', 'Var', (68, 84))	('patients', 'Species', '9606', (16, 24))	('bevacizumab', 'Chemical', 'MESH:D000068258', (249, 260))	('accumulates', 'PosReg', (112, 123))	('metastatic renal cell carcinoma', 'Disease', (30, 61))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (30, 61))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))	('bevacizumab', 'Chemical', 'MESH:D000068258', (100, 111))	('bevacizumab', 'Chemical', 'MESH:D000068258', (73, 84))
20005	31931429	More than 90% of embryos undergoing injection of U87MG cells survived the procedure (an efficiency that was similar to the in utero electroporation), and 92% of them presented tumor foci at E18.5 (Figure 1B, tumor xenografts [TX]).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('U87MG cells', 'Var', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('U87MG', 'CellLine', 'CVCL:0022', (49, 54))
20006	31931429	The number of dsRed+ human U87MG TX per brain (Figure 1C) increased until E18.5 (mean 2 at E13.5; 4 at E15.5, and 6 at E18.5 Figure 1C, red dots), whereas it decreased after birth (mean 5 at postnatal day 7 [P7], Figure 1C, red dot).	('E13.5', 'Var', (91, 96))	('human', 'Species', '9606', (21, 26))	('E15.5', 'Var', (103, 108))	('E18.5', 'Var', (119, 124))	('U87MG', 'CellLine', 'CVCL:0022', (27, 32))
20008	31931429	Measurements of TX revealed an exponential growth of their volume in both embryonic and postnatal mouse brains, but the highest volumetric increment occurred between E18.5 and P7 (Figures 1D and 1E, mean tumor volume 0.0038 +- 0.0009 mm3 at E13.5; 0.0351 +- 0.0081 mm3 at E15.5; 0.3339 +- 0.1276 mm3 at E18.5; and 3.7902 +- 1.0249 mm3 at P7).	('E18.5', 'Var', (166, 171))	('E18.5', 'Var', (303, 308))	('0.0351 +- 0.0081 mm3', 'Var', (248, 268))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('0.0038 +- 0.0009 mm3', 'Var', (217, 237))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('E13.5', 'Var', (241, 246))	('E15.5', 'Var', (272, 277))	('tumor', 'Disease', (204, 209))	('mouse', 'Species', '10090', (98, 103))
20016	31931429	Volumetric analysis (Figure 2A and Video S1 and S2) revealed a significant increase in PDX volume and in the percentage of host brain occupancy from E18.5 to P7 (Figure 2B and Video S1 and S2), although at E18.5 mean volume of PDX was significantly smaller than TX at the same time post-injection (Figure 2B PDX: 0.017 +- 0.01 mm3 versus TX: 0.33 +- 0.13 mm3 E18.5).	('PDX volume', 'CPA', (87, 97))	('PDX', 'Chemical', 'MESH:C113421', (87, 90))	('PDX', 'Chemical', 'MESH:C113421', (227, 230))	('PDX', 'Chemical', 'MESH:C113421', (308, 311))	('increase', 'PosReg', (75, 83))	('smaller', 'NegReg', (249, 256))	('E18.5', 'Var', (206, 211))
20017	31931429	In contrast, nuclear density in PDX did not change between E18.5 and P7 (Figure 2C), being comparable with TX at respective times (Figure 1).	('nuclear', 'MPA', (13, 20))	('PDX', 'Chemical', 'MESH:C113421', (32, 35))	('E18.5', 'Var', (59, 64))
20053	31931429	We first quantified total lymphocytes by flow cytometry forward and side scattering in bone marrow (BM) and peripheral blood from control mice at P7, P15, P21, and adult (Figures 5A and S3).	('P15', 'Gene', (150, 153))	('P21', 'Var', (155, 158))	('mice', 'Species', '10090', (138, 142))	('P15', 'Gene', '12579', (150, 153))
20058	31931429	Remarkably, nearly 60% of brains supported human PDX at P28, whereas the number of human TX (U87MG cell line) dramatically decreased postnatally (Figure 5E), in agreement with the known immune-escape properties of GBM in patients.	('patients', 'Species', '9606', (221, 229))	('PDX', 'Chemical', 'MESH:C113421', (49, 52))	('U87MG', 'CellLine', 'CVCL:0022', (93, 98))	('GBM', 'Phenotype', 'HP:0012174', (214, 217))	('decreased', 'NegReg', (123, 132))	('P28', 'Var', (56, 59))	('human', 'Species', '9606', (83, 88))	('human', 'Species', '9606', (43, 48))
20063	31931429	We found infiltration of IBA1+ cells in TX and PDX from E13.5 up to P28 (Figures 5F-5I and S4).	('E13.5', 'Var', (56, 61))	('IBA1', 'Gene', '199', (25, 29))	('IBA1', 'Gene', (25, 29))	('PDX', 'Chemical', 'MESH:C113421', (47, 50))
20065	31931429	Quantification of tumor cell composition at P7 and P28 revealed a similar decrease in proportions of dsRed+ cells in both TX and PDX (Figures 5F and S4; proportions of total dsRed+ or IBA1+ cells over total nuclei in TX or PDX per brain).	('IBA1', 'Gene', '199', (184, 188))	('decrease', 'NegReg', (74, 82))	('P28', 'Var', (51, 54))	('PDX', 'Chemical', 'MESH:C113421', (223, 226))	('tumor', 'Disease', (18, 23))	('PDX', 'Chemical', 'MESH:C113421', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('IBA1', 'Gene', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
20069	31931429	In contrast, the proportion of IBA1+CD68 + cells over total IBA1+ cells in PDX significantly decreased from E18.5 to P21 and was significantly lower at P7 compared with TX, consistent with the higher number of PDX compared with TX tumors in postnatal brains of WT mice (Figure 5E).	('E18.5', 'Var', (108, 113))	('PDX', 'Chemical', 'MESH:C113421', (210, 213))	('IBA1', 'Gene', (60, 64))	('P21', 'Var', (117, 120))	('PDX', 'Disease', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('lower', 'NegReg', (143, 148))	('TX tumors', 'Disease', 'MESH:D009369', (228, 237))	('decreased', 'NegReg', (93, 102))	('mice', 'Species', '10090', (264, 268))	('PDX', 'Chemical', 'MESH:C113421', (75, 78))	('IBA1', 'Gene', (31, 35))	('IBA1', 'Gene', '199', (31, 35))	('TX tumors', 'Disease', (228, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('IBA1', 'Gene', '199', (60, 64))
20070	31931429	Because PDX persisted longer in postnatal brains and a lower proportion of reactive microglia/macrophages was associated with PDX, compared with TX, these results indicate that our model allows one to study tumor-specific interactions with the immune system of the WT host.	('PDX', 'Chemical', 'MESH:C113421', (126, 129))	('PDX', 'Chemical', 'MESH:C113421', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('lower', 'NegReg', (55, 60))	('tumor', 'Disease', (207, 212))	('PDX', 'Var', (126, 129))	('interactions', 'Interaction', (222, 234))
20096	31903105	Conclusions: In HER2+ BC oncogenic miR-429 is able to regulate HIF1alpha pathway by directly targeting VHL mRNA, a molecule important for the degradation of HIF1alpha.	('BC', 'Phenotype', 'HP:0003002', (22, 24))	('HIF1alpha', 'Gene', (157, 166))	('VHL', 'Gene', '7428', (103, 106))	('regulate', 'Reg', (54, 62))	('miR-429', 'Var', (35, 42))	('HIF1alpha', 'Gene', '3091', (157, 166))	('HIF1alpha', 'Gene', (63, 72))	('BC', 'Disease', 'MESH:D001943', (22, 24))	('HIF1alpha', 'Gene', '3091', (63, 72))	('targeting', 'Reg', (93, 102))	('VHL', 'Gene', (103, 106))
20097	31903105	The overexpression of miR-429, observed in HER2+ BC, causes increased proliferation and migration of the BC cells.	('miR-429', 'Gene', (22, 29))	('HER2+', 'Var', (43, 48))	('BC', 'Phenotype', 'HP:0003002', (105, 107))	('BC', 'Disease', 'MESH:D001943', (105, 107))	('proliferation', 'CPA', (70, 83))	('migration', 'CPA', (88, 97))	('overexpression', 'PosReg', (4, 18))	('BC', 'Phenotype', 'HP:0003002', (49, 51))	('increased', 'PosReg', (60, 69))	('BC', 'Disease', 'MESH:D001943', (49, 51))
20098	31903105	More important, silencing miR-429 succeeds in delaying tumor growth, thus miR-429 could be proposed as a therapeutic probe in HER2+ BC tumors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('BC', 'Disease', 'MESH:D001943', (132, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('miR-429', 'Gene', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (55, 60))	('silencing', 'Var', (16, 25))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('BC', 'Phenotype', 'HP:0003002', (132, 134))	('delaying', 'NegReg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
20104	31903105	In 1987, D. Slamon described amplification of HER2 gene in ~30% of all clinical samples of BC.	('BC', 'Phenotype', 'HP:0003002', (91, 93))	('amplification', 'Var', (29, 42))	('BC', 'Disease', 'MESH:D001943', (91, 93))	('HER2', 'Protein', (46, 50))	('clinical samples', 'Species', '191496', (71, 87))
20116	31903105	miR-429 demonstrated to be a diagnostic molecule involved in the control of HIF1alpha pathway, having as a direct target VHL gene.	('VHL', 'Gene', '7428', (121, 124))	('VHL', 'Gene', (121, 124))	('miR-429', 'Var', (0, 7))	('HIF1alpha', 'Gene', (76, 85))	('HIF1alpha', 'Gene', '3091', (76, 85))
20149	31903105	miRNA increase or decrease were obtained in SKBR3 cell line by transfection of sense or antisense oligonucleotide (Sigma Aldrich) with metafectene reagents (Biontex, Germany), following manufacturer's instruction.	('antisense', 'Var', (88, 97))	('metafectene', 'Chemical', 'MESH:C500466', (135, 146))	('SKBR3', 'CellLine', 'CVCL:0033', (44, 49))	('transfection', 'Reg', (63, 75))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('decrease', 'NegReg', (18, 26))	('Ge', 'Chemical', 'MESH:D005857', (166, 168))	('increase', 'PosReg', (6, 14))
20157	31903105	After washing the cells, new fresh medium was added, and miRNAs were modulated by transfection, as described before.	('modulated', 'Reg', (69, 78))	('transfection', 'Var', (82, 94))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))
20158	31903105	To study the invasion ability of the cells, we performed the Boyden's chamber test on SKBR3 in the presence of miR-429 silencing.	('silencing', 'Var', (119, 128))	('SKBR3', 'CellLine', 'CVCL:0033', (86, 91))	('miR-429', 'Gene', (111, 118))
20175	31903105	From our analysis miR-429 control 33 genes over 484 in 3 coupled pathways, miR-190 and miR-584 controls 30 and 49 genes over 693 in 3 and 2 coupled pathways, respectively (Table S3).	('miR-584', 'Gene', (87, 94))	('miR-429', 'Var', (18, 25))	('miR-190', 'Gene', (75, 82))	('miR-584', 'Gene', '693169', (87, 94))	('miR-190', 'Gene', '406965', (75, 82))
20177	31903105	miR-429 regulates the major number of pathways: "HIF1 signaling", "Acute Phase Response signaling", "Glioblastoma Multiforme signaling", "P2Y Purigenic Receptor signaling", "CXCR4 signaling " and "Growth hormone signaling".	('regulates', 'Reg', (8, 17))	('Glioblastoma Multiforme', 'Disease', (101, 124))	('miR-429', 'Var', (0, 7))	('Glioblastoma Multiforme', 'Disease', 'MESH:D005909', (101, 124))	('Glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('HIF1', 'Gene', '3091', (49, 53))	('CXCR4', 'Gene', '7852', (174, 179))	('CXCR4', 'Gene', (174, 179))	('HIF1', 'Gene', (49, 53))	('Acute', 'MPA', (67, 72))	('Growth hormone signaling', 'MPA', (197, 221))
20181	31903105	The SKBR3 HER2+ cells compared to MCF10A cells have significantly higher levels of miR-429 compared to normal-like cells (Figure S1A and Figure S2) and lower levels of both miR-190, and miR-584 (Figure S1B and C, respectively).	('levels', 'MPA', (73, 79))	('miR-584', 'Gene', (186, 193))	('miR-190', 'Gene', (173, 180))	('miR-429', 'MPA', (83, 90))	('HER2+', 'Var', (10, 15))	('lower', 'NegReg', (152, 157))	('higher', 'PosReg', (66, 72))	('MCF10A', 'CellLine', 'CVCL:0598', (34, 40))	('SKBR3 HER2+', 'CellLine', 'CVCL:3285', (4, 15))	('miR-190', 'Gene', '406965', (173, 180))	('SKBR3 HER2+', 'Var', (4, 15))	('miR-584', 'Gene', '693169', (186, 193))
20192	31903105	Considering that miR-429 is predicted by in silico analysis to regulate also pathways involved in cell migration and invasion (i.e CXCR4 pathway), we focused on the effects of As miR-429 modulation in wound healing and Boyden's chamber tests.	('CXCR4', 'Gene', (131, 136))	('modulation', 'Var', (187, 197))	('miR-429', 'Gene', (179, 186))	('CXCR4', 'Gene', '7852', (131, 136))	('cell migration', 'CPA', (98, 112))
20226	31903105	Our in vivo experiments on HER2+ BC mouse models confirmed that the silencing of miR-429 impact on tumor cell growth and on tumor volume.	('tumor', 'Disease', (99, 104))	('miR-429', 'Gene', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BC', 'Disease', 'MESH:D001943', (33, 35))	('impact', 'Reg', (89, 95))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('silencing', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('BC', 'Phenotype', 'HP:0003002', (33, 35))	('mouse', 'Species', '10090', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
20237	31903105	The silencing of miR-429, by regulating cell proliferation and invasion by targeting VHL mRNA, could be proposed a new anti-proliferative and anti-metastatic therapeutic strategy, alone or in combination with other drugs, for HER2+ BC patients' treatment.	('BC', 'Disease', 'MESH:D001943', (232, 234))	('VHL', 'Gene', (85, 88))	('targeting', 'Reg', (75, 84))	('miR-429', 'Gene', (17, 24))	('patients', 'Species', '9606', (235, 243))	('invasion', 'CPA', (63, 71))	('VHL', 'Gene', '7428', (85, 88))	('regulating', 'PosReg', (29, 39))	('cell proliferation', 'CPA', (40, 58))	('silencing', 'Var', (4, 13))	('BC', 'Phenotype', 'HP:0003002', (232, 234))
20242	31847917	Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors.	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('mutational', 'Var', (186, 196))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))
20244	31847917	Because this technology produces genome-wide somatic mutation profiles within a reasonable timeframe and at a reasonable cost, many research groups, particularly International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), have produced population-scale whole-exome sequencing (WES) and whole-genome sequencing (WGS) datasets from most common cancer types.	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('mutation', 'Var', (53, 61))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Cancer', 'Disease', (216, 222))	('Cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('Cancer', 'Disease', 'MESH:D009369', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (364, 370))
20247	31847917	Sometimes, mutation calls are contaminated by experimental artifacts that accumulate during tissue handling and sequencing procedures, such as preparation of tissues into formalin-fixed paraffin-embedded (FFPE) samples, 8-oxoG-mediated errors, chimeric reads, and others.	('chimeric reads', 'Var', (244, 258))	('8-oxoG-mediated', 'MPA', (220, 235))	('paraffin', 'Chemical', 'MESH:D010232', (186, 194))	('formalin', 'Chemical', 'MESH:D005557', (171, 179))	('mutation', 'Var', (11, 19))
20248	31847917	In a routine genotyping of KRAS mutations in metastatic colorectal cancer patients, 53 (4.7%) out of 1130 FFPE samples had KRAS mutations that were validated as artifacts due to DNA fragmentation.	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('KRAS', 'Gene', '3845', (27, 31))	('mutations', 'Var', (128, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (123, 127))
20249	31847917	In another study validating the detection of the T790M mutation in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) patients, up to 48.5% of T790M mutations were FFPE-related artifacts.	('NSCLC', 'Disease', (147, 152))	('T790M mutations', 'Var', (179, 194))	('epidermal growth factor receptor', 'Gene', '1956', (71, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('EGFR', 'Gene', '1956', (105, 109))	('patients', 'Species', '9606', (154, 162))	('T790M', 'Mutation', 'rs121434569', (179, 184))	('non-small cell lung cancer', 'Disease', (119, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('epidermal growth factor receptor', 'Gene', (71, 103))	('EGFR', 'Gene', (105, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('T790M', 'Mutation', 'rs121434569', (49, 54))	('T790M', 'Var', (49, 54))
20250	31847917	Moreover, in a clinical trial that investigated the efficacy of the tyrosine kinase inhibitor (TKI) erlotinib in NSCLC patients, previously unidentified EGFR mutations were reported.	('erlotinib', 'Chemical', 'MESH:D000069347', (100, 109))	('patients', 'Species', '9606', (119, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('EGFR', 'Gene', '1956', (153, 157))	('EGFR', 'Gene', (153, 157))	('NSCLC', 'Disease', (113, 118))	('mutations', 'Var', (158, 167))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
20251	31847917	The study concluded a lack of survival benefits in using erlotinib for patients with EGFR mutations and no clinical evidence to distinguish EGFR-mutant and wild-type patients for administration of the TKI.	('EGFR', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('EGFR', 'Gene', (140, 144))	('patients', 'Species', '9606', (71, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (57, 66))	('EGFR', 'Gene', '1956', (85, 89))	('patients', 'Species', '9606', (166, 174))	('EGFR', 'Gene', '1956', (140, 144))
20254	31847917	Recently, the Pan-cancer Analysis of Whole Genomes (PCAWG) consortium generated 65 single-base substitution (SBS) mutational signatures from over 4600 whole cancer genomes and 19,000 cancer exomes; these signatures have been incorporated as version 3 into the v89 release of Catalog of Somatic Mutations in Cancer (COSMIC).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('Pan', 'Gene', '51816', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Disease', (157, 163))	('Cancer', 'Disease', 'MESH:D009369', (307, 313))	('Cancer', 'Disease', (307, 313))	('single-base', 'Var', (83, 94))	('Pan', 'Gene', (14, 17))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
20255	31847917	For example, one of the signatures, termed SBS7, features preferential C>T mutations, whereas SBS4, a mutational spectrum of tobacco smoke exposure, is characterized by C>A mutations with a strong transcriptional strand bias.	('S7', 'Gene', '6264', (45, 47))	('preferential', 'PosReg', (58, 70))	('C>T mutations', 'Var', (71, 84))	('tobacco', 'Species', '4097', (125, 132))
20256	31847917	In fact, the single nucleotide substitutions observed in these artifactual signatures were shown to be enriched in false positive variant calls by a previous investigation on the reliability of WES in breast cancer samples.	('variant', 'Var', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancer', 'Disease', (201, 214))	('single nucleotide substitutions', 'Var', (13, 44))
20260	31847917	In particular, 18 signatures associated with sequencing artifacts are exploited: SBS27, SBS43, SBS45, SBS46, SBS47, SBS48, SBS49, SBS50, SBS51, SBS52, SBS53, SBS54, SBS55, SBS56, SBS57, SBS58, SBS59, and SBS60 (Additional file 2: Figures S5 and S6).	('SBS27', 'Var', (81, 86))	('SBS49', 'Var', (123, 128))	('SBS56', 'Var', (172, 177))	('SBS58', 'Var', (186, 191))	('SBS43', 'Chemical', '-', (88, 93))	('SBS59', 'Var', (193, 198))	('SBS54', 'Var', (158, 163))	('SBS48', 'Var', (116, 121))	('SBS57', 'Var', (179, 184))	('SBS52', 'Var', (144, 149))	('SBS50', 'Var', (130, 135))	('SBS45', 'Var', (95, 100))	('SBS43', 'Var', (88, 93))	('SBS60', 'Var', (204, 209))	('SBS53', 'Var', (151, 156))	('SBS55', 'Var', (165, 170))	('SBS47', 'Var', (109, 114))	('SBS46', 'Var', (102, 107))	('SBS51', 'Var', (137, 142))
20264	31847917	Therefore, M = Mh + Ml, where:  We define the reference mutational signatures as follows:  Note that  represents the probability of the mechanism i (e.g., ultraviolet radiation) to cause a mutation type of j (e.g., cytosine to thymine transition at dipyrimidines) in the COSMIC mutational signatures (65 signatures in version 3).	('cytosine', 'Chemical', 'MESH:D003596', (215, 223))	('cause', 'Reg', (181, 186))	('mutation', 'Var', (189, 197))	('thymine', 'Chemical', 'MESH:D013941', (227, 234))	('dipyrimidines', 'Chemical', '-', (249, 262))
20267	31847917	For the evaluation of FIREVAT variant refinement performance, we used three datasets: the MC3 dataset, TCGA Genomic Data Commons (GDC) dataset, and multi-region WES of breast cancer dataset (Additional file 1: Note S3).	('MC3', 'Gene', (90, 93))	('MC3', 'Gene', '4159', (90, 93))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', (168, 181))	('variant', 'Var', (30, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('GDC', 'Chemical', '-', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
20272	31847917	To establish ground truth, we herein describe how we determined real somatic and artifactual mutations in the MC3 dataset.	('MC3', 'Gene', '4159', (110, 113))	('MC3', 'Gene', (110, 113))	('mutations', 'Var', (93, 102))
20273	31847917	We further selected variants that were validated and statistically powered in either WGS or targeted sequencing in terms of read evidence according to the MC3 definition ("mutval_targeted_status" = "validated_powered" or "mutval_wgs_status" = "validated_powered").	('variants', 'Var', (20, 28))	('MC3', 'Gene', (155, 158))	('MC3', 'Gene', '4159', (155, 158))
20280	31847917	To evaluate the FIREVAT variant refinement performance on the multi-region WES breast cancer samples, we downloaded the supplementary tables from the original manuscript for technical and biological replicates.	('WES breast cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('WES breast cancer', 'Disease', 'MESH:D001943', (75, 92))	('variant', 'Var', (24, 31))
20295	31847917	The second dataset utilized for evaluation of FIREVAT variant refinement performance was the multi-region WES dataset, where breast cancer samples were sequenced multiple times by biological and technical replicates.	('variant', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
20297	31847917	The increase in precision resulting from FIREVAT refinement was also observed in the ICGC-TCGA-DREAM Somatic Mutation Calling Challenge dataset and in additional benchmarking studies.	('DREAM', 'Gene', (95, 100))	('refinement', 'Var', (49, 59))	('precision', 'MPA', (16, 25))	('DREAM', 'Gene', '30818', (95, 100))	('increase', 'PosReg', (4, 12))
20299	31847917	However, a substantial fraction of mutations was attributed to sequencing error signatures such as SBS45 (median weight = 28.4%), SBS43 (median weight = 14.9%), and SBS50 (median weight = 14.7%) (Fig.	('SBS50', 'Var', (165, 170))	('SBS45', 'Gene', (99, 104))	('SBS43', 'Var', (130, 135))	('SBS43', 'Chemical', '-', (130, 135))	('mutations', 'Var', (35, 44))
20311	31847917	For example, in the TCGA-LAML cohort, the artifactual mutations favored regions of repeated adenine sequences (3 bases upstream and 7 bases downstream).	('mutations', 'Var', (54, 63))	('adenine', 'Chemical', 'MESH:D000225', (92, 99))	('favored', 'PosReg', (64, 71))
20314	31847917	In the multi-region WES dataset (SRP070662), SBS51 was detected in 20 (83.3%) out of 24 samples with a median weight of 21.1%, while the first base immediately upstream or downstream of the variant position was commonly guanine.	('guanine', 'Chemical', 'MESH:D006147', (220, 227))	('SBS51', 'Gene', (45, 50))	('guanine', 'Var', (220, 227))
20331	31847917	In conclusion, we have developed a publicly available software toolkit that efficiently removes artifactual variants in cancer samples using mutational signatures.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('variants', 'Var', (108, 116))
20393	30673344	An MR scan within 3 days after resection was obtained in 77 patients (100%) who underwent resection in Amsterdam and in 68 (65%) of 104 in Utrecht.	('resection', 'Var', (90, 99))	('Amsterdam', 'Disease', (103, 112))	('patients', 'Species', '9606', (60, 68))
20446	31215632	Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections in these patients and previous data suggest that fluorescence and 18F-FET-PET both demarcate larger tumor volumes than gadolinium enhanced magnet resonance imaging (MRI).	('5-ALA', 'Chemical', 'MESH:D000622', (26, 31))	('demarcate', 'Reg', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('gadolinium', 'Chemical', 'MESH:D005682', (195, 205))	('tumor', 'Disease', (176, 181))	('fluorescence', 'Var', (125, 137))	('patients', 'Species', '9606', (85, 93))	('18F-FET-PET', 'Var', (142, 153))	('aminolevulinic acid', 'Chemical', 'MESH:D000622', (5, 24))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
20458	31215632	Retrospective and prospective cohort studies have repeatedly demonstrated the resection of Gd+ tumor to be associated with improved prognosis.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('Gd+', 'Chemical', 'MESH:D005682', (91, 94))	('resection', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
20552	31215632	Deficits from surgery in GBM patients have been associated with decreased survival.	('GBM', 'Disease', (25, 28))	('patients', 'Species', '9606', (29, 37))	('GBM', 'Disease', 'MESH:D005909', (25, 28))	('Deficits', 'Var', (0, 8))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('survival', 'MPA', (74, 82))	('decreased', 'NegReg', (64, 73))
20574	31248184	Therefore, their modulation offers a novel strategy to enhance the penetration and improve the efficacy of drugs into the brain, especially for drug-resistant CNS tumors.	('modulation', 'Var', (17, 27))	('efficacy', 'MPA', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('enhance', 'PosReg', (55, 62))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('improve', 'PosReg', (83, 90))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('pro', 'Chemical', 'MESH:D011392', (85, 88))	('penetration', 'CPA', (67, 78))
20595	31248184	In particular, the combination of compound Si306 (Figure 1a), a pyrazolo[3,4-d]pyrimidine derivative with radiotherapy strongly potentiated the suppression of U87 xenograft growth in nude mice with respect to control and single treatments.	('U87 xenograft growth', 'CPA', (159, 179))	('potentiated', 'PosReg', (128, 139))	('nude mice', 'Species', '10090', (183, 192))	('combination', 'Interaction', (19, 30))	('Si306', 'Chemical', '-', (43, 48))	('pyrazolo[3,4-d]pyrimidine', 'Chemical', 'MESH:C014175', (64, 89))	('compound Si306', 'Var', (34, 48))	('suppression', 'NegReg', (144, 155))
20596	31248184	injection, Si306 brain concentration progressively increased during the following 24 h, and the compound appeared to accumulate in the brain.	('Si306', 'Var', (11, 16))	('brain concentration', 'MPA', (17, 36))	('increased', 'PosReg', (51, 60))	('Si306', 'Chemical', '-', (11, 16))	('pro', 'Chemical', 'MESH:D011392', (37, 40))
20597	31248184	Single oral treatment with Si306 prolonged by 30% the survival of mice orthotopically injected with U87 cells.	('prolonged', 'PosReg', (33, 42))	('Si306', 'Var', (27, 32))	('mice', 'Species', '10090', (66, 70))	('pro', 'Chemical', 'MESH:D011392', (33, 36))	('Si306', 'Chemical', '-', (27, 32))	('survival', 'CPA', (54, 62))
20600	31248184	In this study, we investigated the effect of Si306 and its prodrug on P-gp-mediated efflux, interaction with cytochrome P450 isoform 3A4 (CYP3A4), and suggested their potential use as sensitizers in combination with chemotherapeutics.	('investigated', 'Reg', (18, 30))	('Si306', 'Chemical', '-', (45, 50))	('pro', 'Chemical', 'MESH:D011392', (59, 62))	('Si306', 'Var', (45, 50))	('cytochrome P450', 'Gene', '13079', (109, 124))	('cytochrome P450', 'Gene', (109, 124))	('CYP3A4', 'Gene', (138, 144))	('P-gp-mediated efflux', 'MPA', (70, 90))	('interaction', 'Interaction', (92, 103))	('CYP3A4', 'Gene', '1576', (138, 144))
20605	31248184	Si306 and pro-Si306 exerted identical growth inhibitory effect in U87 cells with approximate IC50 values of 3 microM.	('pro-Si306', 'Chemical', '-', (10, 19))	('pro', 'Chemical', 'MESH:D011392', (10, 13))	('Si306', 'Chemical', '-', (0, 5))	('pro', 'Chemical', 'MESH:D011392', (83, 86))	('Si306', 'Chemical', '-', (14, 19))	('Si306', 'Var', (0, 5))	('growth inhibitory', 'MPA', (38, 55))
20606	31248184	Pro-Si306 retained unchanged efficacy in U87-TxR cells and LN-229, while IC50 for Si306 increased to 4.8 microM for U87-TxR and to 8.0 microM for LN-229.	('efficacy', 'MPA', (29, 37))	('Si306', 'Chemical', '-', (82, 87))	('IC50', 'MPA', (73, 77))	('increased', 'PosReg', (88, 97))	('Si306', 'Chemical', '-', (4, 9))	('Si306', 'Var', (82, 87))
20609	31248184	The expression of mRNA mdr1 was unaffected by all examined c-Src inhibitors (Figure 2a), while only dasatinib increased P-gp expression (Figure 2b).	('Src', 'Gene', '20779', (61, 64))	('mdr1', 'Gene', (23, 27))	('P-gp expression', 'MPA', (120, 135))	('Src', 'Gene', (61, 64))	('increased', 'PosReg', (110, 119))	('expression', 'MPA', (4, 14))	('dasatinib', 'Chemical', 'MESH:D000069439', (100, 109))	('mdr1', 'Gene', '18669', (23, 27))	('inhibitors', 'Var', (65, 75))
20610	31248184	According to rhodamine (Rho) 123 (fluorescent P-gp substrate) intracellular accumulation after 30 min, Si306 and its prodrug considerably inhibited P-gp activity, while dasatinib did not show a similar activity (Figure 2c).	('Si306', 'Var', (103, 108))	('pro', 'Chemical', 'MESH:D011392', (117, 120))	('Rho', 'Chemical', 'MESH:D012235', (24, 27))	('Si306', 'Chemical', '-', (103, 108))	('rhodamine', 'Chemical', 'MESH:D012235', (13, 22))	('inhibited', 'NegReg', (138, 147))	('dasatinib', 'Chemical', 'MESH:D000069439', (169, 178))	('P-gp activity', 'MPA', (148, 161))
20613	31248184	Si306 and pro-Si306 led to the inhibition of P-gp function in a concentration-dependent manner illustrated by the progressive increase in Rho 123 accumulation (Figure 3).	('inhibition', 'NegReg', (31, 41))	('pro-Si306', 'Chemical', '-', (10, 19))	('pro', 'Chemical', 'MESH:D011392', (10, 13))	('pro', 'Chemical', 'MESH:D011392', (114, 117))	('P-gp', 'Protein', (45, 49))	('pro-Si306', 'Var', (10, 19))	('Rho', 'Chemical', 'MESH:D012235', (138, 141))	('Rho 123 accumulation', 'MPA', (138, 158))	('Si306', 'Chemical', '-', (0, 5))	('Si306', 'Chemical', '-', (14, 19))	('increase', 'PosReg', (126, 134))	('Si306', 'Var', (0, 5))	('function', 'MPA', (50, 58))
20614	31248184	The IC50 values of P-gp inhibition for Si306 and pro-Si306 were 8.5 microM and 3.8 microM, respectively (Table 2).	('Si306', 'Chemical', '-', (53, 58))	('Si306', 'Chemical', '-', (39, 44))	('pro-Si306', 'Chemical', '-', (49, 58))	('Si306', 'Var', (39, 44))	('inhibition', 'NegReg', (24, 34))	('P-gp', 'Protein', (19, 23))
20616	31248184	Considering the potential of Si306 and pro-Si306 to inhibit P-gp function, we examined their ability to reverse paclitaxel (PTX) resistance in U87-TxR cells (Figure 4 and Table 3).	('PTX', 'Chemical', 'MESH:D017239', (124, 127))	('P-gp', 'Protein', (60, 64))	('pro-Si306', 'Var', (39, 48))	('inhibit', 'NegReg', (52, 59))	('Si306', 'Chemical', '-', (29, 34))	('Si306', 'Chemical', '-', (43, 48))	('Si306', 'Var', (29, 34))	('pro-Si306', 'Chemical', '-', (39, 48))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))
20619	31248184	Si306 and pro-Si306 interaction with CYP3A4 isoform has been evaluated in vitro using testosterone as probe through the quantification of its CYP-3A4 metabolite 6beta-hydroxytestosterone in presence or absence of different concentrations (1-50 muM range) of Si306 and pro-Si306.	('pro-Si306', 'Chemical', '-', (268, 277))	('pro', 'Chemical', 'MESH:D011392', (268, 271))	('Si306', 'Chemical', '-', (0, 5))	('Si306', 'Var', (0, 5))	('CYP', 'Gene', '228005', (142, 145))	('CYP', 'Gene', (37, 40))	('Si306', 'Chemical', '-', (14, 19))	('CYP3A4', 'Gene', '1576', (37, 43))	('testosterone', 'Chemical', 'MESH:D013739', (174, 186))	('pro-Si306', 'Chemical', '-', (10, 19))	('interaction', 'Interaction', (20, 31))	('pro', 'Chemical', 'MESH:D011392', (10, 13))	('Si306', 'Chemical', '-', (258, 263))	('CYP', 'Gene', '228005', (37, 40))	('6beta-hydroxytestosterone', 'Chemical', 'MESH:C025591', (161, 186))	('CYP3A4', 'Gene', (37, 43))	('Si306', 'Var', (258, 263))	('muM', 'Gene', '56925', (244, 247))	('Si306', 'Chemical', '-', (272, 277))	('testosterone', 'Chemical', 'MESH:D013739', (86, 98))	('muM', 'Gene', (244, 247))	('CYP', 'Gene', (142, 145))	('pro', 'Chemical', 'MESH:D011392', (102, 105))
20620	31248184	At the highest concentration used the maximum of inhibition (20%, not significative) was promoted by Si306, while pro-Si306 inhibited the testosterone hydroxylation at a lower concentration (-15%) (Figure 5a).	('testosterone hydroxylation', 'MPA', (138, 164))	('Si306', 'Chemical', '-', (101, 106))	('pro-Si306', 'Var', (114, 123))	('Si306', 'Chemical', '-', (118, 123))	('Si306', 'Var', (101, 106))	('pro', 'Chemical', 'MESH:D011392', (114, 117))	('testosterone', 'Chemical', 'MESH:D013739', (138, 150))	('pro-Si306', 'Chemical', '-', (114, 123))	('mum', 'Gene', '56925', (42, 45))	('inhibited', 'NegReg', (124, 133))	('mum', 'Gene', (42, 45))	('pro', 'Chemical', 'MESH:D011392', (89, 92))
20622	31248184	The plasmatic protein-binding profiles of Si306 and pro-Si306 in 10 muM Human Serum Albumin (HSA) and Alpha-1-acid glycoprotein (AGP) solutions are illustrated in Figure 6.	('Si306', 'Var', (42, 47))	('pro-Si306', 'Chemical', '-', (52, 61))	('pro', 'Chemical', 'MESH:D011392', (120, 123))	('muM', 'Gene', (68, 71))	('muM', 'Gene', '56925', (68, 71))	('pro', 'Chemical', 'MESH:D011392', (14, 17))	('Human', 'Species', '9606', (72, 77))	('pro', 'Chemical', 'MESH:D011392', (52, 55))	('pro-Si306', 'Var', (52, 61))	('Si306', 'Chemical', '-', (42, 47))	('Serum Albumin', 'Gene', '11657', (78, 91))	('Si306', 'Chemical', '-', (56, 61))	('Serum Albumin', 'Gene', (78, 91))	('pro', 'Chemical', 'MESH:D011392', (30, 33))
20623	31248184	Both Si306 and its prodrug presented a one-site binding kinetics for HSA and AGP.	('HSA', 'Protein', (69, 72))	('Si306', 'Chemical', '-', (5, 10))	('AGP', 'Protein', (77, 80))	('Si306', 'Var', (5, 10))	('pro', 'Chemical', 'MESH:D011392', (19, 22))
20624	31248184	As shown, Si306 displayed a high affinity for HSA and AGP (KD 0.35 and 11.49 microM respectively, Table 4).	('HSA', 'Protein', (46, 49))	('affinity', 'Interaction', (33, 41))	('AGP', 'Protein', (54, 57))	('Si306', 'Chemical', '-', (10, 15))	('Si306', 'Var', (10, 15))
20626	31248184	However, for AGP, KD values for Si306 and pro-Si306 were comparable (KD 9.28 muM, Table 4).	('muM', 'Gene', (77, 80))	('Si306', 'Chemical', '-', (32, 37))	('pro-Si306', 'Chemical', '-', (42, 51))	('Si306', 'Var', (32, 37))	('muM', 'Gene', '56925', (77, 80))	('Si306', 'Chemical', '-', (46, 51))
20628	31248184	A pharmacokinetic and biodistribution study was performed in order to further investigate if the observed in vitro inhibitory activity of Si306 against P-gp could significantly affect its gastrointestinal (GI) absorption and its brain penetration.	('Si306', 'Var', (138, 143))	('affect', 'Reg', (177, 183))	('P-gp', 'Protein', (152, 156))	('Si306', 'Chemical', '-', (138, 143))	('brain penetration', 'CPA', (229, 246))
20640	31248184	On the other hand, orally administered Si306 showed its Cmax in liver and kidneys at 1.5 h and 2 h respectively (Figure 7b).	('Si306', 'Chemical', '-', (39, 44))	('Si306', 'Var', (39, 44))	('Cmax', 'MPA', (56, 60))
20642	31248184	Treatment of mice with Si306 did not produce treatment-related mortality at the limit test dose (100 mg/kg), and besides, throughout the four days observation period, no significant changes occurred in the behavior, such as apathy, hyperactivity, vomiting, diarrhea, and morbidity, among the tested animals.	('mice', 'Species', '10090', (13, 17))	('Si306', 'Chemical', '-', (23, 28))	('hyperactivity', 'Disease', 'MESH:D006948', (232, 245))	('diarrhea', 'Phenotype', 'HP:0002014', (257, 265))	('apathy', 'Disease', 'None', (224, 230))	('apathy', 'Disease', (224, 230))	('diarrhea', 'Disease', (257, 265))	('vomiting', 'Phenotype', 'HP:0002013', (247, 255))	('hyperactivity', 'Disease', (232, 245))	('diarrhea', 'Disease', 'MESH:D003967', (257, 265))	('hyperactivity', 'Phenotype', 'HP:0000752', (232, 245))	('Si306', 'Var', (23, 28))	('vomiting', 'Disease', (247, 255))	('vomiting', 'Disease', 'MESH:D014839', (247, 255))	('pro', 'Chemical', 'MESH:D011392', (37, 40))	('apathy', 'Phenotype', 'HP:0000741', (224, 230))
20656	31248184	administration, pro-Si306 demonstrated a comparable efficacy with a slightly increasing median survival time of mice in an orthotopic GBM model.	('pro-Si306', 'Var', (16, 25))	('increasing', 'PosReg', (77, 87))	('median survival time', 'CPA', (88, 108))	('pro-Si306', 'Chemical', '-', (16, 25))	('mice', 'Species', '10090', (112, 116))
20659	31248184	Considering the results obtained in our previous study, herein we decided to evaluate the effect of Si306 and pro-Si306 on P-gp efflux pump, which accounts for GI absorption and BBB penetration of different substrates, including anticancer drugs and TKIs.	('P-gp efflux pump', 'MPA', (123, 139))	('Si306', 'Chemical', '-', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Si306', 'Var', (100, 105))	('pro-Si306', 'Chemical', '-', (110, 119))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('Si306', 'Chemical', '-', (100, 105))
20662	31248184	We showed that the novel c-Src inhibitor Si306 and its prodrug possess higher cell growth inhibitory potential with almost double efficacy in comparison with dasatinib.	('higher', 'PosReg', (71, 77))	('Si306', 'Var', (41, 46))	('Src', 'Gene', '20779', (27, 30))	('pro', 'Chemical', 'MESH:D011392', (55, 58))	('cell growth inhibitory potential', 'CPA', (78, 110))	('Src', 'Gene', (27, 30))	('dasatinib', 'Chemical', 'MESH:D000069439', (158, 167))	('Si306', 'Chemical', '-', (41, 46))
20663	31248184	In addition, the effect of Si306 and pro-Si306 was not affected by the presence of MDR phenotype.	('Si306', 'Var', (27, 32))	('MDR', 'Gene', '18669', (83, 86))	('pro-Si306', 'Chemical', '-', (37, 46))	('MDR', 'Gene', (83, 86))	('Si306', 'Chemical', '-', (27, 32))	('Si306', 'Chemical', '-', (41, 46))
20667	31248184	Moreover, Si306 and pro-Si306 induced significant suppression of P-gp activity and their effect was dose-dependent.	('pro-Si306', 'Chemical', '-', (20, 29))	('activity', 'MPA', (70, 78))	('pro-Si306', 'Var', (20, 29))	('P-gp', 'Protein', (65, 69))	('Si306', 'Chemical', '-', (24, 29))	('Si306', 'Chemical', '-', (10, 15))	('suppression', 'NegReg', (50, 61))	('Si306', 'Var', (10, 15))
20669	31248184	In our experimental setting of 72 h simultaneous combined treatment, 0.5 muM of Si306 and pro-Si306 reverted PTX resistance in MDR GBM cells by 3.34 and 7.98-fold, respectively.	('MDR', 'Gene', '18669', (127, 130))	('Si306', 'Chemical', '-', (94, 99))	('pro-Si306', 'Chemical', '-', (90, 99))	('PTX', 'Chemical', 'MESH:D017239', (109, 112))	('reverted', 'PosReg', (100, 108))	('Si306', 'Var', (80, 85))	('PTX resistance', 'MPA', (109, 123))	('muM', 'Gene', '56925', (73, 76))	('MDR', 'Gene', (127, 130))	('muM', 'Gene', (73, 76))	('pro-Si306', 'Var', (90, 99))	('Si306', 'Chemical', '-', (80, 85))
20670	31248184	The sensitization of U87-TxR cells was achieved by concentrations that were significantly lower than those necessary for the optimal cell growth inhibition or P-gp inhibition induced by Si306 and pro-Si306.	('pro-Si306', 'Chemical', '-', (196, 205))	('Si306', 'Chemical', '-', (186, 191))	('Si306', 'Var', (186, 191))	('pro-Si306', 'Var', (196, 205))	('P-gp', 'Enzyme', (159, 163))	('inhibition', 'NegReg', (164, 174))	('Si306', 'Chemical', '-', (200, 205))
20673	31248184	Stronger effects regarding P-gp inhibition and reversal of PTX resistance were observed after pro-Si306 application, indicating a more potent activity of prodrug against P-gp.	('activity', 'MPA', (142, 150))	('inhibition', 'NegReg', (32, 42))	('P-gp', 'MPA', (27, 31))	('pro', 'Chemical', 'MESH:D011392', (94, 97))	('pro-Si306', 'Chemical', '-', (94, 103))	('more potent', 'PosReg', (130, 141))	('PTX', 'Chemical', 'MESH:D017239', (59, 62))	('pro', 'Chemical', 'MESH:D011392', (154, 157))	('pro-Si306', 'Var', (94, 103))
20684	31248184	The evidence that the testosterone 6beta-hydroxylation is not also inhibited by the two compounds at the highest concentration used clearly indicates that both Si306 and its prodrug did not interact with the CYP3A4.	('pro', 'Chemical', 'MESH:D011392', (174, 177))	('testosterone', 'Chemical', 'MESH:D013739', (22, 34))	('Si306', 'Chemical', '-', (160, 165))	('interact', 'Interaction', (190, 198))	('CYP3A4', 'Gene', (208, 214))	('Si306', 'Var', (160, 165))	('CYP3A4', 'Gene', '1576', (208, 214))
20689	31248184	For these reasons, the binding to albumin and alpha 1-acid glycoprotein of Si306 and pro-Si306 was evaluated.	('albumin', 'Protein', (34, 41))	('alpha 1-acid glycoprotein', 'Protein', (46, 71))	('Si306', 'Chemical', '-', (75, 80))	('Si306', 'Chemical', '-', (89, 94))	('Si306', 'Var', (75, 80))	('pro-Si306', 'Chemical', '-', (85, 94))	('binding', 'Interaction', (23, 30))	('pro', 'Chemical', 'MESH:D011392', (85, 88))	('pro', 'Chemical', 'MESH:D011392', (64, 67))
20692	31248184	On the other hand, the very poorly water soluble Si306 displayed a very high affinity for albumin, 60-fold greater than pro-Si306.	('albumin', 'Protein', (90, 97))	('Si306', 'Var', (49, 54))	('affinity', 'Interaction', (77, 85))	('greater', 'PosReg', (107, 114))	('Si306', 'Chemical', '-', (49, 54))	('pro-Si306', 'Chemical', '-', (120, 129))	('water', 'Chemical', 'MESH:D014867', (35, 40))	('Si306', 'Chemical', '-', (124, 129))
20696	31248184	To prove that Si306 could be considered a good drug candidate for the treatment of GBM that is worthy of further development, a PK study after p.o.	('pro', 'Chemical', 'MESH:D011392', (3, 6))	('Si306', 'Var', (14, 19))	('GBM', 'Disease', (83, 86))	('Si306', 'Chemical', '-', (14, 19))
20698	31248184	The plasma half-life (t1/2) resulted comparable between the two routes of administration and the oral bioavailability of Si306 has been estimated around 33.3% in mice, being higher than that reported for dasatinib (14% in mice).	('mice', 'Species', '10090', (222, 226))	('oral bioavailability', 'MPA', (97, 117))	('Si306', 'Var', (121, 126))	('higher', 'PosReg', (174, 180))	('mice', 'Species', '10090', (162, 166))	('dasatinib', 'Chemical', 'MESH:D000069439', (204, 213))	('Si306', 'Chemical', '-', (121, 126))
20701	31248184	In both cases, the concentration of the compound slowly decreased during the next 24 h. Overall, our new results demonstrated a good absorption of Si306 by GI and, most interestingly, an optimal brain penetration, with a 12-fold higher AUC brain/plasma when Si306 was orally administered with respect to the i.v.	('Si306', 'Var', (147, 152))	('higher', 'PosReg', (229, 235))	('AUC brain/plasma', 'MPA', (236, 252))	('brain penetration', 'CPA', (195, 212))	('Si306', 'Chemical', '-', (258, 263))	('Si306', 'Chemical', '-', (147, 152))	('absorption', 'MPA', (133, 143))
20702	31248184	The higher and very fast brain accumulation of oral Si306 could be related to the greater inhibition of p-gp, and possibly saturation of p-gp sites at the BBB, which could be simply a consequence of the orally administrated dose, which was twice that of the i.v..	('inhibition', 'NegReg', (90, 100))	('Si306', 'Var', (52, 57))	('p-gp', 'Gene', (104, 108))	('p-gp', 'Gene', '67078', (137, 141))	('p-gp', 'Gene', '67078', (104, 108))	('p-gp', 'Gene', (137, 141))	('Si306', 'Chemical', '-', (52, 57))	('brain accumulation', 'MPA', (25, 43))
20704	31248184	Finally, in order to verify the safety of Si306 in vivo, an intravenously single-dose toxicity study was performed.	('Si306', 'Var', (42, 47))	('Si306', 'Chemical', '-', (42, 47))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))
20720	31248184	Following the overnight incubation, cells were treated with Si306, pro-Si306 and dasatinib (1-25 microM) for 72 h. In addition, the combined effects of Si306 and pro-Si306 with PTX were evaluated in MDR GBM cells.	('Si306', 'Chemical', '-', (166, 171))	('PTX', 'Chemical', 'MESH:D017239', (177, 180))	('pro-Si306', 'Chemical', '-', (162, 171))	('MDR', 'Gene', '18669', (199, 202))	('dasatinib', 'Chemical', 'MESH:D000069439', (81, 90))	('Si306', 'Chemical', '-', (71, 76))	('Si306', 'Chemical', '-', (60, 65))	('Si306', 'Var', (152, 157))	('pro-Si306', 'Chemical', '-', (67, 76))	('MDR', 'Gene', (199, 202))	('Si306', 'Chemical', '-', (152, 157))	('pro-Si306', 'Var', (162, 171))
20721	31248184	To that end, two concentrations of Si306 and pro-Si306 (0.2 muM and 0.5 muM) were combined with increasing concentrations of PTX (0.1-2 muM) in simultaneous treatment.	('muM', 'Gene', (60, 63))	('PTX', 'Chemical', 'MESH:D017239', (125, 128))	('pro-Si306', 'Chemical', '-', (45, 54))	('muM', 'Gene', (136, 139))	('muM', 'Gene', '56925', (72, 75))	('Si306', 'Var', (35, 40))	('muM', 'Gene', (72, 75))	('pro-Si306', 'Var', (45, 54))	('muM', 'Gene', '56925', (60, 63))	('Si306', 'Chemical', '-', (49, 54))	('muM', 'Gene', '56925', (136, 139))	('Si306', 'Chemical', '-', (35, 40))
20724	31248184	U87-TxR cells, untreated and treated with 5 muM of each compound Si306, pro-Si306 and dasatinib for 72 h were used to isolate total RNA and perform the RT reaction.	('muM', 'Gene', (44, 47))	('Si306', 'Var', (65, 70))	('pro-Si306', 'Chemical', '-', (72, 81))	('Si306', 'Chemical', '-', (65, 70))	('dasatinib', 'Chemical', 'MESH:D000069439', (86, 95))	('muM', 'Gene', '56925', (44, 47))	('Si306', 'Chemical', '-', (76, 81))
20727	31248184	To assess mRNA mdr1 expression level in U87-TxR cells upon 5 muM Si306, pro-Si306 and dasatinib treatments, the quantitative real time PCR (qRT-PCR) was used.	('pro-Si306', 'Chemical', '-', (72, 81))	('Si306', 'Var', (65, 70))	('mdr1', 'Gene', (15, 19))	('muM', 'Gene', (61, 64))	('mdr1', 'Gene', '18669', (15, 19))	('Si306', 'Chemical', '-', (65, 70))	('dasatinib', 'Chemical', 'MESH:D000069439', (86, 95))	('Si306', 'Chemical', '-', (76, 81))	('mRNA', 'MPA', (10, 14))	('expression level', 'MPA', (20, 36))	('muM', 'Gene', '56925', (61, 64))
20735	31248184	Studies were carried out with Si306, pro-Si306, dasatinib, Dex-VER and TQ in U87-TxR cells.	('pro-Si306', 'Var', (37, 46))	('Si306', 'Chemical', '-', (30, 35))	('dasatinib', 'Chemical', 'MESH:D000069439', (48, 57))	('pro-Si306', 'Chemical', '-', (37, 46))	('Dex-VER', 'Chemical', 'MESH:D014700', (59, 66))	('Si306', 'Chemical', '-', (41, 46))	('Si306', 'Var', (30, 35))	('TQ', 'Chemical', 'MESH:C402343', (71, 73))
20738	31248184	To obtain IC50 values for P-gp inhibition, 5 muM Rho 123 was simultaneously applied with the increasing concentrations of Si306, pro-Si306, Dex-VER (1, 2, 5, 10 and 20 muM) and TQ (1, 2, 5, 10 and 20 nM).	('Si306', 'Chemical', '-', (133, 138))	('muM', 'Gene', (168, 171))	('muM', 'Gene', '56925', (45, 48))	('Si306', 'Chemical', '-', (122, 127))	('Dex-VER', 'Chemical', 'MESH:D014700', (140, 147))	('Rho', 'Chemical', 'MESH:D012235', (49, 52))	('muM', 'Gene', (45, 48))	('pro-Si306', 'Chemical', '-', (129, 138))	('TQ', 'Chemical', 'MESH:C402343', (177, 179))	('Si306', 'Var', (122, 127))	('muM', 'Gene', '56925', (168, 171))	('pro-Si306', 'Var', (129, 138))
20743	31248184	In order to determine the binding affinity for Si306 and pro-Si306 to HSA (human serum albumin) and AGP (alpha-1-acid glycoprotein), the protein fluorescence has been monitored by spectroscopy.	('pro', 'Chemical', 'MESH:D011392', (137, 140))	('pro', 'Chemical', 'MESH:D011392', (123, 126))	('pro', 'Chemical', 'MESH:D011392', (57, 60))	('Si306', 'Chemical', '-', (61, 66))	('Si306', 'Chemical', '-', (47, 52))	('pro-Si306', 'Chemical', '-', (57, 66))	('serum albumin', 'Gene', '11657', (81, 94))	('serum albumin', 'Gene', (81, 94))	('human', 'Species', '9606', (75, 80))	('Si306', 'Var', (47, 52))	('binding', 'Interaction', (26, 33))
20745	31248184	The inhibition of cytochrome P450 3A4 isoform by Si306 and pro-Si306 was measured by determining its activity on the substrate testosterone.	('activity on the substrate testosterone', 'MPA', (101, 139))	('cytochrome P450', 'Gene', (18, 33))	('testosterone', 'Chemical', 'MESH:D013739', (127, 139))	('cytochrome P450', 'Gene', '13079', (18, 33))	('Si306', 'Var', (49, 54))	('Si306', 'Chemical', '-', (63, 68))	('Si306', 'Chemical', '-', (49, 54))	('inhibition', 'NegReg', (4, 14))	('pro-Si306', 'Chemical', '-', (59, 68))
20747	31248184	The amount of 6beta-hydroxylated metabolite was assessed in the absence and presence of Si306, pro-Si306 and ketoconazole (testosterone concentration of 100 muM in phosphate buffer 0.025 M, pH 7.4).	('Si306', 'Chemical', '-', (88, 93))	('muM', 'Gene', (157, 160))	('ketoconazole', 'Chemical', 'MESH:D007654', (109, 121))	('testosterone', 'Chemical', 'MESH:D013739', (123, 135))	('6beta-hydroxylated', 'Chemical', '-', (14, 32))	('Si306', 'Chemical', '-', (99, 104))	('Si306', 'Var', (88, 93))	('pro-Si306', 'Chemical', '-', (95, 104))	('phosphate', 'Chemical', 'MESH:D010710', (164, 173))	('muM', 'Gene', '56925', (157, 160))
20788	31248184	Moreover, we reported that Src inhibitors, Si306 and its prodrug possess valuable characteristics for GBM treatment.	('pro', 'Chemical', 'MESH:D011392', (57, 60))	('Src', 'Gene', '20779', (27, 30))	('Si306', 'Chemical', '-', (43, 48))	('Src', 'Gene', (27, 30))	('Si306', 'Var', (43, 48))	('GBM', 'Disease', (102, 105))
20790	31248184	In addition, Si306 and pro-Si306 do not interact with CYP3A4 and possess the ability of binding to plasma proteins.	('CYP3A4', 'Gene', (54, 60))	('pro-Si306', 'Var', (23, 32))	('pro', 'Chemical', 'MESH:D011392', (106, 109))	('CYP3A4', 'Gene', '1576', (54, 60))	('interact', 'Interaction', (40, 48))	('Si306', 'Chemical', '-', (13, 18))	('pro-Si306', 'Chemical', '-', (23, 32))	('Si306', 'Chemical', '-', (27, 32))	('plasma proteins', 'Protein', (99, 114))	('pro', 'Chemical', 'MESH:D011392', (23, 26))	('binding', 'Interaction', (88, 95))	('Si306', 'Var', (13, 18))
20792	31248184	All these features imply that the Src inhibitor Si306 could be considered as a valuable strategy for GBM treatment alone or in combination with other chemotherapeutics.	('Si306', 'Var', (48, 53))	('Src', 'Gene', '20779', (34, 37))	('Src', 'Gene', (34, 37))	('GBM', 'Disease', (101, 104))	('Si306', 'Chemical', '-', (48, 53))
20793	31248184	Furthermore, Si306 could facilitate the accumulation of co-administered drugs into the brain and GBM site, due to its high activity against P-gp present in BBB.	('facilitate', 'PosReg', (25, 35))	('P-gp', 'Protein', (140, 144))	('accumulation', 'MPA', (40, 52))	('Si306', 'Chemical', '-', (13, 18))	('activity', 'MPA', (123, 131))	('Si306', 'Var', (13, 18))
20794	31248184	The following are available online at , Figure S1: Rho 123 accumulation in U87-TxR cells treated with increasing concentrations of TQ (A), Dex-VER (B), Si306 (C) and pro-Si306 (D), Figure S2: LC-MS chromatogram for Si306, Figure S3: LC-MS chromatogram for Si34, used as internal standard for Si306, Figure S4: Mass spectra of (a) Si306 and (b) Si34.	('Dex-VER', 'Chemical', 'MESH:D014700', (139, 146))	('Si306', 'Chemical', '-', (170, 175))	('accumulation', 'PosReg', (59, 71))	('pro-Si306', 'Chemical', '-', (166, 175))	('Si306', 'Chemical', '-', (215, 220))	('Si306', 'Var', (152, 157))	('Rho', 'Chemical', 'MESH:D012235', (51, 54))	('TQ', 'Chemical', 'MESH:C402343', (131, 133))	('Si34', 'Chemical', '-', (344, 348))	('Si306', 'Chemical', '-', (152, 157))	('Si306', 'Chemical', '-', (292, 297))	('Si34', 'Chemical', '-', (256, 260))	('Si306', 'Chemical', '-', (330, 335))
20795	31248184	Table S1: Sensitivity of glioblastoma multiforme (GBM) cells to Si306 and pro-Si306 expressed as IC50 values +- S.D.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (25, 48))	('Si306', 'Chemical', '-', (78, 83))	('Si306', 'Chemical', '-', (64, 69))	('glioblastoma multiforme', 'Disease', (25, 48))	('pro-Si306', 'Chemical', '-', (74, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('Si306', 'Var', (64, 69))
20805	31138764	Kaplan-Meier survival analysis showed that the survival time of all the patients with high IGFBP2 tumors had shorter survival than those with low IGFBP2 (P<0.01).	('survival', 'MPA', (117, 125))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('IGFBP2', 'Gene', '3485', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('IGFBP2', 'Gene', (146, 152))	('IGFBP2', 'Gene', '3485', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('survival', 'MPA', (47, 55))	('IGFBP2', 'Gene', (91, 97))	('high', 'Var', (86, 90))	('shorter', 'NegReg', (109, 116))	('patients', 'Species', '9606', (72, 80))
20807	31138764	Furthermore, expression of IGFBP2 mRNA was related to the occurrence of isocitrate dehydrogenase 1 (IDH1) mutation, high heat shock protein 27 (Hsp27) expression and telomerase reverse transcriptase (TERT) promoter mutation (TERTp+) (P=0.013, 0.015 and 0.016, respectively), and patients with TERTp+/IGFBP2high showed the shortest survival.	('IGFBP2', 'Gene', (27, 33))	('shortest', 'NegReg', (322, 330))	('TERTp', 'Gene', (293, 298))	('TERTp', 'Gene', '7015', (293, 298))	('IGFBP2', 'Gene', '3485', (300, 306))	('mutation', 'Var', (106, 114))	('TERTp', 'Gene', (225, 230))	('TERTp', 'Gene', '7015', (225, 230))	('shock', 'Phenotype', 'HP:0031273', (126, 131))	('IDH1', 'Gene', (100, 104))	('TERT', 'Gene', (225, 229))	('IGFBP2', 'Gene', (300, 306))	('TERT', 'Gene', '7015', (225, 229))	('Hsp27', 'Gene', '3315', (144, 149))	('expression', 'MPA', (151, 161))	('telomerase reverse transcriptase', 'Gene', (166, 198))	('patients', 'Species', '9606', (279, 287))	('isocitrate dehydrogenase 1', 'Gene', (72, 98))	('isocitrate dehydrogenase 1', 'Gene', '3417', (72, 98))	('TERT', 'Gene', (200, 204))	('IGFBP2', 'Gene', '3485', (27, 33))	('TERT', 'Gene', '7015', (200, 204))	('IDH1', 'Gene', '3417', (100, 104))	('Hsp27', 'Gene', (144, 149))	('telomerase reverse transcriptase', 'Gene', '7015', (166, 198))	('TERT', 'Gene', (293, 297))	('TERT', 'Gene', '7015', (293, 297))
20808	31138764	In conclusion, IGFBP2 mRNA expression status is an independent prognostic biomarker in GBMs, and the combination of IGFBP2 mRNA and TERTp status might serve as a prognostic indicator in patients with GBM.	('IGFBP2', 'Gene', '3485', (15, 21))	('IGFBP2', 'Gene', '3485', (116, 122))	('IGFBP2', 'Gene', (116, 122))	('combination', 'Var', (101, 112))	('GBMs', 'Disease', (87, 91))	('IGFBP2', 'Gene', (15, 21))	('TERTp', 'Gene', (132, 137))	('TERTp', 'Gene', '7015', (132, 137))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (200, 203))	('GBMs', 'Phenotype', 'HP:0012174', (87, 91))	('patients', 'Species', '9606', (186, 194))
20818	31138764	RNA sequencing analysis showed that high IGFBP2 transcript level is associated with malignant clinical features of GBMs.	('IGFBP2', 'Gene', (41, 47))	('associated', 'Reg', (68, 78))	('GBMs', 'Phenotype', 'HP:0012174', (115, 119))	('transcript', 'MPA', (48, 58))	('GBMs', 'Disease', (115, 119))	('GBM', 'Phenotype', 'HP:0012174', (115, 118))	('IGFBP2', 'Gene', '3485', (41, 47))	('high', 'Var', (36, 40))
20834	31138764	The probe of human gene IGF binding protein 2 (IGFBP2) was against the transcript NM_000597.2, bp 490 - 1423, ACD#313061, and those of Ubiquitin C (UBC, NM_021009, bp 342-1503, ACD#310041) and DapB (ACD#310043) were used as positive and negative controls, respectively.	('IGF binding protein 2', 'Gene', (24, 45))	('human', 'Species', '9606', (13, 18))	('UBC', 'Gene', '7316', (148, 151))	('bp 490 - 1423', 'Var', (95, 108))	('NM_021009', 'Var', (153, 162))	('UBC', 'Gene', (148, 151))	('NM_000597.2', 'Var', (82, 93))	('IGF binding protein 2', 'Gene', '3485', (24, 45))	('Ubiquitin C', 'Gene', '7316', (135, 146))	('IGFBP2', 'Gene', '3485', (47, 53))	('IGFBP2', 'Gene', (47, 53))	('Ubiquitin C', 'Gene', (135, 146))	('DapB', 'Chemical', '-', (193, 197))
20838	31138764	Nested PCR was performed to amplify the target region of the TERT promoter containing C228 and C250 (chr5: 1295228; chr5: 1295250, respectively; hg19).	('TERT', 'Gene', (61, 65))	('TERT', 'Gene', '7015', (61, 65))	('C250', 'Var', (95, 99))	('C228', 'Var', (86, 90))
20849	31138764	For the same cases, we previously reported high expression of Hsp27 protein and isocitrate dehydrogenase 1 (IDH1) mutation in tumors.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('IDH1', 'Gene', '3417', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('expression', 'MPA', (48, 58))	('Hsp27', 'Gene', (62, 67))	('Hsp27', 'Gene', '3315', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutation', 'Var', (114, 122))	('isocitrate dehydrogenase 1', 'Gene', (80, 106))	('IDH1', 'Gene', (108, 112))	('isocitrate dehydrogenase 1', 'Gene', '3417', (80, 106))
20851	31138764	In the 180 tumors tested, TERT promoter presented a mutation in 55.3% cases (30.3% as C250T and 69.7% as C228T).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('TERT', 'Gene', (26, 30))	('C228T', 'Mutation', 'c.228C>T', (105, 110))	('mutation', 'Reg', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('TERT', 'Gene', '7015', (26, 30))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('C250T', 'Var', (86, 91))	('C228T', 'Var', (105, 110))	('C250T', 'Mutation', 'c.250C>T', (86, 91))
20853	31138764	By the analysis of IGFBP2 mRNA expression and OS of the patients, we observed that the high expression of IGFBP2 mRNA predicts a shorter survival than the low IGFBP2 (mOS = 11.6 vs 16.9 months, P=0.0046, Figure 3A).	('patients', 'Species', '9606', (56, 64))	('IGFBP2', 'Gene', (159, 165))	('mOS', 'Gene', '17451', (167, 170))	('IGFBP2', 'Gene', '3485', (19, 25))	('IGFBP2', 'Gene', (19, 25))	('high', 'Var', (87, 91))	('OS', 'Gene', '17451', (46, 48))	('survival', 'MPA', (137, 145))	('IGFBP2', 'Gene', '3485', (106, 112))	('IGFBP2', 'Gene', (106, 112))	('mOS', 'Gene', (167, 170))	('IGFBP2', 'Gene', '3485', (159, 165))	('shorter', 'NegReg', (129, 136))	('OS', 'Gene', '17451', (168, 170))
20854	31138764	When we exclude the patients who did not receive standard therapy, predicting prognosis of high IGFBP2 expression was more significant (P=0.0008, Figure 3B).	('IGFBP2', 'Gene', (96, 102))	('high', 'Var', (91, 95))	('expression', 'MPA', (103, 113))	('patients', 'Species', '9606', (20, 28))	('IGFBP2', 'Gene', '3485', (96, 102))
20860	31138764	In patients with TERTp mutation (TERTp+), the difference of IGFBP2 mRNA expression divides the patients into two subgroups: low IGFBP2 presented a longer survival, and those with both TERTp mutation (TERTp+) and high IGFBP2 (IGFBP2high) the shortest (mOS = 14.8 vs 9.8 months, P<0.001, Figure 3E).	('IGFBP2', 'Gene', '3485', (128, 134))	('IGFBP2', 'Gene', (225, 231))	('survival', 'MPA', (154, 162))	('IGFBP2', 'Gene', (128, 134))	('longer', 'PosReg', (147, 153))	('mOS', 'Gene', (251, 254))	('TERTp', 'Gene', (184, 189))	('IGFBP2', 'Gene', '3485', (60, 66))	('TERTp', 'Gene', (200, 205))	('TERTp', 'Gene', (33, 38))	('TERTp', 'Gene', '7015', (200, 205))	('patients', 'Species', '9606', (3, 11))	('TERTp', 'Gene', '7015', (184, 189))	('IGFBP2', 'Gene', '3485', (217, 223))	('TERTp', 'Gene', '7015', (33, 38))	('TERTp', 'Gene', (17, 22))	('mOS', 'Gene', '17451', (251, 254))	('TERTp', 'Gene', '7015', (17, 22))	('IGFBP2', 'Gene', '3485', (225, 231))	('patients', 'Species', '9606', (95, 103))	('low', 'Var', (124, 127))	('IGFBP2', 'Gene', (60, 66))	('IGFBP2', 'Gene', (217, 223))
20874	31138764	In 2008, whole-genome analysis led to the discovery of recurrent mutations of IDH1 in secondary (those progressing from lower grade gliomas) rather than in primary GBMs.	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('IDH1', 'Gene', (78, 82))	('GBM', 'Phenotype', 'HP:0012174', (164, 167))	('IDH1', 'Gene', '3417', (78, 82))	('GBMs', 'Phenotype', 'HP:0012174', (164, 168))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('mutations', 'Var', (65, 74))
20880	31138764	Therefore, RISH results of IGFBP2 can predict the survival for the patients with TERT promoter mutation, including those who had received postoperative adjuvant therapy (chemotherapy and/or radiotherapy).	('IGFBP2', 'Gene', (27, 33))	('patients', 'Species', '9606', (67, 75))	('predict', 'Reg', (38, 45))	('TERT', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (81, 85))	('IGFBP2', 'Gene', '3485', (27, 33))	('mutation', 'Var', (95, 103))
20898	30392137	Molecular markers like 1p/19q co-deletion, MGMT promoter methylation and mutation in IDH1 gene are strong predictors of survival for gliomas.	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('MGMT', 'Gene', '4255', (43, 47))	('IDH1', 'Gene', (85, 89))	('MGMT', 'Gene', (43, 47))	('gliomas', 'Disease', (133, 140))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('mutation', 'Var', (73, 81))	('IDH1', 'Gene', '3417', (85, 89))
20935	30392137	Cox multivariate regression was carried out in the training set on 1289 lncRNA controlling for effects from other covariates like age, gender, tumor grade and IDH1 mutation status.	('IDH1', 'Gene', (159, 163))	('tumor', 'Disease', (143, 148))	('IDH1', 'Gene', '3417', (159, 163))	('mutation', 'Var', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
20944	30392137	Despite its high variance, we tested whether including AF131216.5 in the final model will improve the performance of UVA9 on our training (TCGA) and testing dataset (CGGA).	('tested', 'Reg', (30, 36))	('improve', 'PosReg', (90, 97))	('AF131216.5', 'Var', (55, 65))	('performance', 'MPA', (102, 113))	('AF131216', 'Chemical', '-', (55, 63))
20957	30392137	Interestingly, the risk score derived from UVA8 is higher in patients older than 40 years, patients in grade III vs grade II and patients harboring wild-type IDH1 gene (Figure S6).	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (61, 69))	('IDH1', 'Gene', (158, 162))	('higher', 'PosReg', (51, 57))	('UVA8', 'Var', (43, 47))	('IDH1', 'Gene', '3417', (158, 162))
20974	30392137	As expected, prognostic signatures that were specific to GBMs (Zhang6_2013 and Zhou6_2017) show poor concordance index when used to predict survival of lower-grade glioma patients.	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('Zhou6_2017', 'Var', (79, 89))	('patients', 'Species', '9606', (171, 179))	('Zhang6_2013', 'Var', (63, 74))	('poor', 'NegReg', (96, 100))	('concordance', 'MPA', (101, 112))	('glioma', 'Disease', (164, 170))
20982	30392137	Out of 8, 6 lncRNAs (RP11-266K4.14, FLJ37035, RP11-118K6.3, RP11-142A22.3, LINC00641 and RP11-96H19.1) are clustered together because they are more negatively correlated with genes of interferon gamma response pathway (Figure 6C).	('RP11', 'Gene', '26121', (89, 93))	('LINC00641', 'Gene', (75, 84))	('RP11', 'Gene', '26121', (21, 25))	('interferon gamma', 'Gene', '3458', (184, 200))	('RP11', 'Gene', (46, 50))	('negatively', 'NegReg', (148, 158))	('RP11', 'Gene', '26121', (46, 50))	('RP11', 'Gene', (60, 64))	('H19.1', 'CellLine', 'CVCL:H782', (96, 101))	('interferon gamma', 'Gene', (184, 200))	('RP11', 'Gene', '26121', (60, 64))	('RP11', 'Gene', (21, 25))	('LINC00641', 'Gene', '283624', (75, 84))	('RP11', 'Gene', (89, 93))	('FLJ37035', 'Var', (36, 44))
20987	30392137	Based on this dataset, there seems to be somatic mutations in these lncRNAs in other cancers (most prominently DGCR9) but no somatic mutations were found in the 8 lncRNAs in the TCGA lower grade glioma patients.	('DGCR9', 'Gene', '25787', (111, 116))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('mutations', 'Var', (49, 58))	('DGCR9', 'Gene', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('patients', 'Species', '9606', (202, 210))	('glioma', 'Disease', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
20988	30392137	Thus, copy number variation by itself may be predictive for two of the lncRNAs (FLJ37035 and LINC01561), but oddly for the second, there is no correlation between the CNV and level of expression.	('LINC01561', 'Gene', '404216', (93, 102))	('copy number variation', 'Var', (6, 27))	('FLJ37035', 'Var', (80, 88))	('LINC01561', 'Gene', (93, 102))
21002	30392137	Except LINC01561, all 7 lncRNAs (RP11-266K4.14, FLJ37035, RP11-118K6.3, DGCR9, RP11-142A22.3, LINC00641 and RP11-96H19.1) are negatively correlated to most of the protein-coding genes which are up-regulated in response to interferon gamma/alpha, genes regulated by NF-kB in response to TNF, inflammatory response, and genes up-regulated by IL6 via STAT3.	('RP11', 'Gene', (108, 112))	('interferon gamma/alpha', 'Gene', (222, 244))	('RP11', 'Gene', '26121', (58, 62))	('RP11', 'Gene', '26121', (33, 37))	('interferon gamma/alpha', 'Gene', '3458', (222, 244))	('DGCR9', 'Gene', '25787', (72, 77))	('NF-kB', 'Gene', (265, 270))	('up-regulated', 'PosReg', (324, 336))	('RP11', 'Gene', '26121', (79, 83))	('STAT3', 'Gene', (348, 353))	('LINC00641', 'Gene', '283624', (94, 103))	('LINC01561', 'Gene', (7, 16))	('LINC01561', 'Gene', '404216', (7, 16))	('H19.1', 'CellLine', 'CVCL:H782', (115, 120))	('RP11', 'Gene', (58, 62))	('STAT3', 'Gene', '6774', (348, 353))	('IL6', 'Gene', '3569', (340, 343))	('DGCR9', 'Gene', (72, 77))	('TNF', 'Gene', (286, 289))	('RP11', 'Gene', '26121', (108, 112))	('RP11', 'Gene', (33, 37))	('up-regulated', 'PosReg', (194, 206))	('LINC00641', 'Gene', (94, 103))	('RP11', 'Gene', (79, 83))	('IL6', 'Gene', (340, 343))	('FLJ37035', 'Var', (48, 56))	('TNF', 'Gene', '7124', (286, 289))
21009	30392137	For example, DRAIC expression predicts good outcome in gliomas, melanomas, and cancers of the prostate, stomach, liver, kidney and lung.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('DRAIC', 'Gene', '145837', (13, 18))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('melanomas', 'Disease', (64, 73))	('DRAIC', 'Gene', (13, 18))	('kidney', 'Disease', (120, 126))	('stomach', 'Disease', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('liver', 'Disease', (113, 118))	('expression', 'Var', (19, 29))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('cancers of the prostate', 'Disease', (79, 102))	('cancers of the prostate', 'Disease', 'MESH:D011471', (79, 102))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))
21010	30392137	In contrast, expression of LINC00152/CYTOR is predictive of poor outcome in gliomas, and cancers of the head & neck, lung, kidney, liver and pancreas (our unpublished work).	('CYTOR', 'Gene', (37, 42))	('LINC00152', 'Gene', '112597', (27, 36))	('gliomas', 'Disease', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('LINC00152', 'Gene', (27, 36))	('and', 'Disease', (137, 140))	('expression', 'Var', (13, 23))	('CYTOR', 'Gene', '112597', (37, 42))	('cancers', 'Disease', (89, 96))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
21059	28924347	Disruptions of the MMP may lead to broken electron transfer chain, decline in ATP synthesis, and release of proapoptotic molecules from the mitochondria to cytoplasm.	('Disruptions', 'Var', (0, 11))	('release of proapoptotic molecules', 'MPA', (97, 130))	('ATP', 'Chemical', 'MESH:D000255', (78, 81))	('ATP synthesis', 'MPA', (78, 91))	('decline', 'NegReg', (67, 74))	('broken electron transfer chain', 'MPA', (35, 65))	('MMP', 'Gene', (19, 22))
21075	28924347	Similarly, GQDs also significantly dose-dependently increased ROS generation and induced autophagy with an increase in the expression of LC3-II/I and Beclin-1 in macrophages or U251 human glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('increased', 'PosReg', (52, 61))	('expression', 'MPA', (123, 133))	('increase', 'PosReg', (107, 115))	('Beclin-1', 'Gene', (150, 158))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('induced', 'Reg', (81, 88))	('human', 'Species', '9606', (182, 187))	('Beclin-1', 'Gene', '8678', (150, 158))	('increased ROS generation', 'Phenotype', 'HP:0025464', (52, 76))	('autophagy', 'CPA', (89, 98))	('LC3-II/I', 'Gene', (137, 145))	('U251', 'CellLine', 'CVCL:0021', (177, 181))	('glioma', 'Disease', (188, 194))	('GQDs', 'Var', (11, 15))	('ROS', 'MPA', (62, 65))	('ROS', 'Chemical', '-', (62, 65))
21088	28924347	GBMs have been shown to induce mitochondrial damage and provoke autophagy in a human bronchial epithelial cell line (BEAS-2B cells).	('human', 'Species', '9606', (79, 84))	('induce', 'Reg', (24, 30))	('mitochondrial damage', 'Disease', (31, 51))	('provoke', 'PosReg', (56, 63))	('mitochondrial damage', 'Disease', 'MESH:D028361', (31, 51))	('GBMs', 'Var', (0, 4))	('BEAS-2B', 'CellLine', 'CVCL:0168', (117, 124))	('autophagy', 'CPA', (64, 73))
21089	28924347	ROS and NO generation after GNPs treatment resulted in decreased numbers of mitochondria, ER, and Golgi apparatus, and mitochondrial fission-initiated mitochondrial autophagy.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', '-', (0, 3))	('mitochondrial autophagy', 'CPA', (151, 174))	('decreased numbers of mitochondria', 'Phenotype', 'HP:0040013', (55, 88))	('decreased', 'NegReg', (55, 64))
21107	28924347	The results of previous studies have demonstrated that GO/CDDP potentiates CT26 cell death through programmed necrosis when the cells are exposed to a concentration of 50 mg/mL for 24 h. GO/CDDP induces programmed necrosis by increasing the levels of RIP1, RIP3, and HMGB1, a nuclear protein that is released into cytosol and then released from cells after the initiation of necrosis.	('necrosis', 'Disease', (375, 383))	('necrosis', 'Disease', 'MESH:D009336', (110, 118))	('HMGB1', 'Gene', (267, 272))	('RIP1', 'Gene', (251, 255))	('HMGB1', 'Gene', '3146', (267, 272))	('necrosis', 'Disease', 'MESH:D009336', (214, 222))	('CT26', 'CellLine', 'CVCL:7254', (75, 79))	('CDDP', 'Chemical', '-', (190, 194))	('necrosis', 'Disease', (110, 118))	('necrosis', 'Disease', (214, 222))	('GO/CDDP', 'Var', (187, 194))	('induces', 'Reg', (195, 202))	('increasing', 'PosReg', (226, 236))	('levels', 'MPA', (241, 247))	('RIP1', 'Gene', '8737', (251, 255))	('RIP3', 'Gene', '11035', (257, 261))	('RIP3', 'Gene', (257, 261))	('necrosis', 'Disease', 'MESH:D009336', (375, 383))	('CDDP', 'Chemical', '-', (58, 62))
21130	28924347	For example, apoptosis and necrosis appear to be regulated by different forms of caspase-8: a fully processed, heterotetrameric form of caspase-8 induces apoptosis; however, caspase-8 mutants and caspase-8 inhibition activate necroptosis in some cell lines.	('caspase-8', 'Gene', (174, 183))	('caspase-8', 'Gene', '841', (136, 145))	('caspase-8', 'Gene', '841', (81, 90))	('caspase-8', 'Gene', '841', (174, 183))	('necroptosis', 'CPA', (226, 237))	('caspase-8', 'Gene', (196, 205))	('activate', 'PosReg', (217, 225))	('caspase-8', 'Gene', '841', (196, 205))	('apoptosis', 'CPA', (154, 163))	('necrosis', 'Disease', 'MESH:D009336', (27, 35))	('mutants', 'Var', (184, 191))	('caspase-8', 'Gene', (81, 90))	('induces', 'Reg', (146, 153))	('caspase-8', 'Gene', (136, 145))	('necrosis', 'Disease', (27, 35))
21134	28924347	ROS induces the loss of the mitochondrial membrane that potentially initiates both apoptosis and necrosis.	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', '-', (0, 3))	('necrosis', 'Disease', (97, 105))	('mitochondrial', 'Protein', (28, 41))	('loss', 'NegReg', (16, 20))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))	('apoptosis', 'CPA', (83, 92))	('initiates', 'Reg', (68, 77))
21159	27626497	We show that ART enhances the killing effect of TMZ in glioblastoma cell lines and in glioblastoma stem-like cells.	('TMZ', 'Chemical', 'MESH:D000077204', (48, 51))	('ART', 'Var', (13, 16))	('glioblastoma', 'Disease', (55, 67))	('killing effect', 'CPA', (30, 44))	('enhances', 'PosReg', (17, 25))	('ART', 'Chemical', 'MESH:D000077332', (13, 16))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))
21170	27626497	Among these, the minor adduct O6-methylguanine (O6-MeG) represents the most severe killing lesion, provided it is not repaired by O6-methylguanine-DNA methyltransferase (MGMT).	('MGMT', 'Gene', '4255', (170, 174))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (130, 168))	('MGMT', 'Gene', (170, 174))	('O6-methylguanine', 'Var', (30, 46))	('O6-MeG', 'Chemical', 'MESH:C008449', (48, 54))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (130, 146))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (30, 46))	('O6-methylguanine-DNA methyltransferase', 'Gene', (130, 168))
21171	27626497	Mispairing of O6-MeG with thymine during DNA replication leads to O6-MeG/T mismatches that are recognized by the mismatch repair system (MMR), which then performs erroneous repair cycles.	('O6-MeG', 'Chemical', 'MESH:C008449', (14, 20))	('thymine', 'Chemical', 'MESH:D013941', (26, 33))	('O6-MeG/T mismatches', 'Var', (66, 85))	('O6-MeG', 'Chemical', 'MESH:C008449', (66, 72))	('Mispairing', 'Var', (0, 10))	('leads to', 'Reg', (57, 65))
21174	27626497	In addition to apoptosis, it was shown that TMZ also induces autophagy and senescence in glioma cells.	('TMZ', 'Var', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('senescence', 'CPA', (75, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (44, 47))	('glioma', 'Disease', (89, 95))	('autophagy', 'CPA', (61, 70))	('induces', 'Reg', (53, 60))
21179	27626497	Previously, we have shown that ART is a powerful inducer of reactive oxygen species (ROS) in tumor cells, triggering DNA damage including 8-oxo-guanine and DSB.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('triggering', 'Reg', (106, 116))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (60, 83))	('DSB', 'MPA', (156, 159))	('ART', 'Var', (31, 34))	('DSB', 'Chemical', '-', (156, 159))	('8-oxo-guanine', 'MPA', (138, 151))	('ART', 'Chemical', 'MESH:D000077332', (31, 34))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))	('DNA damage', 'MPA', (117, 127))	('8-oxo-guanine', 'Chemical', 'MESH:C024829', (138, 151))
21189	27626497	As shown in Figure 1A, ART induces cell death dose-dependently, with LN229 and A172 strongly responding, while U87MG was more refractory.	('U87MG', 'CellLine', 'CVCL:0022', (111, 116))	('LN229', 'CellLine', 'CVCL:0393', (69, 74))	('ART', 'Var', (23, 26))	('ART', 'Chemical', 'MESH:D000077332', (23, 26))	('cell death', 'CPA', (35, 45))
21190	27626497	The time course experiment shows that cell death occurs 48 h after the onset of treatment and increases further in LN229 and A172 (Figure 1B).	('A172', 'Var', (125, 129))	('LN229', 'CellLine', 'CVCL:0393', (115, 120))	('cell death', 'CPA', (38, 48))	('LN229', 'Var', (115, 120))
21192	27626497	As previously shown, ART provokes intracellular radical formation and DNA breaks.	('DNA breaks', 'CPA', (70, 80))	('provokes', 'Reg', (25, 33))	('ART', 'Var', (21, 24))	('ART', 'Chemical', 'MESH:D000077332', (21, 24))	('intracellular radical formation', 'MPA', (34, 65))
21195	27626497	As shown in Figure 2A, A172 and U87MG cells had a similar basal ROS level, which was however significantly lower than that determined in LN229 cells.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('LN229', 'CellLine', 'CVCL:0393', (137, 142))	('lower', 'NegReg', (107, 112))	('U87MG', 'CellLine', 'CVCL:0022', (32, 37))	('U87MG', 'Var', (32, 37))	('A172', 'Var', (23, 27))
21199	27626497	Further, we investigated in LN229 cells whether ART induces necroptosis and whether ROS formation is mediated by the necrosome, a trigger of necroptosis.	('LN229', 'CellLine', 'CVCL:0393', (28, 33))	('necroptosis', 'CPA', (60, 71))	('induces', 'Reg', (52, 59))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('ART', 'Var', (48, 51))	('ART', 'Chemical', 'MESH:D000077332', (48, 51))
21210	27626497	To investigate whether ART enhances the killing response of glioblastoma cells to TMZ, we compared their survival after single and combined TMZ/ART treatment.	('glioblastoma', 'Disease', (60, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (60, 72))	('ART', 'Var', (23, 26))	('killing', 'CPA', (40, 47))	('ART', 'Chemical', 'MESH:D000077332', (23, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (60, 72))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (140, 143))	('ART', 'Chemical', 'MESH:D000077332', (144, 147))
21211	27626497	As shown in Figure 3, ART significantly enhanced reproductive cell death induced by TMZ in LN229 (Figure 3A, 3B), A172 (Figure 3C, 3D) and U87MG cells (Figure 3E, 3F).	('U87MG', 'CellLine', 'CVCL:0022', (139, 144))	('TMZ', 'Var', (84, 87))	('ART', 'Chemical', 'MESH:D000077332', (22, 25))	('reproductive cell death', 'CPA', (49, 72))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('LN229', 'CellLine', 'CVCL:0393', (91, 96))	('enhanced', 'PosReg', (40, 48))	('LN229', 'Gene', (91, 96))
21215	27626497	Of note, U87MG were more resistant to TMZ than LN229 and A172 cells, which is conform to data obtained with ART (see Figure 1A).	('ART', 'Chemical', 'MESH:D000077332', (108, 111))	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('U87MG', 'CellLine', 'CVCL:0022', (9, 14))	('resistant', 'MPA', (25, 34))	('U87MG', 'Var', (9, 14))	('LN229', 'CellLine', 'CVCL:0393', (47, 52))
21225	27626497	The quantification of gammaH2AX foci revealed that the low dose ART (15 mug/ml) used in this setting did not induce much gammaH2AX (16, 3 and 2 foci/cell for LN229, A172 and U87MG respectively, which was only for LN229 slightly above the control level).	('LN229', 'Var', (158, 163))	('A172', 'Var', (165, 169))	('gammaH2AX', 'Chemical', '-', (22, 31))	('gammaH2AX', 'Chemical', '-', (121, 130))	('ART', 'Chemical', 'MESH:D000077332', (64, 67))	('U87MG', 'CellLine', 'CVCL:0022', (174, 179))	('LN229', 'CellLine', 'CVCL:0393', (213, 218))	('U87MG', 'Var', (174, 179))	('LN229', 'CellLine', 'CVCL:0393', (158, 163))
21244	27626497	Inhibition of NHEJ by DNA-PKi was without effect on TMZ-induced cell death while ameliorating death following ART (Figure 6E).	('DNA-PK', 'Gene', '5591', (22, 28))	('NHEJ', 'Gene', (14, 18))	('death following ART', 'MPA', (94, 113))	('DNA-PK', 'Gene', (22, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('Inhibition', 'Var', (0, 10))	('ameliorating', 'PosReg', (81, 93))	('rat', 'Species', '10116', (87, 90))	('ART', 'Chemical', 'MESH:D000077332', (110, 113))
21247	27626497	We have recently demonstrated that TMZ induces autophagy, which serves as a survival mechanism inhibiting apoptosis.	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('TMZ', 'Var', (35, 38))	('autophagy', 'CPA', (47, 56))	('rat', 'Species', '10116', (24, 27))	('induces', 'Reg', (39, 46))
21251	27626497	TMZ clearly induced autophagy in LN229 glioblastoma cells, while treatment with ART did not affect significantly the basal autophagy level in LN229 and A172 cells, and only slightly enhanced the level in U87MG cells (Figure 7).	('autophagy', 'CPA', (20, 29))	('glioblastoma', 'Disease', (39, 51))	('U87MG', 'CellLine', 'CVCL:0022', (204, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('LN229', 'CellLine', 'CVCL:0393', (142, 147))	('ART', 'Chemical', 'MESH:D000077332', (80, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('TMZ', 'Var', (0, 3))	('LN229', 'CellLine', 'CVCL:0393', (33, 38))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('induced', 'Reg', (12, 19))
21253	27626497	In previous studies we showed that TMZ induces senescence, which reduces the level of cell death by apoptosis and necrosis.	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('necrosis', 'Disease', (114, 122))	('reduces', 'NegReg', (65, 72))	('level of cell death', 'MPA', (77, 96))	('TMZ', 'Var', (35, 38))	('necrosis', 'Disease', 'MESH:D009336', (114, 122))	('senescence', 'MPA', (47, 57))
21262	27626497	Having shown that ART enhances the killing effect of TMZ in vitro, we studied whether ART has an impact on tumor growth following TMZ in a mouse model.	('killing effect', 'CPA', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('enhances', 'PosReg', (22, 30))	('TMZ', 'Chemical', 'MESH:D000077204', (53, 56))	('mouse', 'Species', '10090', (139, 144))	('ART', 'Var', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('ART', 'Chemical', 'MESH:D000077332', (86, 89))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('ART', 'Chemical', 'MESH:D000077332', (18, 21))
21279	27626497	Since TMZ also produces DSB following processing of O6-MeG/T mispairs by the mismatch repair machinery, we hypothesized that the killing effect of TMZ could be ameliorated by concomitant ART treatment.	('ART', 'Chemical', 'MESH:D000077332', (187, 190))	('O6-MeG/T mispairs', 'Var', (52, 69))	('DSB', 'MPA', (24, 27))	('rat', 'Species', '10116', (166, 169))	('DSB', 'Chemical', '-', (24, 27))	('O6-MeG', 'Chemical', 'MESH:C008449', (52, 58))	('TMZ', 'Chemical', 'MESH:D000077204', (147, 150))	('TMZ', 'Chemical', 'MESH:D000077204', (6, 9))
21282	27626497	TMZ induces mostly apoptosis in glioblastoma cells, which is a late response, and this response was enhanced when ART was administered up to 72 h after TMZ application.	('ART', 'Chemical', 'MESH:D000077332', (114, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('apoptosis', 'CPA', (19, 28))	('TMZ', 'Chemical', 'MESH:D000077204', (152, 155))	('enhanced', 'PosReg', (100, 108))	('TMZ', 'Var', (0, 3))	('glioblastoma', 'Disease', (32, 44))	('glioblastoma', 'Disease', 'MESH:D005909', (32, 44))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
21292	27626497	Interestingly, in the low ART dose range used we did not observe an increase in DNA damage following TMZ/ ART, compared to TMZ single treatment.	('DNA damage', 'MPA', (80, 90))	('ART', 'Chemical', 'MESH:D000077332', (26, 29))	('TMZ', 'Chemical', 'MESH:D000077204', (101, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (123, 126))	('ART', 'Chemical', 'MESH:D000077332', (106, 109))	('TMZ/ ART', 'Var', (101, 109))
21296	27626497	Previously we have shown that apoptosis induced by TMZ is preceded by autophagy, which is triggered by the same critical DNA damage that induces apoptosis, namely O6-MeG.	('autophagy', 'CPA', (70, 79))	('apoptosis', 'CPA', (30, 39))	('TMZ', 'Var', (51, 54))	('O6-MeG', 'Chemical', 'MESH:C008449', (163, 169))	('TMZ', 'Chemical', 'MESH:D000077204', (51, 54))
21301	27626497	We should note that ART was previously shown to have the potential of inhibiting autophagy, which was however not assessed in the context of TMZ and low doses of ART.	('TMZ', 'Chemical', 'MESH:D000077204', (141, 144))	('ART', 'Chemical', 'MESH:D000077332', (162, 165))	('inhibiting', 'NegReg', (70, 80))	('ART', 'Var', (20, 23))	('ART', 'Chemical', 'MESH:D000077332', (20, 23))	('autophagy', 'CPA', (81, 90))
21302	27626497	Previously, we also showed that the O6-MeG lesion activates senescence, which is like autophagy a survival mechanism.	('O6-MeG', 'Chemical', 'MESH:C008449', (36, 42))	('activates', 'PosReg', (50, 59))	('senescence', 'CPA', (60, 70))	('O6-MeG lesion', 'Var', (36, 49))	('lesion', 'Var', (43, 49))
21303	27626497	Here we confirm that TMZ induces senescence in glioblastoma cells.	('glioblastoma', 'Disease', (47, 59))	('induces', 'Reg', (25, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('TMZ', 'Var', (21, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('senescence', 'MPA', (33, 43))	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))
21310	27626497	This damage causes mispairings with thymine, which are processed by mismatch repair, resulting in replication blocking secondary lesions, very likely extended DNA gaps and DSB in the second post-treatment replication cycle.	('thymine', 'Chemical', 'MESH:D013941', (36, 43))	('DSB', 'Chemical', '-', (172, 175))	('DSB', 'Disease', (172, 175))	('mispairings', 'Var', (19, 30))	('replication blocking', 'MPA', (98, 118))
21311	27626497	These secondary replication blocking lesions are processed or tolerated by HR, which has a strong impact on the survival of cells following DNA methylation.	('methylation', 'Var', (144, 155))	('rat', 'Species', '10116', (66, 69))	('secondary replication', 'CPA', (6, 27))
21325	27626497	For TMZ it was shown that ART enhances the killing response of rat C6 glioma cells, Here, we extend these studies and report that combined treatment of human glioblastoma cells with TMZ and low dose of ART is superior over single treatments, enhancing killing of glioblastoma and glioblastoma stem-like cells in vitro and in a xenograft mouse model.	('killing', 'CPA', (252, 259))	('ART', 'Chemical', 'MESH:D000077332', (26, 29))	('glioblastoma', 'Disease', (158, 170))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('human', 'Species', '9606', (152, 157))	('C6', 'CellLine', 'CVCL:X905', (67, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('TMZ', 'Chemical', 'MESH:D000077204', (182, 185))	('rat', 'Species', '10116', (63, 66))	('glioblastoma', 'Disease', 'MESH:D005909', (280, 292))	('glioblastoma', 'Disease', (280, 292))	('glioblastoma', 'Disease', 'MESH:D005909', (263, 275))	('ART', 'Var', (26, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (280, 292))	('mouse', 'Species', '10090', (337, 342))	('TMZ', 'Chemical', 'MESH:D000077204', (4, 7))	('enhancing', 'PosReg', (242, 251))	('glioblastoma', 'Disease', (263, 275))	('glioma', 'Disease', (70, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (263, 275))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('ART', 'Chemical', 'MESH:D000077332', (202, 205))
21333	27626497	G112SP cells possess stemness attributes including the propensity for self-renewal, phenotypic plasticity and the ability to generate clonal gliomaspheres in vitro.	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('rat', 'Species', '10116', (129, 132))	('G112SP', 'Var', (0, 6))	('stemness', 'CPA', (21, 29))	('phenotypic plasticity', 'CPA', (84, 105))	('self-renewal', 'CPA', (70, 82))	('gliomas', 'Disease', (141, 148))	('gliomas', 'Disease', 'MESH:D005910', (141, 148))
21335	27626497	The G112SP cells were grown under serum-free condition in Neurobasal-A medium (Life Technologies) containing B-27 supplement (Life Technologies), 20 ng/ml EGF (Biochrom), 10 ng/ml FGF-basic (Biochrom) and 0.1% bovine serum albumin (BSA).	('G112SP', 'Var', (4, 10))	('serum albumin', 'Gene', '213', (217, 230))	('bovine', 'Species', '9913', (210, 216))	('serum albumin', 'Gene', (217, 230))
21342	27626497	To inhibit DNA-PK activity cells were incubated with 1 muM KU-0060648 (Selleckchem) 1 h prior TMZ as well as ART treatment.	('KU-0060648', 'Var', (59, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (94, 97))	('muM', 'Gene', '56925', (55, 58))	('DNA-PK', 'Gene', (11, 17))	('DNA-PK', 'Gene', '5591', (11, 17))	('muM', 'Gene', (55, 58))	('ART', 'Chemical', 'MESH:D000077332', (109, 112))	('inhibit', 'NegReg', (3, 10))	('KU-0060648', 'Chemical', 'MESH:C576809', (59, 69))
21360	27626497	Upon transient transfection with I-SceI expressing plasmid (Addgene), the endonuclease cleaves the modified GFP gene leading to a DSB.	('GFP gene', 'Gene', (108, 116))	('DSB', 'Chemical', '-', (130, 133))	('DSB', 'Disease', (130, 133))	('modified', 'Var', (99, 107))	('cleaves', 'Var', (87, 94))	('leading to', 'Reg', (117, 127))
21484	27471070	Survival was significantly longer in patients receiving cisplatinum plus BCNU compared with that in patients receiving cisplatinum plus etoposide or carboplatinum plus BCNU, with a median survival time of 21.5, 15, and 15 months, respectively (log-rank test P = 0.01).	('cisplatinum', 'Var', (56, 67))	('patients', 'Species', '9606', (37, 45))	('Survival', 'MPA', (0, 8))	('cisplatinum', 'Chemical', 'MESH:D002945', (56, 67))	('BCNU', 'Chemical', 'MESH:D002330', (168, 172))	('longer', 'PosReg', (27, 33))	('BCNU', 'Var', (73, 77))	('patients', 'Species', '9606', (100, 108))	('etoposide', 'Chemical', 'MESH:D005047', (136, 145))	('BCNU', 'Chemical', 'MESH:D002330', (73, 77))	('carboplatinum', 'Chemical', 'MESH:D016190', (149, 162))	('cisplatinum', 'Chemical', 'MESH:D002945', (119, 130))
21558	26105207	In the orthotopic xenograft model, mice implanted with non-target or Src or Fyn knockdown cells showed no differences in survival.	('knockdown', 'Var', (80, 89))	('mice', 'Species', '10090', (35, 39))	('Fyn', 'Gene', (76, 79))
21560	26105207	Those implanted with Lyn knockdown cells had shorter survival, associated with higher overall tumor burden.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('survival', 'CPA', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('shorter', 'NegReg', (45, 52))	('Lyn', 'Gene', (21, 24))	('tumor', 'Disease', (94, 99))	('higher', 'PosReg', (79, 85))	('knockdown', 'Var', (25, 34))
21570	26105207	In gliomas, amplification of the epidermal growth factor (EGF) or the platelet-derived growth factor (PDGF) receptors, or upregulation of integrin receptors such as alphavbeta3 and alphavbeta5 result in increased SFK activity that mediates tumorigenesis.	('activity', 'MPA', (217, 225))	('epidermal growth factor', 'Gene', (33, 56))	('epidermal growth factor', 'Gene', '1950', (33, 56))	('gliomas', 'Disease', (3, 10))	('increased', 'PosReg', (203, 212))	('alphavbeta3', 'Protein', (165, 176))	('tumor', 'Disease', (240, 245))	('alphavbeta5', 'Protein', (181, 192))	('amplification', 'Var', (12, 25))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('SFK', 'Enzyme', (213, 216))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('integrin receptors', 'Protein', (138, 156))	('platelet-derived', 'Protein', (70, 86))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('increased SFK', 'Phenotype', 'HP:0003236', (203, 216))	('upregulation', 'PosReg', (122, 134))
21582	26105207	To begin to understand the molecular details of dasatinib effects in GBM, we used a targeted shRNA approach to knock down expression of Src, Fyn, Yes, and Lyn, in the context of both conventional and xenograft glioma cell line models.	('Yes', 'Gene', (146, 149))	('Fyn', 'Gene', (141, 144))	('Src', 'Gene', (136, 139))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('dasatinib', 'Chemical', 'MESH:D000069439', (48, 57))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('Lyn', 'Gene', (155, 158))	('knock', 'Var', (111, 116))	('glioma', 'Disease', (210, 216))
21584	26105207	We also examined knockdown effects on tumor natural history in vivo, observing characteristics such as survival time, overall tumor burden, density, proliferation, and migration.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('migration', 'CPA', (168, 177))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('proliferation', 'CPA', (149, 162))	('density', 'CPA', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('survival time', 'CPA', (103, 116))	('knockdown', 'Var', (17, 26))	('tumor', 'Disease', (126, 131))
21599	26105207	Human Src (Hs00178494_m1), human Fyn (Hs00941600_m1), human Yes1 (Hs00736972_m1), human Lyn (Hs00176719_m1) and human GAPDH (Hs99999905_m1) primer/probe sets were purchased from Applied Biosystems.	('Hs00941600_m1', 'Var', (38, 51))	('Human', 'Species', '9606', (0, 5))	('Hs00736972_m1', 'Var', (66, 79))	('Yes1', 'Gene', (60, 64))	('human', 'Species', '9606', (27, 32))	('Hs00178494_m1', 'Var', (11, 24))	('Yes1', 'Gene', '7525', (60, 64))	('Hs00176719_m1', 'Var', (93, 106))	('GAPDH', 'Gene', '2597', (118, 123))	('GAPDH', 'Gene', (118, 123))	('human', 'Species', '9606', (112, 117))	('human', 'Species', '9606', (54, 59))	('human', 'Species', '9606', (82, 87))
21604	26105207	Briefly, cells were serum-starved overnight, then 1x105 cells/well in serum-free media were plated on collagen-coated, 8um pore size transwell inserts and allowed to migrate at 37 C, 5% CO2 for 6 hours toward the following chemoattractants: 0.5% FBS (LN229 and SF767), 2% FBS (U251 and TP483) or 5% FBS (U87).	('LN229', 'CellLine', 'CVCL:0393', (251, 256))	('U251', 'Var', (277, 281))	('CO2', 'Chemical', '-', (186, 189))	('TP483', 'Var', (286, 291))
21613	26105207	Whole cell lysates of LN229, SF767, or short-term explant GBM8 cells, either expressing NT or SFK shRNAs, or treated for 17-24 hours with DMSO vehicle or 10microM dasatinib, were prepared using RIPA buffer as described previously.	('shRNAs', 'Gene', (98, 104))	('RIPA buffer', 'Chemical', '-', (194, 205))	('NT', 'Chemical', '-', (88, 90))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('LN229', 'CellLine', 'CVCL:0393', (22, 27))	('SFK', 'Var', (94, 97))	('dasatinib', 'Chemical', 'MESH:D000069439', (163, 172))	('DMSO', 'Chemical', 'MESH:D004121', (138, 142))
21645	26105207	Knockdown of Lyn also slowed LN229 and SF767 growth, but to a lesser (although still statistically significant) extent (Fig.	('slowed', 'NegReg', (22, 28))	('LN229', 'CellLine', 'CVCL:0393', (29, 34))	('Knockdown', 'Var', (0, 9))	('Lyn', 'Gene', (13, 16))
21646	26105207	Using a transwell migration assay, knockdown of Src, Fyn and Yes significantly reduced migration of LN229 cells, but to different extents, while Lyn knockdown had no effect (Fig.	('knockdown', 'Var', (35, 44))	('migration of LN229 cells', 'CPA', (87, 111))	('reduced', 'NegReg', (79, 86))	('LN229', 'CellLine', 'CVCL:0393', (100, 105))	('Src', 'Gene', (48, 51))	('Fyn', 'Gene', (53, 56))
21647	26105207	To understand the differing effects of SFK knockdown on cell growth and migration, we initially examined phosphorylation at the Y416 SFK activation loop site (Supplemental Figure 2).	('Y416', 'Chemical', '-', (128, 132))	('Y416', 'Var', (128, 132))	('SFK', 'Gene', (133, 136))	('examined', 'Reg', (96, 104))
21648	26105207	In general, knockdown of any one SFK produced a decrease in phosphorylation at Y416, but to varying degrees of effect.	('phosphorylation', 'MPA', (60, 75))	('SFK', 'Gene', (33, 36))	('Y416', 'Var', (79, 83))	('knockdown', 'Var', (12, 21))	('decrease', 'NegReg', (48, 56))	('Y416', 'Chemical', '-', (79, 83))
21650	26105207	Specifically, Y228 on p120 catenin, Y172 on Vav2, Y410 on p130 Cas, Y925 on FAK, and Y1105 on p190 RhoGAP A are all known SFK targets.	('FAK', 'Gene', (76, 79))	('FAK', 'Gene', '5747', (76, 79))	('Vav2', 'Gene', (44, 48))	('Vav2', 'Gene', '7410', (44, 48))	('Y228', 'Var', (14, 18))	('p130 Cas', 'Gene', (58, 66))	('p120 catenin', 'Gene', (22, 34))	('Y172', 'Var', (36, 40))	('Y925', 'Var', (68, 72))	('p190 RhoGAP', 'Gene', (94, 105))	('p120 catenin', 'Gene', '1500', (22, 34))	('p190 RhoGAP', 'Gene', '2909', (94, 105))	('Y410', 'Var', (50, 54))	('p130 Cas', 'Gene', '9564', (58, 66))	('Y1105', 'Var', (85, 90))
21652	26105207	Specifically, in LN229 cells knockdown of all four SFKs decreased Y228 phosphorylation on p120 catenin, but only shSrc, shFyn, and shYes were associated with decreased Y172 Vav2, Y410 p130 Cas, and Y925 FAK phosphorylation (Fig.	('LN229', 'CellLine', 'CVCL:0393', (17, 22))	('p120 catenin', 'Gene', '1500', (90, 102))	('decreased', 'NegReg', (158, 167))	('Vav2', 'Gene', '7410', (173, 177))	('p120 catenin', 'Gene', (90, 102))	('Y172', 'Var', (168, 172))	('p130 Cas', 'Gene', '9564', (184, 192))	('decreased', 'NegReg', (56, 65))	('FAK', 'Gene', '5747', (203, 206))	('Y925', 'Var', (198, 202))	('FAK', 'Gene', (203, 206))	('p130 Cas', 'Gene', (184, 192))	('Vav2', 'Gene', (173, 177))
21656	26105207	ShLyn had little effect on LN229 growth and migration and also did not greatly alter the phosphorylation patterns of the motility-related signaling proteins, while knockdown of Src, Fyn, and Yes altered cell growth, migration, and motility-related phosphorylation patterns.	('cell growth', 'CPA', (203, 214))	('altered', 'Reg', (195, 202))	('motility-related', 'CPA', (231, 247))	('Fyn', 'Gene', (182, 185))	('LN229', 'CellLine', 'CVCL:0393', (27, 32))	('Yes', 'Gene', (191, 194))	('knockdown', 'Var', (164, 173))	('migration', 'CPA', (216, 225))	('Src', 'Gene', (177, 180))
21677	26105207	While the survival experiments were ongoing, we assessed the phosphorylation state of the Y416 SFK activation loop site, as well as the motility-related signaling proteins in the GBM8 lines.	('Y416', 'Chemical', '-', (90, 94))	('SFK', 'Gene', (95, 98))	('Y416', 'Var', (90, 94))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))
21679	26105207	ShLyn and shFyn decreased phosphorylation of Y228 on p120 catenin, Y172 on Vav2, Y410 on p130 Cas, and pY925 on FAK .	('Y228', 'Var', (45, 49))	('p130 Cas', 'Gene', (89, 97))	('Vav2', 'Gene', (75, 79))	('pY925', 'Var', (103, 108))	('Y410', 'Var', (81, 85))	('p120 catenin', 'Gene', (53, 65))	('FAK', 'Gene', (112, 115))	('FAK', 'Gene', '5747', (112, 115))	('p120 catenin', 'Gene', '1500', (53, 65))	('Vav2', 'Gene', '7410', (75, 79))	('p130 Cas', 'Gene', '9564', (89, 97))	('Y172', 'Var', (67, 71))	('decreased', 'NegReg', (16, 25))	('phosphorylation', 'MPA', (26, 41))
21680	26105207	ShSrc had no effect on Y228 p120 catenin, Y172 Vav2, or Y410 p130 Cas phosphorylation, but did decrease Y925 FAK phosphorylation.	('decrease', 'NegReg', (95, 103))	('FAK', 'Gene', '5747', (109, 112))	('p120 catenin, Y172 Vav2', 'Gene', '1500', (28, 51))	('FAK', 'Gene', (109, 112))	('p130 Cas', 'Gene', '9564', (61, 69))	('p130 Cas', 'Gene', (61, 69))	('Y925', 'Var', (104, 108))
21681	26105207	ShYes had no effect on Y228 p120 catenin, Y410 p130 Cas, or Y925 FAK phosphorylation, but increased Y172 Vav2 phosphorylation.	('Vav2', 'Gene', '7410', (105, 109))	('Y172', 'Var', (100, 104))	('increased', 'PosReg', (90, 99))	('p130 Cas', 'Gene', '9564', (47, 55))	('FAK', 'Gene', '5747', (65, 68))	('phosphorylation', 'MPA', (69, 84))	('FAK', 'Gene', (65, 68))	('p120 catenin', 'Gene', '1500', (28, 40))	('Vav2', 'Gene', (105, 109))	('p130 Cas', 'Gene', (47, 55))	('p120 catenin', 'Gene', (28, 40))
21683	26105207	Finally, to more closely examine the histological differences and opposite effects on survival of the GBM8-shLyn vs. -shYes tumors, we implanted these cells orthotopically into nude mice and then sacrificed the mice four weeks later.	('-shYes', 'Phenotype', 'HP:0100962', (117, 123))	('GBM8-shLyn', 'Var', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('mice', 'Species', '10090', (182, 186))	('nude mice', 'Species', '10090', (177, 186))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('mice', 'Species', '10090', (211, 215))
21686	26105207	Brains from mice implanted with GBM8-shLyn had a statistically higher % of STEM121-positive pixels compared to the GBM8-NT-implanted brains, indicating that overall tumor burden was higher for these mice (Fig.	('STEM121-positive', 'Gene', (75, 91))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mice', 'Species', '10090', (199, 203))	('GBM8-NT', 'Chemical', '-', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('higher', 'PosReg', (182, 188))	('GBM8-shLyn', 'Var', (32, 42))	('mice', 'Species', '10090', (12, 16))	('GBM', 'Phenotype', 'HP:0012174', (115, 118))	('higher', 'PosReg', (63, 69))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))	('tumor', 'Disease', (165, 170))
21687	26105207	GBM8-shYes-implanted brains had a lower tumor burden vs. the NT mice, but the difference did not reach statistical significance.	('NT', 'Chemical', '-', (61, 63))	('lower', 'NegReg', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('GBM8-shYes-implanted', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mice', 'Species', '10090', (64, 68))	('-shYes', 'Phenotype', 'HP:0100962', (4, 10))
21691	26105207	By both measures there were significantly fewer proliferating GBM8-shYes tumor cells compared to GBM8-NT; there were no differences in proliferation between GBM8-shLyn vs. -NT.	('NT', 'Chemical', '-', (173, 175))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('GBM', 'Phenotype', 'HP:0012174', (157, 160))	('proliferating', 'CPA', (48, 61))	('GBM8-shLyn', 'Var', (157, 167))	('NT', 'Chemical', '-', (102, 104))	('GBM8-NT', 'Chemical', '-', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('tumor', 'Disease', (73, 78))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))	('-shYes', 'Phenotype', 'HP:0100962', (66, 72))
21695	26105207	In addition, a higher overall tumor burden may contribute to the decreased survival of the GBM8-shLyn mice, but the higher tumor burden in these mice is not due to changes in proliferation or the ability of single cells to migrate.	('mice', 'Species', '10090', (102, 106))	('survival', 'CPA', (75, 83))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('tumor', 'Disease', (123, 128))	('higher', 'PosReg', (15, 21))	('decreased', 'NegReg', (65, 74))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('GBM8-shLyn', 'Var', (91, 101))
21701	26105207	The data argue that, unlike cell migration, individual SFKs (Yes, Fyn and Src, but not Lyn) are essential for glioma cell growth in culture.	('glioma', 'Disease', (110, 116))	('Fyn', 'Var', (66, 69))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('Src', 'Var', (74, 77))
21702	26105207	For example, knockdown of Src decreased phosphoY410 p130 Cas in LN229 cells, had little effect on phosphoY410 p130 Cas in SF767 cells, and slightly increased phosphoY410 p130 Cas in GBM8 cells.	('LN229', 'CellLine', 'CVCL:0393', (64, 69))	('p130 Cas', 'Gene', '9564', (110, 118))	('p130 Cas', 'Gene', '9564', (52, 60))	('p130 Cas', 'Gene', '9564', (170, 178))	('Src', 'Gene', (26, 29))	('increased', 'PosReg', (148, 157))	('GBM', 'Phenotype', 'HP:0012174', (182, 185))	('p130 Cas', 'Gene', (110, 118))	('p130 Cas', 'Gene', (52, 60))	('p130 Cas', 'Gene', (170, 178))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (30, 39))
21703	26105207	For example, knockdown of Yes significantly reduced cell growth in all three cell lines as well as migration in the two lines tested (LN229 and SF767).	('cell growth in', 'CPA', (52, 66))	('Yes', 'Gene', (26, 29))	('reduced', 'NegReg', (44, 51))	('migration', 'CPA', (99, 108))	('LN229', 'CellLine', 'CVCL:0393', (134, 139))	('knockdown', 'Var', (13, 22))
21706	26105207	Based on our in culture examination of the individual SFKs relative to growth and migration, we expected that knockdown of Src, Fyn, or Yes would disrupt the tumor biology of orthotopically-implanted GBM8 cells; we expected Lyn knockdown to have no effect in this model.	('knockdown', 'Var', (110, 119))	('Src', 'Gene', (123, 126))	('tumor', 'Disease', (158, 163))	('Fyn', 'Gene', (128, 131))	('disrupt', 'NegReg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Yes', 'Gene', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('GBM', 'Phenotype', 'HP:0012174', (200, 203))
21707	26105207	In line with our expectations, mice implanted with GBM8-shYes cells survived longer compared to mice implanted with GBM8-NT cells.	('longer', 'PosReg', (77, 83))	('mice', 'Species', '10090', (96, 100))	('-shYes', 'Phenotype', 'HP:0100962', (55, 61))	('GBM8-shYes', 'Var', (51, 61))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('mice', 'Species', '10090', (31, 35))	('survived', 'CPA', (68, 76))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('GBM8-NT', 'Chemical', '-', (116, 123))
21717	26105207	Even more surprising than the Src and Fyn results, mice implanted with GBM8-shLyn cells did worse than mice implanted with GBM8-NT or any of the other knockdowns, exhibiting a significant reduction in survival time.	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('mice', 'Species', '10090', (51, 55))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('GBM8-shLyn cells', 'Var', (71, 87))	('mice', 'Species', '10090', (103, 107))	('survival time', 'CPA', (201, 214))	('reduction', 'NegReg', (188, 197))	('GBM8-NT', 'Chemical', '-', (123, 130))
21718	26105207	This last result is particularly striking, as Lyn knockdown had little to no effect on cell growth in culture for any of the three cell lines, had no significant effect on migration of LN229 or SF767 cells (the lines tested in culture), and also had little effect on motility-related signaling in these two cell lines, although it did reduce motility-related phosphorylation in the GBM8 cells.	('knockdown', 'Var', (50, 59))	('motility-related phosphorylation', 'MPA', (342, 374))	('reduce', 'NegReg', (335, 341))	('motility-related signaling', 'MPA', (267, 293))	('GBM', 'Phenotype', 'HP:0012174', (382, 385))	('Lyn', 'Gene', (46, 49))	('LN229', 'CellLine', 'CVCL:0393', (185, 190))
21722	26105207	And in the short-term in vivo experiment, brains from mice implanted with GBM8-shLyn had a higher tumor burden than did the NT mice.	('mice', 'Species', '10090', (127, 131))	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('higher', 'PosReg', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NT', 'Chemical', '-', (124, 126))	('tumor', 'Disease', (98, 103))	('mice', 'Species', '10090', (54, 58))	('GBM8-shLyn', 'Var', (74, 84))
21727	26105207	The in vivo results suggest that signaling through Lyn can be anti-tumorigenic.	('signaling', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('Lyn', 'Protein', (51, 54))
21745	26105207	Perhaps more useful in the context of our results, MLR-1023 is an intriguing allosteric activator of Lyn that does not alter Src or Fyn activity (Yes and Lck were not tested), has already shown clinical usefulness as an antiulcer therapeutic, and is currently in pre-clinical studies for the treatment of Type II diabetes.	('Lck', 'Gene', '3932', (154, 157))	('MLR-1023', 'Var', (51, 59))	('Type II diabetes', 'Disease', 'MESH:D003924', (305, 321))	('Type II diabetes', 'Phenotype', 'HP:0005978', (305, 321))	('Type II diabetes', 'Disease', (305, 321))	('Lck', 'Gene', (154, 157))
21753	25903655	qRT-PCR was performed to examine the distribution of miR-21, miR-103, miR-24, and miR-125.	('miR-21', 'Gene', '406991', (53, 59))	('miR-125', 'Var', (82, 89))	('miR-24', 'Var', (70, 76))	('miR-103', 'Var', (61, 68))	('miR-21', 'Gene', (53, 59))
21781	25903655	We quantitated the absolute copy number of miRNAs frequently used in EV analysis of clinical glioblastoma specimens, in microvesicles and exosomes, including miR-21, miR-103, miR-24, and miR-125.	('miR-125', 'Var', (187, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('miR-24', 'Var', (175, 181))	('miR-103', 'Var', (166, 173))	('glioblastoma', 'Disease', (93, 105))	('miR-21', 'Gene', '406991', (158, 164))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('miR-21', 'Gene', (158, 164))
21797	25903655	The exoRNeasy kit recovered similar amounts of miRNA transcripts (miR-21, miR24, and miR-125) despite lower overall RNA yield.	('lower', 'NegReg', (102, 107))	('RNA yield', 'MPA', (116, 125))	('miR-125', 'Var', (85, 92))	('miRNA transcripts', 'MPA', (47, 64))	('miR-21', 'Gene', (66, 72))	('miR24', 'Var', (74, 79))	('miR-21', 'Gene', '406991', (66, 72))
21825	33036204	However, mutations activating Wnt have been identified primarily in the classic medulloblastoma subtype, which is thought to derive primarily from stem and/or progenitor cells of the ventricular zone in the cerebellum.	('activating', 'PosReg', (19, 29))	('medulloblastoma', 'Disease', (80, 95))	('Wnt', 'Gene', (30, 33))	('mutations', 'Var', (9, 18))	('medulloblastoma', 'Disease', 'MESH:D008527', (80, 95))	('medulloblastoma', 'Phenotype', 'HP:0002885', (80, 95))
21844	33036204	showed that inhibition of vasculogenesis, but not sprouting angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('inhibition', 'Var', (12, 22))	('vasculogenesis', 'CPA', (26, 40))	('mice', 'Species', '10090', (135, 139))	('glioblastoma', 'Disease', (101, 113))
21860	33036204	The same effect of DLL4-Notch signaling has been also observed in gliomas where it was shown that inhibiting the DLL4-Notch signaling pathway increases the degree of vessel sprouting inside the tumor.	('vessel sprouting inside the', 'CPA', (166, 193))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('increases', 'PosReg', (142, 151))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('DLL4', 'Gene', '54567', (113, 117))	('DLL4', 'Gene', '54567', (19, 23))	('tumor', 'Disease', (194, 199))	('gliomas', 'Disease', 'MESH:D005910', (66, 73))	('inhibiting', 'Var', (98, 108))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('gliomas', 'Disease', (66, 73))	('DLL4', 'Gene', (113, 117))	('DLL4', 'Gene', (19, 23))
21888	33036204	In trans-differentiation, the expression of differentiation markers that are typical of EC is higher compared to their expression in cells generated via VM.	('expression', 'MPA', (119, 129))	('expression', 'MPA', (30, 40))	('rat', 'Species', '10116', (143, 146))	('trans-differentiation', 'Var', (3, 24))	('higher', 'PosReg', (94, 100))
21890	33036204	In particular, in vitro studies have shown that glioblastoma stem cells in endothelial cell promoting media can express EC markers like CD31, CD34, and von Willebrand factor, and they can form tubular structures.	('von Willebrand', 'Disease', (152, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('von Willebrand', 'Disease', 'MESH:D014842', (152, 166))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('CD31', 'Gene', (136, 140))	('CD31', 'Gene', '5175', (136, 140))	('glioblastoma', 'Disease', (48, 60))	('tubular structures', 'CPA', (193, 211))	('form', 'Reg', (188, 192))	('CD34', 'Var', (142, 146))
21902	33036204	Regarding pediatric brain tumors, it has been described that loss of the tumor suppressor gene PTEN in medulloblastoma creates an abnormal perivascular niche of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('medulloblastoma', 'Disease', 'MESH:D008527', (103, 118))	('medulloblastoma', 'Phenotype', 'HP:0002885', (103, 118))	('PTEN', 'Gene', '5728', (95, 99))	('brain tumors', 'Disease', (20, 32))	('tumor', 'Disease', (161, 166))	('perivascular niche', 'Phenotype', 'HP:0012520', (139, 157))	('medulloblastoma', 'Disease', (103, 118))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (26, 31))	('loss', 'Var', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('brain tumors', 'Disease', 'MESH:D001932', (20, 32))	('brain tumors', 'Phenotype', 'HP:0030692', (20, 32))	('PTEN', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('brain tumor', 'Phenotype', 'HP:0030692', (20, 31))
21914	33036204	Since the endothelial cells have a key role in the maintenance of functional capillaries, and thus the supply of tissues with oxygen and nutrients, a deregulation of the endothelium is a hallmark in many pathologies, e.g., cardiovascular diseases, tumor growth, and metastasis.	('oxygen', 'Chemical', 'MESH:D010100', (126, 132))	('tumor', 'Disease', (248, 253))	('cardiovascular diseases', 'Disease', (223, 246))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (223, 246))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (223, 246))	('metastasis', 'CPA', (266, 276))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('deregulation', 'Var', (150, 162))
21933	33036204	Finally, high TGF-beta-induced Smad activity has been shown to confer poor prognosis in glioblastoma patients and to promote cell proliferation through the induction of PDGF-B in gliomas.	('glioblastoma', 'Disease', (88, 100))	('patients', 'Species', '9606', (101, 109))	('PDGF-B', 'Gene', (169, 175))	('TGF-beta', 'Gene', (14, 22))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('Smad', 'Protein', (31, 35))	('activity', 'MPA', (36, 44))	('gliomas', 'Phenotype', 'HP:0009733', (179, 186))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('rat', 'Species', '10116', (137, 140))	('cell proliferation', 'CPA', (125, 143))	('PDGF-B', 'Gene', '5155', (169, 175))	('TGF-beta', 'Gene', '7039', (14, 22))	('promote', 'PosReg', (117, 124))	('gliomas', 'Disease', (179, 186))	('gliomas', 'Disease', 'MESH:D005910', (179, 186))	('high', 'Var', (9, 13))
21945	33036204	miR expression can be altered in cancer in a way that favors tumorigenesis and angiogenesis through a variety of mechanisms, including chromosomal changes, epigenetic defects, mutations, and alterations in the machinery involved in miR biogenesis.	('miR', 'Gene', '100616427', (0, 3))	('epigenetic defects', 'Var', (156, 174))	('mutations', 'Var', (176, 185))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('alterations', 'Reg', (191, 202))	('chromosomal changes', 'Var', (135, 154))	('miR', 'Gene', '100616427', (232, 235))	('favors', 'PosReg', (54, 60))	('miR', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('altered', 'Reg', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('rat', 'Species', '10116', (195, 198))	('angiogenesis', 'CPA', (79, 91))	('tumor', 'Disease', (61, 66))	('miR', 'Gene', (232, 235))
21970	33036204	The hypoxic microenvironment of the tumor and the disruption of the BBB observed in most brain malignancies facilitates the recruitment of immune cells such as peripheral macrophages and resident microglial cells to the tumor.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('recruitment', 'MPA', (124, 135))	('BBB', 'Gene', (68, 71))	('disruption', 'Var', (50, 60))	('tumor', 'Disease', (220, 225))	('brain malignancies', 'Disease', 'MESH:D009369', (89, 107))	('facilitates', 'PosReg', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (36, 41))	('brain malignancies', 'Phenotype', 'HP:0030692', (89, 107))	('brain malignancies', 'Disease', (89, 107))
21975	33036204	The interaction of RAGE with its ligand leads to downstream signaling that favors VEGF secretion and genetic disruption of RAGE signaling in mouse glioma models led to prolonged survival.	('RAGE', 'Gene', (19, 23))	('VEGF secretion', 'MPA', (82, 96))	('interaction', 'Interaction', (4, 15))	('RAGE', 'Gene', '11596', (123, 127))	('survival', 'CPA', (178, 186))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('RAGE', 'Gene', (123, 127))	('genetic disruption', 'Var', (101, 119))	('favors', 'PosReg', (75, 81))	('prolonged', 'PosReg', (168, 177))	('mouse', 'Species', '10090', (141, 146))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('glioma', 'Disease', (147, 153))	('RAGE', 'Gene', '11596', (19, 23))
21986	33036204	Therefore, more mutations can be acquired in the DNA which eventually favor the tumor growth even more.	('favor', 'PosReg', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', (80, 85))
21995	33036204	In particular, ROS-induced mutations on p53 can lead to dysregulation of neoangiogenesis and the progression from low- to high-grade gliomas via transcriptional activation of VEGF and FGF expression.	('mutations', 'Var', (27, 36))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('expression', 'MPA', (188, 198))	('FGF', 'Protein', (184, 187))	('p53', 'Gene', (40, 43))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('gliomas', 'Disease', (133, 140))	('p53', 'Gene', '7157', (40, 43))	('lead to', 'Reg', (48, 55))	('activation', 'PosReg', (161, 171))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('neoangiogenesis', 'CPA', (73, 88))	('VEGF', 'Protein', (175, 179))	('dysregulation', 'MPA', (56, 69))	('low-', 'Disease', (114, 118))
21996	33036204	Second, ROS can lead to the activation of membrane receptors with key role in the regulation of the intracellular signaling such as the EGFR and the PDGFR.	('membrane receptors', 'Protein', (42, 60))	('PDGFR', 'Gene', (149, 154))	('PDGFR', 'Gene', '5159', (149, 154))	('ROS', 'Var', (8, 11))	('ROS', 'Chemical', 'MESH:D017382', (8, 11))	('activation', 'PosReg', (28, 38))
22038	33036204	When it comes to chemotherapy, temozolomide (TMZ) is the most commonly used anti-glioma chemotherapeutic agent which acts by alkylating guanine residues and inducing DNA damage and cell cycle arrest.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('arrest', 'Disease', (192, 198))	('DNA damage', 'MPA', (166, 176))	('temozolomide', 'Chemical', 'MESH:D000077204', (31, 43))	('glioma', 'Disease', (81, 87))	('TMZ', 'Chemical', 'MESH:D000077204', (45, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (181, 198))	('arrest', 'Disease', 'MESH:D006323', (192, 198))	('alkylating guanine', 'Chemical', '-', (125, 143))	('alkylating', 'Var', (125, 135))	('guanine residues', 'Protein', (136, 152))	('inducing', 'PosReg', (157, 165))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
22041	33036204	It is also important to mention that according to another study, although TMZ has a very good cytotoxic effect on the glioblastoma cells per se, it has almost no effect on glioblastoma-associated EC and is unable to reduce the peritumoral vascular density in vivo.	('TMZ', 'Var', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('TMZ', 'Chemical', 'MESH:D000077204', (74, 77))	('tumor', 'Disease', (231, 236))	('glioblastoma', 'Disease', (172, 184))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('cytotoxic effect', 'CPA', (94, 110))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
22062	33036204	According to two publications published by two independent groups in 2016, the combined targeting of Ang-2 and VEGF inhibits tumor growth and improves overall survival via targeting not only the EC but also the surrounding TAMs and the resident microglia.	('targeting', 'Var', (88, 97))	('VEGF', 'Gene', (111, 115))	('overall survival', 'CPA', (151, 167))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TAMs', 'Chemical', '-', (223, 227))	('targeting', 'Reg', (172, 181))	('tumor', 'Disease', (125, 130))	('Ang-2', 'Gene', '285', (101, 106))	('Ang-2', 'Gene', (101, 106))	('improves', 'PosReg', (142, 150))	('inhibits', 'NegReg', (116, 124))
22075	33072746	This article focuses on the mechanism of m6A and its effects on the differentiation of cancer stem cells, to provide a basis for elucidating the tumorigenesis mechanisms and exploring new potential therapeutic approaches.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', (145, 150))	('m6A', 'Var', (41, 44))
22078	33072746	Recent emerging studies suggested that m6A is not only involved in the normal physiological processes but also associated with the occurrence of and development of multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (164, 180))	('associated', 'Reg', (111, 121))	('m6A', 'Var', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('multiple cancers', 'Disease', (164, 180))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))
22085	33072746	Therefore, this review focuses on the mechanism of m6A and its role in the differentiation of stem cells and CSCs to determine their roles in malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('malignant tumors', 'Disease', (142, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('malignant tumors', 'Disease', 'MESH:D009369', (142, 158))	('m6A', 'Var', (51, 54))
22088	33072746	The m6A modification affects the pathogenesis of multiple diseases and cancers, not only by affecting coding RNAs but also by affecting non-coding RNAs, such as microRNAs, lncRNAs and circRNAs.	('lncRNAs', 'Disease', (172, 179))	('modification', 'Var', (8, 20))	('non-coding RNAs', 'MPA', (136, 151))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('multiple diseases and cancers', 'Disease', 'MESH:D009369', (49, 78))	('affecting', 'Reg', (126, 135))	('affects', 'Reg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('m6A', 'Gene', (4, 7))	('coding RNAs', 'MPA', (102, 113))	('circRNAs', 'Disease', (184, 192))	('microRNAs', 'Disease', (161, 170))	('affecting', 'Reg', (92, 101))
22097	33072746	ALKBH5, also belonging to the AlkB family, has been identified as a demethylase for m6A modification of RNAs.	('ALKBH5', 'Gene', (0, 6))	('demethylase', 'Gene', (68, 79))	('demethylase', 'Gene', '8932', (68, 79))	('m6A', 'Var', (84, 87))	('ALKBH5', 'Gene', '54890', (0, 6))
22099	33072746	The reversible chemical modification requires the recognition of the m6A-modified RNAs by reader proteins such as YTH domain proteins, nuclear heterogeneous ribonucleoprotein (hnRNP), and eukaryotic initiation factors (eIF), which are involved in the translation, degradation, and miRNA processing of downstream targets in the pathway.	('RNAs', 'Gene', (82, 86))	('hnRNP', 'Gene', '3183', (176, 181))	('hnRNP', 'Gene', (176, 181))	('m6A-modified', 'Var', (69, 81))
22106	33072746	also found that the m6A modification was involved in the regulation of the circadian clock through the clock gene Bmal1.	('circadian clock', 'MPA', (75, 90))	('Bmal1', 'Gene', (114, 119))	('involved', 'Reg', (41, 49))	('regulation', 'MPA', (57, 67))	('Bmal1', 'Gene', '406', (114, 119))	('m6A', 'Var', (20, 23))
22108	33072746	Another study found that m6A modulates sex determination in drosophila.	('drosophila', 'Species', '7227', (60, 70))	('modulates', 'Reg', (29, 38))	('sex determination', 'CPA', (39, 56))	('m6A', 'Var', (25, 28))
22109	33072746	As Sxl (Sex-lethal) is a switch gene involved in sex determination, the m6A modification of the pre-mRNA of Sxl, affected its selective splicing and thereby the regulation of drosophila sex development.	('affected', 'Reg', (113, 121))	('drosophila', 'Species', '7227', (175, 185))	('Sxl', 'Gene', (3, 6))	('selective splicing', 'MPA', (126, 144))	('m6A modification', 'Var', (72, 88))	('Sxl', 'Gene', (108, 111))	('Sxl', 'Gene', '3772180', (3, 6))	('Sex-lethal', 'Gene', (8, 18))	('Sxl', 'Gene', '3772180', (108, 111))	('Sex-lethal', 'Gene', '3772180', (8, 18))
22110	33072746	The m6A modification also causes diseases such as neurodevelopmental delay, immunodeficiency, and male infertility.	('neurodevelopmental delay', 'Disease', 'MESH:D002658', (50, 74))	('causes', 'Reg', (26, 32))	('immunodeficiency', 'Phenotype', 'HP:0002721', (76, 92))	('neurodevelopmental delay', 'Disease', (50, 74))	('m6A modification', 'Var', (4, 20))	('male infertility', 'Disease', (98, 114))	('male infertility', 'Disease', 'MESH:D007248', (98, 114))	('immunodeficiency', 'Disease', 'MESH:D007153', (76, 92))	('male infertility', 'Phenotype', 'HP:0003251', (98, 114))	('neurodevelopmental delay', 'Phenotype', 'HP:0012758', (50, 74))	('infertility', 'Phenotype', 'HP:0000789', (103, 114))	('immunodeficiency', 'Disease', (76, 92))	('modification', 'Var', (8, 20))
22111	33072746	The m6A modulates murine spermatogenesis; after the inactivation of m6A methyltransferases, the level of m6A modification significantly reduced, which could lead to sperm formation disorder.	('sperm formation disorder', 'CPA', (165, 189))	('lead to', 'Reg', (157, 164))	('level', 'MPA', (96, 101))	('m6A modification', 'MPA', (105, 121))	('methyltransferases', 'Enzyme', (72, 90))	('m6A', 'Gene', (68, 71))	('inactivation', 'Var', (52, 64))	('sperm formation disorder', 'Phenotype', 'HP:0008669', (165, 189))	('reduced', 'NegReg', (136, 143))	('murine', 'Species', '10090', (18, 24))
22113	33072746	found that m6A modification controlled T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways.	('STAT5', 'Gene', '20850', (80, 85))	('targeting', 'Reg', (61, 70))	('modification', 'Var', (15, 27))	('SOCS', 'Gene', '12700', (86, 90))	('IL-7', 'Gene', (75, 79))	('STAT5', 'Gene', (80, 85))	('T cell homeostasis', 'MPA', (39, 57))	('SOCS', 'Gene', (86, 90))	('IL-7', 'Gene', '16196', (75, 79))
22115	33072746	It was not surprising, therefore, to find that m6A modification was involved in the occurrence and development of different types of malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('involved', 'Reg', (68, 76))	('malignant tumors', 'Disease', (133, 149))	('malignant tumors', 'Disease', 'MESH:D009369', (133, 149))	('modification', 'Var', (51, 63))	('m6A', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
22116	33072746	m6A modification affects tumor proliferation, differentiation, tumorigenesis, invasion, and metastasis by regulating proto-oncogenes and tumor suppressor genes.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('invasion', 'CPA', (78, 86))	('tumor', 'Disease', (25, 30))	('metastasis', 'CPA', (92, 102))	('regulating', 'Reg', (106, 116))	('affects', 'Reg', (17, 24))	('differentiation', 'CPA', (46, 61))	('modification', 'Var', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('proto-oncogenes', 'MPA', (117, 132))	('m6A', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
22117	33072746	The translation of the m6A modified gene was changed, which affected the development and progression of the tumor.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('affected', 'Reg', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('m6A modified', 'Var', (23, 35))	('translation', 'MPA', (4, 15))	('development', 'CPA', (73, 84))	('changed', 'Reg', (45, 52))
22119	33072746	In human hepatocellular carcinoma, knockdown of METTL3 decreased SOCS2 mRNA modification and increased SOCS2 mRNA expression, suppressing the progression of liver cancer.	('SOCS2', 'Gene', (103, 108))	('human', 'Species', '9606', (3, 8))	('increased', 'PosReg', (93, 102))	('liver cancer', 'Disease', (157, 169))	('hepatocellular carcinoma', 'Disease', (9, 33))	('suppressing', 'NegReg', (126, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('progression', 'CPA', (142, 153))	('knockdown', 'Var', (35, 44))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (9, 33))	('decreased', 'NegReg', (55, 64))	('SOCS2', 'Gene', '8835', (65, 70))	('liver cancer', 'Disease', 'MESH:D006528', (157, 169))	('SOCS2', 'Gene', (65, 70))	('mRNA expression', 'MPA', (109, 124))	('METTL3', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mRNA modification', 'MPA', (71, 88))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (9, 33))	('SOCS2', 'Gene', '8835', (103, 108))	('liver cancer', 'Phenotype', 'HP:0002896', (157, 169))
22120	33072746	Dysregulation of this process results in the development of diseases such as acute myeloid leukemia (AML), an aggressive clonal disease of abnormal HSCs, and primitive progenitors that blocks their myeloid differentiation to generate self-renewing leukemia stem cells (LSCs).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (77, 99))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('abnormal HSCs', 'Disease', 'MESH:D018376', (139, 152))	('Dysregulation', 'Var', (0, 13))	('acute myeloid leukemia', 'Disease', (77, 99))	('leukemia', 'Disease', (248, 256))	('results in', 'Reg', (30, 40))	('AML', 'Disease', (101, 104))	('leukemia', 'Disease', 'MESH:D007938', (248, 256))	('leukemia', 'Phenotype', 'HP:0001909', (248, 256))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (83, 99))	('blocks', 'NegReg', (185, 191))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (77, 99))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('leukemia', 'Disease', 'MESH:D007938', (91, 99))	('leukemia', 'Disease', (91, 99))	('abnormal HSCs', 'Disease', (139, 152))
22122	33072746	demonstrated that G protein-coupled receptor 183 (Gpr183) signaling repressed Notch signaling before the onset of EHT, serving as an indispensable switch for HSPC emergence, and the inhibition of Gpr183 abolished HSPC emergence by significantly upregulating Notch signaling.	('Notch signaling', 'MPA', (258, 273))	('abolished', 'NegReg', (203, 212))	('Gpr183', 'Gene', (50, 56))	('G protein-coupled receptor 183', 'Gene', (18, 48))	('inhibition', 'Var', (182, 192))	('Notch signaling', 'MPA', (78, 93))	('Gpr183', 'Gene', '1880', (50, 56))	('Gpr183', 'Gene', (196, 202))	('Gpr183', 'Gene', '1880', (196, 202))	('HSPC', 'Disease', (213, 217))	('G protein-coupled receptor 183', 'Gene', '1880', (18, 48))	('upregulating', 'PosReg', (245, 257))
22123	33072746	Another investigation revealed that in zebrafish, the stability of notch 1 was mediated by METTL3 through m6A modification and recognized by YTHDF2 to maintain the balance of gene expression during the EHT process, thus regulating the fate of HSCs.	('METTL3', 'Gene', (91, 97))	('notch 1', 'Gene', '30718', (67, 74))	('zebrafish', 'Species', '7955', (39, 48))	('maintain', 'Reg', (151, 159))	('regulating', 'Reg', (220, 230))	('m6A', 'Gene', (106, 109))	('modification', 'Var', (110, 122))	('balance of gene expression', 'MPA', (164, 190))	('notch 1', 'Gene', (67, 74))
22126	33072746	used the conditional mouse model of Ythdf2 knockout and found that the number of functional HSCs increased without skewing lineage differentiation or causing hematopoietic malignancies.	('increased', 'PosReg', (97, 106))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (158, 184))	('mouse', 'Species', '10090', (21, 26))	('knockout', 'Var', (43, 51))	('Ythdf2', 'Gene', (36, 42))	('hematopoietic malignancies', 'Disease', (158, 184))
22128	33072746	reported the aberrant expression of METTL14 in AML cells and its involvement in the regulation of the expression of MYB and MYC through m6A-based post-transcriptional regulation, indicating the critical role of METTL14 in the self-renewal of LSCs/LICs and development of AML.	('AML', 'Disease', (271, 274))	('self-renewal', 'CPA', (226, 238))	('LICs', 'Disease', (247, 251))	('MYC', 'Gene', (124, 127))	('MYC', 'Gene', '4609', (124, 127))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('AML', 'Disease', 'MESH:D015470', (271, 274))	('LICs', 'Disease', 'None', (247, 251))	('METTL14', 'Gene', '57721', (36, 43))	('MYB', 'Gene', '4602', (116, 119))	('AML', 'Disease', (47, 50))	('METTL14', 'Gene', (211, 218))	('METTL14', 'Gene', (36, 43))	('METTL14', 'Gene', '57721', (211, 218))	('involvement', 'Reg', (65, 76))	('MYB', 'Gene', (116, 119))	('aberrant', 'Var', (13, 21))
22129	33072746	demonstrated the oncogenic role of m6A in myeloid leukemia by promoting the translation of c-MYC, BCL2, and PTEN mRNAs (Figure 2).	('m6A', 'Var', (35, 38))	('c-MYC', 'Gene', '4609', (91, 96))	('PTEN', 'Gene', (108, 112))	('promoting', 'PosReg', (62, 71))	('BCL2', 'Gene', (98, 102))	('PTEN', 'Gene', '5728', (108, 112))	('myeloid leukemia', 'Disease', (42, 58))	('myeloid leukemia', 'Disease', 'MESH:D007951', (42, 58))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (42, 58))	('c-MYC', 'Gene', (91, 96))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('BCL2', 'Gene', '596', (98, 102))	('translation', 'MPA', (76, 87))
22135	33072746	In addition to the role of m6A in the regulation of the differentiation of normal hematopoietic process and leukemia hematopoietic process, recent evidence focuses on the role of m6A in regulating tumorigenesis in solid tumors by affecting the fate of CSCs (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('affecting', 'Reg', (230, 239))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', (220, 225))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('leukemia', 'Disease', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('fate of CSCs', 'CPA', (244, 256))	('m6A', 'Var', (179, 182))
22140	33072746	found that abnormal CXCL12/IGF1 signaling and Src activities in patients with breast tumors predicted an increased risk of bone relapse.	('Src', 'Gene', '6714', (46, 49))	('IGF1', 'Gene', '3479', (27, 31))	('patients', 'Species', '9606', (64, 72))	('breast tumors', 'Disease', 'MESH:D001943', (78, 91))	('abnormal', 'Var', (11, 19))	('CXCL12', 'Gene', '6387', (20, 26))	('bone relapse', 'CPA', (123, 135))	('breast tumors', 'Disease', (78, 91))	('IGF1', 'Gene', (27, 31))	('CXCL12', 'Gene', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('breast tumors', 'Phenotype', 'HP:0100013', (78, 91))	('Src', 'Gene', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
22143	33072746	Using animal models found that HIF-induced expression of ALKBH5, an m6A demethylase, promoted the BCSCs phenotype by demethylating and increasing the mRNA levels of NANOG, a pluripotency factor.	('ALKBH5', 'Gene', '54890', (57, 63))	('NANOG', 'Gene', '79923', (165, 170))	('ALKBH5', 'Gene', (57, 63))	('expression', 'Var', (43, 53))	('promoted', 'PosReg', (85, 93))	('NANOG', 'Gene', (165, 170))	('BCSCs', 'Disease', (98, 103))	('demethylase', 'Gene', (72, 83))	('demethylating', 'MPA', (117, 130))	('demethylase', 'Gene', '8932', (72, 83))	('increasing', 'PosReg', (135, 145))
22145	33072746	These findings verified the participation of m6A modification in the differentiation of BCSCs and provided novel therapeutic targets for breast cancer patients, especially in the hypoxic tumor microenvironment (Figure 3).	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('patients', 'Species', '9606', (151, 159))	('modification', 'Var', (49, 61))	('hypoxic tumor', 'Disease', (179, 192))	('participation', 'Reg', (28, 41))	('m6A', 'Gene', (45, 48))	('hypoxic tumor', 'Disease', 'MESH:D009369', (179, 192))
22149	33072746	verified the critical role of m6A modification in the self-renewal and tumorigenesis of glioblastoma stem cells (GSCs) by artificially modifying the expression of METTL3 or METTL14, the key components of the RNA methyltransferase complex, in vitro and in vivo.	('glioblastoma', 'Disease', (88, 100))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('modifying', 'Reg', (135, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('m6A', 'Gene', (30, 33))	('modification', 'Var', (34, 46))	('METTL14', 'Gene', '57721', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('METTL3', 'Gene', (163, 169))	('METTL14', 'Gene', (173, 180))	('expression', 'MPA', (149, 159))	('GSC', 'Chemical', '-', (113, 116))	('tumor', 'Disease', (71, 76))	('self-renewal', 'CPA', (54, 66))
22151	33072746	The abnormal expression of ALKBH5 was also detected in GSCs, to demethylate FOXM1 nascent transcript and enhance the expression of Forkhead box protein M1 (FOXM1).	('ALKBH5', 'Gene', '54890', (27, 33))	('FOXM1', 'Gene', '2305', (76, 81))	('FOXM1', 'Gene', (76, 81))	('GSC', 'Chemical', '-', (55, 58))	('expression', 'MPA', (117, 127))	('Forkhead box protein M1', 'Gene', (131, 154))	('FOXM1', 'Gene', '2305', (156, 161))	('FOXM1', 'Gene', (156, 161))	('nascent transcript', 'MPA', (82, 100))	('Forkhead box protein M1', 'Gene', '2305', (131, 154))	('enhance', 'PosReg', (105, 112))	('demethylate', 'Var', (64, 75))	('ALKBH5', 'Gene', (27, 33))
22155	33072746	found a high level of entire METTL3-mediated m6A modification, associated with the maintenance of stem-like cells and the dedifferentiation of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('associated', 'Reg', (63, 73))	('glioma', 'Disease', (143, 149))	('modification', 'Var', (49, 61))	('METTL3-mediated', 'Gene', (29, 44))	('m6A', 'Protein', (45, 48))
22156	33072746	Further experiments revealed that the pluripotency factor SOX2 was the m6A target of METTL3, and it was stabilized by recruiting Human antigen R (HuR) to m6A-modified SOX2 mRNA, resulting in decreased sensitivity to gamma-irradiation.	('SOX2', 'Gene', (58, 62))	('m6A-modified', 'Var', (154, 166))	('SOX2', 'Gene', '6657', (58, 62))	('sensitivity to gamma-irradiation', 'MPA', (201, 233))	('HuR', 'Gene', (146, 149))	('HuR', 'Gene', '1994', (146, 149))	('SOX2', 'Gene', '6657', (167, 171))	('Human antigen R', 'Gene', (129, 144))	('decreased', 'NegReg', (191, 200))	('SOX2', 'Gene', (167, 171))	('Human antigen R', 'Gene', '1994', (129, 144))	('recruiting', 'PosReg', (118, 128))
22164	33072746	Further investigation verified that overexpression of the reader protein YTHDF1 promoted colonosphere formation and self-renewal, thought inhibiting Wnt/beta-catenin pathway activities in cells in CRC, while knockdown the expression of YTHDF1, inhibited colonosphere self-renewal while enhancing their differentiation.	('YTHDF1', 'Gene', '54915', (236, 242))	('beta-catenin', 'Gene', (153, 165))	('enhancing', 'PosReg', (286, 295))	('beta-catenin', 'Gene', '1499', (153, 165))	('CRC', 'Disease', 'MESH:D015179', (197, 200))	('promoted', 'PosReg', (80, 88))	('self-renewal', 'CPA', (116, 128))	('overexpression', 'PosReg', (36, 50))	('inhibiting', 'NegReg', (138, 148))	('differentiation', 'CPA', (302, 317))	('YTHDF1', 'Gene', (73, 79))	('knockdown', 'Var', (208, 217))	('colonosphere self-renewal', 'CPA', (254, 279))	('activities', 'MPA', (174, 184))	('YTHDF1', 'Gene', '54915', (73, 79))	('YTHDF1', 'Gene', (236, 242))	('CRC', 'Disease', (197, 200))	('inhibited', 'NegReg', (244, 253))	('Wnt', 'Gene', '35975', (149, 152))	('colonosphere formation', 'CPA', (89, 111))	('Wnt', 'Gene', (149, 152))
22171	33072746	Importantly, the differentially methylated genes were enriched in signaling pathways regulating the pluripotency of stem cells and correlated with the poor prognosis in patients with osteosarcoma.	('differentially methylated genes', 'Var', (17, 48))	('patients', 'Species', '9606', (169, 177))	('signaling pathways', 'Pathway', (66, 84))	('osteosarcoma', 'Disease', (183, 195))	('osteosarcoma', 'Phenotype', 'HP:0002669', (183, 195))	('osteosarcoma', 'Disease', 'MESH:D012516', (183, 195))	('pluripotency of stem cells', 'MPA', (100, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))
22172	33072746	The m6A modification may be a breakthrough mechanism to improve the treatment of osteosarcoma and provide a fundamental contribution to the search for new therapeutic targets for OS.	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('m6A modification', 'Var', (4, 20))	('treatment', 'Disease', (68, 77))	('improve', 'PosReg', (56, 63))	('modification', 'Var', (8, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))
22411	31547570	Survival analysis on the basis of the expression of NK-specific genes alongside NT5E showed that even in samples with high NT5E expression, median disease-free survival in the presence of over-expressed NK signatures was higher than those cases with low NK and NT5E genes (7.82 months vs. 5.81 months, z = 1; p = 0.0109; Figure 2B, right).	('high', 'Var', (118, 122))	('NT5E', 'Gene', (261, 265))	('NT5E', 'Gene', '4907', (123, 127))	('NT5E', 'Gene', (80, 84))	('disease-free survival', 'CPA', (147, 168))	('over-expressed', 'PosReg', (188, 202))	('NT5E', 'Gene', (123, 127))	('NT5E', 'Gene', '4907', (261, 265))	('NT5E', 'Gene', '4907', (80, 84))	('higher', 'PosReg', (221, 227))
22413	31547570	Analysis of gene expression data from patients extracted from GSE53733 showed that expression of NT5E did not correlate with length of patient survival.	('patient', 'Species', '9606', (135, 142))	('GSE53733', 'Var', (62, 70))	('NT5E', 'Gene', (97, 101))	('patient', 'Species', '9606', (38, 45))	('patients', 'Species', '9606', (38, 46))	('NT5E', 'Gene', '4907', (97, 101))
22447	31547570	Knocking down CD73 expression was, for instance, shown in a recent study to sensitize GBM cells to treatment by the drug vincristine.	('expression', 'MPA', (19, 29))	('CD73', 'Gene', '4907', (14, 18))	('GBM', 'Disease', (86, 89))	('GBM', 'Disease', 'MESH:D005909', (86, 89))	('vincristine', 'Chemical', 'MESH:D014750', (121, 132))	('CD73', 'Gene', (14, 18))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('Knocking', 'Var', (0, 8))
22483	31547570	While our findings suggest that NK cells might induce a higher disease-free survival in GBM patients, correlation between the expression of ADORA2A and NT5E might infer immunosuppression due to adenosinergic signaling on immune cells including NK as well as other cells, leading to poorer overall survival and suggesting that a complex interplay of tumor microenvironment factors is likely to affect pathology of GBM.	('poorer', 'NegReg', (282, 288))	('adenosine', 'Chemical', 'MESH:D000241', (194, 203))	('disease-free survival', 'CPA', (63, 84))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('ADORA2A', 'Gene', (140, 147))	('affect', 'Reg', (393, 399))	('NT5E', 'Gene', (152, 156))	('patients', 'Species', '9606', (92, 100))	('GBM', 'Disease', (413, 416))	('GBM', 'Disease', 'MESH:D005909', (413, 416))	('GBM', 'Disease', (88, 91))	('GBM', 'Disease', 'MESH:D005909', (88, 91))	('GBM', 'Phenotype', 'HP:0012174', (413, 416))	('ADORA2A', 'Gene', '135', (140, 147))	('tumor', 'Disease', (349, 354))	('overall survival', 'MPA', (289, 305))	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('immunosuppression', 'MPA', (169, 186))	('infer', 'Reg', (163, 168))	('expression', 'Var', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('higher', 'PosReg', (56, 62))	('NT5E', 'Gene', '4907', (152, 156))
22555	30388862	On the other hand, we also show that FAD has detrimental effects by disrupting the maintenance of normal NSCs and altering the balance between self-renewal and differentiation of NSCs.	('disrupting', 'NegReg', (68, 78))	('differentiation of NSCs', 'CPA', (160, 183))	('balance', 'MPA', (127, 134))	('altering', 'Reg', (114, 122))	('FAD', 'Chemical', 'MESH:C034379', (37, 40))	('maintenance', 'CPA', (83, 94))	('FAD', 'Var', (37, 40))
22558	30388862	In addition, it was reported that NSCs in hypothalamus control ageing speed in mammals, highlighting the importance of NSCs in the maintenance of the nervous system.	('hypothalamus', 'Disease', 'MESH:D007029', (42, 54))	('ageing speed', 'CPA', (63, 75))	('hypothalamus', 'Disease', (42, 54))	('NSCs', 'Var', (34, 38))
22564	30388862	However, we also give a warning that FAD could disrupt the maintenance of normal NSCs and FAD would alter the balance between self-renewal and differentiation in NSCs by inhibiting Notch pathway.	('disrupt', 'NegReg', (47, 54))	('Notch', 'Gene', '4851', (181, 186))	('FAD', 'Chemical', 'MESH:C034379', (90, 93))	('Notch', 'Gene', (181, 186))	('balance between self-renewal', 'MPA', (110, 138))	('FAD', 'Var', (90, 93))	('FAD', 'Chemical', 'MESH:C034379', (37, 40))	('alter', 'Reg', (100, 105))	('inhibiting', 'NegReg', (170, 180))	('differentiation', 'MPA', (143, 158))
22614	30388862	Together, these data suggest that FAD enhances differentiation of NSCs into neurons and astrocytes.	('FAD', 'Chemical', 'MESH:C034379', (34, 37))	('differentiation', 'CPA', (47, 62))	('enhances', 'PosReg', (38, 46))	('FAD', 'Var', (34, 37))
22615	30388862	To figure out the intracellular and molecular mechanism that FAD disrupts the maintenance of NSCs and induces neuronal and glial differentiation, we performed literature analysis: (1) Previously, Yoshida et al.	('induces', 'Reg', (102, 109))	('disrupts', 'NegReg', (65, 73))	('FAD', 'Chemical', 'MESH:C034379', (61, 64))	('maintenance', 'MPA', (78, 89))	('FAD', 'Var', (61, 64))
22626	30388862	Together, FAD weakens the homeostatic maintenance of normal NSCs by suppressing FoxO-Notch axis.	('Notch', 'Gene', (85, 90))	('FAD', 'Var', (10, 13))	('suppressing', 'NegReg', (68, 79))	('weakens', 'NegReg', (14, 21))	('homeostatic maintenance', 'MPA', (26, 49))	('FAD', 'Chemical', 'MESH:C034379', (10, 13))	('Notch', 'Gene', '4851', (85, 90))
22630	30388862	The anticancer function of FAD was further demonstrated with breast cancer cells in which FAD contributed to autophagy-dependent tumor cell death.	('FAD', 'Chemical', 'MESH:C034379', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('cancer', 'Disease', (8, 14))	('FAD', 'Var', (90, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', (129, 134))	('FAD', 'Chemical', 'MESH:C034379', (27, 30))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
22669	30148071	In a multi-targeting approach, our own group was able to show that TIC10/ONC201 synergizes with ABT263, an inhibitor of anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL, against glioblastoma and that the combination therapy causes tumor regression in vivo.	('Bcl-xL', 'Gene', (167, 173))	('ABT263', 'Chemical', 'MESH:C528561', (96, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (183, 195))	('Bcl-2', 'Gene', (135, 140))	('Bcl-2', 'Gene', '596', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('glioblastoma', 'Disease', (183, 195))	('Bcl-2', 'Gene', (157, 162))	('TIC10/ONC201', 'Var', (67, 79))	('Bcl-2', 'Gene', '596', (157, 162))	('Bcl-xL', 'Gene', '598', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))	('glioblastoma', 'Disease', 'MESH:D005909', (183, 195))
22671	30148071	Prior treatment with bevacizumab and mutated IDH1/2 status were exclusion criteria.	('mutated', 'Var', (37, 44))	('bevacizumab', 'Chemical', 'MESH:D000068258', (21, 32))	('IDH1/2', 'Gene', (45, 51))	('IDH1/2', 'Gene', '3417;3418', (45, 51))
22676	30148071	With respect to toxicity, TIC10/ONC201 was well tolerated with only two transient adverse events in the same patient.	('TIC10/ONC201', 'Var', (26, 38))	('toxicity', 'Disease', 'MESH:D064420', (16, 24))	('toxicity', 'Disease', (16, 24))	('patient', 'Species', '9606', (109, 116))
22677	30148071	Pharmacodynamic studies showed that the treatment reached plasma concentrations above 1 mug/mL which is reported to be above the target threshold and a rise in prolactin levels was noted in response to DRD2 antagonism, one proposed mechanism by which TIC10/ONC201 exerts its antineoplastic activity.	('antagonism', 'Var', (207, 217))	('DRD2', 'Gene', (202, 206))	('prolactin levels', 'MPA', (160, 176))	('rise', 'PosReg', (152, 156))	('antineoplastic activity', 'CPA', (275, 298))	('DRD2', 'Gene', '1813', (202, 206))	('rise in prolactin levels', 'Phenotype', 'HP:0000870', (152, 176))	('TIC10/ONC201', 'Gene', (251, 263))
22707	26308482	Rosette trajectories, oscillate in the radial direction with an angular frequency omega1 = 2pi   f1, while rotating in (kx, ky) plane with angular oscillation frequency omega2 = 2pi   f2, such that:   where kmax = Nx/(2   fov) is the highest spatial frequency sampled, omega1 = pi   SW/nTI; SW is the spectral width of the acquisition; nTI is the number of time interleaves.	('Rosette', 'Phenotype', 'HP:0031925', (0, 7))	('a1 ', 'Gene', (86, 89))	('a1 ', 'Gene', '28881', (86, 89))	('spatial', 'Gene', '219793', (242, 249))	('pi   SW/nTI', 'Var', (278, 289))	('a1 ', 'Gene', (273, 276))	('spatial', 'Gene', (242, 249))	('a1 ', 'Gene', '28881', (273, 276))
22708	26308482	Gmax, dt and gamma = 42.57 MHz/T are the maximum gradient strength along the trajectory, complex data sampling rate, and the 1H gyromagnetic ratio, respectively.	('1H', 'Chemical', '-', (125, 127))	('gamma = 42.57 MHz/T', 'Var', (13, 32))	('Gmax', 'Var', (0, 4))
22715	26308482	In addition, the maximum peak gradients for acquisitions with omega2 = omega1 and omega2 = 0 are equivalent.	('a1 ', 'Gene', '28881', (75, 78))	('omega2 = 0', 'Var', (82, 92))	('a1 ', 'Gene', (75, 78))
22718	26308482	Using the formula in Schirda et al to determine the number of shots required to cover a 2D partition/slice:   when omega2 = omega1, the number of shots (rounding to closest integer) is:   For omega2 = omega1 and omega1 = pi   SW/nTI, the gradient strength and slew rate are constant along the readout trajectory and, using Eqs.	('pi   SW/nTI', 'Var', (221, 232))	('a1 ', 'Gene', (216, 219))	('a1 ', 'Gene', '28881', (216, 219))	('a1 ', 'Gene', (205, 208))	('a1 ', 'Gene', '28881', (205, 208))
22778	26308482	Elliptical phase encoding provides for faster acquisitions than the fully encoded one; however, it does so at the expense of a wider PSF, larger FWHM and bigger effective voxel size; thus, decreased effective resolution.	('decreased', 'NegReg', (189, 198))	('PSF', 'Gene', '6421', (133, 136))	('FWHM', 'MPA', (145, 149))	('effective resolution', 'MPA', (199, 219))	('faster', 'PosReg', (39, 45))	('PSF', 'Gene', (133, 136))	('acquisitions', 'MPA', (46, 58))	('Elliptical', 'Var', (0, 10))
22836	28337458	L-507 and L-493 could separately detect 507 and 493 proteins based on biotin labeling and laser fluorescence scanning techniques, respectively.	('L-507', 'Var', (0, 5))	('proteins', 'Protein', (52, 60))	('detect', 'Reg', (33, 39))	('L-493', 'Var', (10, 15))	('biotin', 'Chemical', 'MESH:D001710', (70, 76))
22844	28337458	The protein array performances among QAH-INF-3, L-507, and L-493 were assessed by the fold change of protein expression between the two concentrations of the loading samples.	('N', 'Chemical', 'MESH:D009584', (42, 43))	('protein expression', 'MPA', (101, 119))	('L-493', 'Var', (59, 64))
22854	28337458	The primary analysis showed that L-493 could detect more available proteins (214, 43.41%) compared to QAH-INF-3 (9, 22.5%) and L-507 (61, 12.03%), suggesting that L-493 is more suitable for detecting proteins in kidney tissue.	('proteins', 'Protein', (67, 75))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('L-493', 'Var', (33, 38))
22923	26659251	More recently, zebrafish have been exploited to analyze tumor development and for chemical screens, leading to the identification of several candidate therapeutics for melanoma and leukemia that are currently being evaluated in patients (NCT02354417, NCT01611675 and NCT01512251).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NCT01512251', 'Var', (267, 278))	('NCT02354417', 'Var', (238, 249))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('NCT01611675', 'Var', (251, 262))	('tumor', 'Disease', (56, 61))	('patients', 'Species', '9606', (228, 236))	('zebrafish', 'Species', '7955', (15, 24))	('melanoma and leukemia', 'Disease', 'MESH:D008545', (168, 189))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
22952	26659251	This revealed a time-dependent linear increase of tumor burden in GBM9-transplanted animals compared with control mNSC cell transplants (Fig.	('increase', 'PosReg', (38, 46))	('GBM9-transplanted', 'Var', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
22974	26659251	In X12 tumors, the percentage of dividing cells was slightly higher and increased from 50 to 69% between 2 and 10 dpt, which was a statistically significant increase (Table 1; Fig.	('increased', 'PosReg', (72, 81))	('X12', 'Var', (3, 6))	('higher', 'PosReg', (61, 67))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('dpt', 'Chemical', '-', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
23023	26659251	In terms of the number of dividing cells, it was 2.7- and 3.6-fold higher in X12 transplanted animals at 5 and 10 dpt, respectively, compared with GBM9 tumor-containing animals (see Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('higher', 'PosReg', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('dpt', 'Chemical', '-', (114, 117))	('tumor', 'Disease', (152, 157))	('X12 transplanted', 'Var', (77, 93))
23032	26659251	The zebrafish larval brain is very amenable to live imaging facilitated by mutant lines, such as casper, that are transparent because of mutations in pigment genes, thus allowing direct visualization of tumor cells in the brain.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('zebrafish', 'Species', '7955', (4, 13))	('tumor', 'Disease', (203, 208))	('mutations', 'Var', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
23051	26659251	GBM9 and X12 cells were obtained from tumor specimens as previously described and modified with GFP to generate GBM9-GFP and X12-v2.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('GBM9-GFP', 'Var', (112, 120))	('X12-v2', 'Var', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
23139	26413814	Several recent studies have found improved OS in both children and adults, ranging from 3-6 months by the inclusion of VPA.	('VPA', 'Chemical', 'MESH:D014635', (119, 122))	('improved', 'PosReg', (34, 42))	('VPA', 'Gene', (119, 122))	('children', 'Species', '9606', (54, 62))	('inclusion', 'Var', (106, 115))
23150	26413814	Mice irradiated with 7Gy had increased apoptosis compared to untreated mice.	('mice', 'Species', '10090', (71, 75))	('apoptosis', 'CPA', (39, 48))	('7Gy', 'Var', (21, 24))	('Mice', 'Species', '10090', (0, 4))
23154	26413814	Cells pre-treated with VPA prior to 4Gy irradiation had significantly less apoptotic cells (12% annexin V positive: P = 0.002), than cells treated with PBS alone (50%; Fig.	('less', 'NegReg', (70, 74))	('annexin V', 'Gene', (96, 105))	('VPA', 'Var', (23, 26))	('apoptotic cells', 'CPA', (75, 90))	('PBS', 'Chemical', 'MESH:D007854', (152, 155))	('VPA', 'Chemical', 'MESH:D014635', (23, 26))	('annexin V', 'Gene', '11747', (96, 105))
23166	26413814	However, pretreatment of Daoy (human medulloblastoma), D54 (human glioma) and GL261(mouse glioma) cells with 0.6 mM VPA for 7 days prior to irradiation led to significant radiosensitization with DMF10 of 2.25, 1.49, and 2.31 for Daoy, D54 and GL261 cells, respectively (Fig 2B).	('glioma', 'Disease', (66, 72))	('medulloblastoma', 'Disease', 'MESH:D008527', (37, 52))	('glioma', 'Disease', (90, 96))	('Daoy', 'CellLine', 'CVCL:1167', (229, 233))	('VPA', 'Chemical', 'MESH:D014635', (116, 119))	('medulloblastoma', 'Phenotype', 'HP:0002885', (37, 52))	('DMF10', 'Chemical', '-', (195, 200))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('medulloblastoma', 'Disease', (37, 52))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('radiosensitization', 'CPA', (171, 189))	('human', 'Species', '9606', (31, 36))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('mouse', 'Species', '10090', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('Daoy', 'CellLine', 'CVCL:1167', (25, 29))	('DMF10', 'Var', (195, 200))	('human', 'Species', '9606', (60, 65))
23179	26413814	Significant accumulation in the G2/M phase (41%) was observed in GL261 cells treated with VPA when compared to untreated PBS control cells (24%) (P = <0.001).	('GL261', 'Gene', (65, 70))	('G2/M phase', 'CPA', (32, 42))	('VPA', 'Chemical', 'MESH:D014635', (90, 93))	('accumulation', 'PosReg', (12, 24))	('PBS', 'Chemical', 'MESH:D007854', (121, 124))	('VPA', 'Var', (90, 93))
23192	26413814	We have previously shown that inhibition of GSK3beta either with small molecule inhibitors or knockdown led to decreased apoptosis in normal hippocampal neurons and normal epithelial cells.	('GSK3beta', 'Gene', '56637', (44, 52))	('inhibition', 'Var', (30, 40))	('decreased', 'NegReg', (111, 120))	('GSK3beta', 'Gene', (44, 52))	('apoptosis', 'CPA', (121, 130))
23208	26413814	Nine mice in each group were then treated with PBS, irradiation alone (five daily fractions of 2 Gy), VPA (300 mg/kg) alone for 5 days, or VPA (300 mg/kg) for 5 days followed by irradiation (five daily fractions of 2Gy).	('VPA', 'Chemical', 'MESH:D014635', (102, 105))	('PBS', 'Chemical', 'MESH:D007854', (47, 50))	('300 mg/kg', 'Var', (144, 153))	('VPA', 'Chemical', 'MESH:D014635', (139, 142))	('mice', 'Species', '10090', (5, 9))	('300 mg/kg', 'Var', (107, 116))
23234	26413814	The selective protection of hippocampal neurons could be due to modulations of radiation-induced pro-apoptotic signaling by VPA (Fig 1E).	('modulations', 'Var', (64, 75))	('hippocampal neurons', 'CPA', (28, 47))	('VPA', 'Gene', (124, 127))	('VPA', 'Chemical', 'MESH:D014635', (124, 127))
23247	26413814	These alterations have been reported in cancer cells but not in normal cells.	('alterations', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('rat', 'Species', '10116', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
23252	26413814	Previously we have shown that inhibition of GSK3beta either with small molecule inhibitor or knockdown protected the hippocampal neurons from radiation-induced apoptosis and increased clonogenic survival.	('GSK3beta', 'Gene', '56637', (44, 52))	('inhibition', 'Var', (30, 40))	('hippocampal neurons', 'CPA', (117, 136))	('GSK3beta', 'Gene', (44, 52))	('clonogenic survival', 'CPA', (184, 203))	('increased', 'PosReg', (174, 183))
23278	26413814	In the heterotopic GL261 and D54 tumor models, mice treated with VPA were half as likely to develop a tumor with a volume greater than 0.6 cm3 than PBS treated mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('develop', 'PosReg', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('VPA', 'Var', (65, 68))	('VPA', 'Chemical', 'MESH:D014635', (65, 68))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Disease', (33, 38))	('PBS', 'Chemical', 'MESH:D007854', (148, 151))	('tumor', 'Disease', (102, 107))	('mice', 'Species', '10090', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
23525	24739422	reported that the survival rates of patients receiving BCNU implants were significantly higher than those of patients in the placebo group during the 12-month implant insertion period (P = 0.029).	('BCNU implants', 'Var', (55, 68))	('higher', 'PosReg', (88, 94))	('patients', 'Species', '9606', (36, 44))	('survival rates', 'CPA', (18, 32))	('patients', 'Species', '9606', (109, 117))	('BCNU', 'Chemical', 'MESH:D002330', (55, 59))
23643	24739422	reported that the median day of onset of seizures was faster in the BCNU implant group (3.5 days) than in the placebo group (55.5 days) (Wilcoxon test: P = 0.01).	('BCNU', 'Chemical', 'MESH:D002330', (68, 72))	('seizures', 'Disease', 'MESH:D012640', (41, 49))	('BCNU implant', 'Var', (68, 80))	('seizures', 'Disease', (41, 49))	('seizures', 'Phenotype', 'HP:0001250', (41, 49))	('seizure', 'Phenotype', 'HP:0001250', (41, 48))
23671	24637491	In vitro silencing of COL1A1 and IFTM1 confirmed the effect of these mesenchymal-associated genes on cell invasion and gliomasphere initiation.	('gliomasphere initiation', 'Disease', (119, 142))	('gliomasphere initiation', 'Disease', 'MESH:D007319', (119, 142))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('silencing', 'Var', (9, 18))	('effect', 'Reg', (53, 59))	('COL1A1', 'Gene', (22, 28))	('IFTM1', 'Gene', (33, 38))	('cell invasion', 'CPA', (101, 114))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))
23686	24637491	identified, alterations of Wnt and Hedgehog signaling pathways as important events conferring self-renewal potential and tumorigenic properties to GSCs.	('self-renewal potential', 'CPA', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('alterations', 'Var', (12, 23))	('conferring', 'Reg', (83, 93))	('tumor', 'Disease', (121, 126))	('Hedgehog signaling pathways', 'Pathway', (35, 62))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
23704	24637491	In contrast, genes involved in astrocyte (GFAP), neuron (HLXB9) and oligodendrocyte (OLIG2) differentiation were found to have a higher expression in GSCs indicating that GSCs are more committed to neural differentiation than H9-HNSCs (Figure 1c).	('GSCs', 'Var', (150, 154))	('H9-HNSCs', 'Disease', (226, 234))	('expression', 'MPA', (136, 146))	('neuron', 'CPA', (49, 55))	('GFAP', 'Gene', '2670', (42, 46))	('OLIG2', 'Gene', (85, 90))	('higher', 'PosReg', (129, 135))	('HLXB9', 'Gene', (57, 62))	('astrocyte', 'CPA', (31, 40))	('HLXB9', 'Gene', '3110', (57, 62))	('H9-HNSCs', 'Disease', 'None', (226, 234))	('OLIG2', 'Gene', '10215', (85, 90))	('GFAP', 'Gene', (42, 46))
23711	24637491	Interestingly, the expression of both genes was shown to be higher in bulk tumors from group TX-2 than in bulk tumors of group TX-1 (Figure 2c).	('TX-2', 'Var', (93, 97))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('expression', 'MPA', (19, 29))	('higher', 'PosReg', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
23714	24637491	However, inhibition of COL1A1 resulted in a decrease of neurosphere-initiating cell frequency, as the number of cells required to form neurospheres was 1/128 for sh-COL1A1 GSC-3 and 1/35 for sh-COL1A1 GSC-9 (Figure 4b).	('decrease', 'NegReg', (44, 52))	('neurosphere-initiating cell frequency', 'CPA', (56, 93))	('COL1A1 GSC-3 and 1/35', 'Gene', '1277', (165, 186))	('COL1A1', 'Gene', (23, 29))	('inhibition', 'Var', (9, 19))
23715	24637491	Altogether, these observations indicate that COL1A1 and IFITM1 knockdown markedly decrease the invasive capacity of GSCs from primary human GBMs.	('human', 'Species', '9606', (134, 139))	('IFITM1', 'Gene', (56, 62))	('decrease', 'NegReg', (82, 90))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('invasive capacity of GSCs from primary human GBMs', 'CPA', (95, 144))	('knockdown', 'Var', (63, 72))	('COL1A1', 'Gene', (45, 51))
23746	24637491	Further, no alteration in factors known to influence patients prognosis (IDH1 and IDH2 mutations or MGMT methylation status) was observed in either group.	('MGMT', 'Gene', '4255', (100, 104))	('patients', 'Species', '9606', (53, 61))	('IDH1', 'Gene', '3417', (73, 77))	('IDH2', 'Gene', (82, 86))	('IDH2', 'Gene', '3418', (82, 86))	('IDH1', 'Gene', (73, 77))	('mutations', 'Var', (87, 96))	('MGMT', 'Gene', (100, 104))
23756	24637491	The genomic region spanning wild-type R132 of IDH1 and R172 of IDH2 was analyzed by direct sequencing as previously described.	('IDH2', 'Gene', '3418', (63, 67))	('IDH1', 'Gene', (46, 50))	('IDH1', 'Gene', '3417', (46, 50))	('R172', 'Var', (55, 59))	('IDH2', 'Gene', (63, 67))
23757	24637491	Methylation status of the MGMT promoter was determined by bisulfite modification and subsequent nested methylation specific-polymerase chain reaction.	('bisulfite', 'Chemical', 'MESH:C042345', (58, 67))	('MGMT', 'Gene', '4255', (26, 30))	('bisulfite', 'Var', (58, 67))	('MGMT', 'Gene', (26, 30))
23777	24637491	Expression of COL1A1, IFITM1, and GAPDH was determined using TaqMan Gene Expression Assays Hs00164004_m1, Hs00705137_s1, Hs Hs99999905_m1 (Applied Biosystems) respectively.	('COL1A1', 'Gene', (14, 20))	('GAPDH', 'Gene', (34, 39))	('Hs00164004_m1', 'Var', (91, 104))	('Hs00705137_s1', 'Var', (106, 119))	('Hs Hs99999905_m1', 'Var', (121, 137))	('GAPDH', 'Gene', '2597', (34, 39))
23831	33674992	Full anticoagulation was defined as receiving phenprocoumon according to INR, receiving a non-Vitamin K antagonist oral anticoagulant or receiving heparin (dosage of at least 40 mg twice daily).	('phenprocoumon', 'Var', (46, 59))	('heparin', 'Chemical', 'MESH:D006493', (147, 154))	('Vitamin K', 'Chemical', 'MESH:D014812', (94, 103))	('phenprocoumon', 'Chemical', 'MESH:D010644', (46, 59))	('Full anticoagulation', 'Disease', (0, 20))
23925	32051289	After binding its natural ligand 4-1BBL, 4-1BB induces intracellular signaling through TNFR-associated factor 2.	('intracellular signaling', 'MPA', (55, 78))	('induces', 'Reg', (47, 54))	('binding', 'Interaction', (6, 13))	('4-1BB', 'Var', (41, 46))	('4-1BBL', 'Gene', (33, 39))	('4-1BBL', 'Gene', '8744', (33, 39))	('TNFR-associated', 'Gene', (87, 102))
23929	32051289	Interestingly, depletion of CD4 T cells abrogated this effect to an even greater extent than CD8 depletion.	('CD8', 'Gene', (93, 96))	('abrogated', 'NegReg', (40, 49))	('CD8', 'Gene', '925', (93, 96))	('depletion', 'Var', (15, 24))
23937	32051289	Another study combining anti-GITR mab with stereotactic radiosurgery showed increased effector CD4 infiltration, as well as elevated IFNy, IL2, and TNFa production but this did not translate into survival benefit.	('TNFa', 'Gene', '7124', (148, 152))	('IFN', 'Gene', '3439', (133, 136))	('IL2', 'Gene', '3558', (139, 142))	('IL2', 'Gene', (139, 142))	('increased', 'PosReg', (76, 85))	('anti-GITR', 'Var', (24, 33))	('IFN', 'Gene', (133, 136))	('rat', 'Species', '10116', (105, 108))	('TNFa', 'Gene', (148, 152))	('effector', 'CPA', (86, 94))	('increased effector CD4 infiltration', 'Phenotype', 'HP:0410394', (76, 111))	('elevated', 'PosReg', (124, 132))
23946	32051289	The ICOS ligand protein and corresponding mRNA are expressed by gliomas and the neutralization of ICOS ligand subsequently reduces Th1 and Th2 cytokines.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('neutralization', 'Var', (80, 94))	('ICOS ligand', 'Gene', (98, 109))	('ICOS ligand', 'Gene', (4, 15))	('ICOS ligand', 'Gene', '102723996', (98, 109))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('ICOS ligand', 'Gene', '102723996', (4, 15))	('reduces', 'NegReg', (123, 130))
23949	32051289	OX40 agonism inhibits Treg immunosuppression, thereby leading to effector T cell proliferation.	('OX40 agonism', 'Var', (0, 12))	('rat', 'Species', '10116', (88, 91))	('Treg immunosuppression', 'CPA', (22, 44))	('leading to', 'Reg', (54, 64))	('inhibits', 'NegReg', (13, 21))	('effector T cell proliferation', 'CPA', (65, 94))
23951	32051289	Murine glioma models have shown that OX40 agonists can induce tumor regression and increase TILs.	('increase', 'PosReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('glioma', 'Disease', 'MESH:D005910', (7, 13))	('TILs', 'CPA', (92, 96))	('glioma', 'Phenotype', 'HP:0009733', (7, 13))	('tumor', 'Disease', (62, 67))	('Murine', 'Species', '10090', (0, 6))	('induce', 'PosReg', (55, 61))	('OX40 agonists', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('glioma', 'Disease', (7, 13))
23952	32051289	One study combining anti-OX40 antibody plus dendritic cell (DC) vaccine plus local cranial radiation demonstrated tumor regression, TIL infiltration, and improved survival compared with mice treated with only two of the three modalities.	('anti-OX40', 'Var', (20, 29))	('improved', 'PosReg', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('TIL infiltration', 'CPA', (132, 148))	('rat', 'Species', '10116', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('antibody plus dendritic', 'Disease', 'MESH:D007635', (30, 53))	('rat', 'Species', '10116', (142, 145))	('tumor', 'Disease', (114, 119))	('mice', 'Species', '10090', (186, 190))	('survival', 'CPA', (163, 171))	('antibody plus dendritic', 'Disease', (30, 53))
23960	32051289	One study found that glioma cells expressing CD70 could induce T cell apoptosis while simultaneously inhibiting glioma growth.	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('T cell apoptosis', 'CPA', (63, 79))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('glioma', 'Disease', (112, 118))	('CD70', 'Var', (45, 49))	('induce', 'PosReg', (56, 62))	('glioma', 'Disease', (21, 27))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('inhibiting', 'NegReg', (101, 111))
23972	32051289	CTLA-4 antibody blockade has also been shown to enhance whole tumor-cell vaccine efficacy and improve survival.	('blockade', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CTLA-4', 'Gene', (0, 6))	('survival', 'CPA', (102, 110))	('tumor', 'Disease', (62, 67))	('enhance', 'PosReg', (48, 55))	('improve', 'PosReg', (94, 101))	('antibody', 'Protein', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
23973	32051289	In mice treated with a herpes simplex oncolytic virus, the combination of anti-CTLA-4 and anti PD-1 therapy was found to improve survival.	('anti-CTLA-4', 'Var', (74, 85))	('survival', 'CPA', (129, 137))	('mice', 'Species', '10090', (3, 7))	('herpes simplex', 'Phenotype', 'HP:0012302', (23, 37))	('improve', 'PosReg', (121, 128))
23974	32051289	Furthermore, combined with intratumoral administration of IL-12, CTLA-4 inhibitors were shown to cause a reduction in tumor burden, decreasing Tregs and increasing effector T cells.	('effector T cells', 'CPA', (164, 180))	('decreasing', 'NegReg', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('CTLA-4', 'Gene', (65, 71))	('Tregs', 'CPA', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('rat', 'Species', '10116', (30, 33))	('reduction', 'NegReg', (105, 114))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('inhibitors', 'Var', (72, 82))	('tumor', 'Disease', (32, 37))	('rat', 'Species', '10116', (48, 51))	('increasing', 'PosReg', (153, 163))
23980	32051289	Similarly, NCT02829931 and NCT03425292 combine CTLA-4, PD-1 and bevacizumab with radiation therapy.	('NCT02829931', 'Var', (11, 22))	('NCT03425292', 'Var', (27, 38))	('PD-1', 'Gene', (55, 59))	('bevacizumab', 'Chemical', 'MESH:D000068258', (64, 75))	('combine', 'PosReg', (39, 46))	('CTLA-4', 'Gene', (47, 53))
23992	32051289	PD-1 blockade combined with oncolytic viral therapy has also been shown to increase survival in mice.	('blockade', 'Var', (5, 13))	('mice', 'Species', '10090', (96, 100))	('PD-1', 'Gene', (0, 4))	('increase', 'PosReg', (75, 83))	('survival', 'CPA', (84, 92))
24005	32051289	In addition to these, Checkmate 548 and 498 are phase III clinical trials examining checkpoint inhibitor therapy in MGMT methylated and unmethylated populations, respectively.	('methylated', 'Var', (121, 131))	('MGMT', 'Gene', '4255', (116, 120))	('Checkmate', 'Chemical', 'MESH:C049437', (22, 31))	('MGMT', 'Gene', (116, 120))
24014	32051289	NCT02359565 and NCT03173950 are examining PD-1 inhibitors among rare or pediatric CNS tumors populations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('NCT02359565', 'Var', (0, 11))	('NCT03173950', 'Var', (16, 27))
24022	32051289	PD-1 and TIGIT coblockage increased IFNy- and TNFa-producing CD8 (and CD4) T cells as compared with monotherapy groups.	('TNFa', 'Gene', '7124', (46, 50))	('coblockage', 'Var', (15, 25))	('IFN', 'Gene', (36, 39))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('IFN', 'Gene', '3439', (36, 39))	('increased', 'PosReg', (26, 35))	('TNFa', 'Gene', (46, 50))
24041	32051289	Increased cyclic AMP upregulates immunosuppressive cytokines, increases PD-1, induces T cell anergy and promotes Treg differentiation.	('induces', 'Reg', (78, 85))	('increases', 'PosReg', (62, 71))	('immunosuppressive cytokines', 'MPA', (33, 60))	('cyclic AMP', 'Chemical', 'MESH:D000242', (10, 20))	('promotes', 'PosReg', (104, 112))	('PD-1', 'Gene', (72, 76))	('upregulates', 'PosReg', (21, 32))	('increases PD', 'Phenotype', 'HP:0008151', (62, 74))	('T cell anergy', 'CPA', (86, 99))	('cyclic', 'Var', (10, 16))	('Treg differentiation', 'CPA', (113, 133))
24043	32051289	Inhibition of A2AR is, therefore, a potential method to stimulate the immune system.	('A2AR', 'Gene', '135', (14, 18))	('A2AR', 'Gene', (14, 18))	('stimulate', 'PosReg', (56, 65))	('Inhibition', 'Var', (0, 10))	('immune system', 'CPA', (70, 83))
24048	32051289	However, more recent experiments of murine B7-H3 conversely suggest that B7-H3 may actually have suppressive effects on cytotoxic T cells by downregulating proinflammatory Th1 cells.	('downregulating', 'NegReg', (141, 155))	('murine', 'Species', '10090', (36, 42))	('proinflammatory Th1 cells', 'MPA', (156, 181))	('B7-H3', 'Var', (73, 78))	('cytotoxic T cells', 'CPA', (120, 137))
24054	32051289	In murine glioma models (GL261), VISTA knockout was shown to prolong survival and synergism with radiation was observed.	('knockout', 'Var', (39, 47))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('survival', 'CPA', (69, 77))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('murine', 'Species', '10090', (3, 9))	('prolong', 'PosReg', (61, 68))	('VISTA', 'Gene', (33, 38))	('glioma', 'Disease', (10, 16))
24057	32051289	B7-H4 (B7S1) is an inhibitory molecule expressed on APC which inhibits T cells.	('B7-H4', 'Var', (0, 5))	('T cells', 'CPA', (71, 78))	('inhibits', 'NegReg', (62, 70))	('B7S1', 'Gene', '79679', (7, 11))	('B7S1', 'Gene', (7, 11))
24062	32051289	The ability to more easily penetrate the BBB makes these small molecule inhibitors particularly attractive for the treatment of glioma.	('rat', 'Species', '10116', (32, 35))	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('small', 'Var', (57, 62))
24068	32051289	Nanobodies are only ~15 kDa, more hydrophilic, more stable and less sterically hindered then their full antibody counterparts, drastically improving their ability to penetrate into tumor and molecular sites.	('tumor', 'Disease', (181, 186))	('Nanobodies', 'Var', (0, 10))	('improving', 'PosReg', (139, 148))	('rat', 'Species', '10116', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
24071	32051289	KN035, an anti-PD-L1 IgV-type nanobody has been shown to bind chiefly through a 21 amino acid segment that includes the Ile54, Tyr56 and Arg113 residues which participate in the PD-1 interaction.	('Arg113 residues', 'Var', (137, 152))	('Ile54', 'Chemical', '-', (120, 125))	('Tyr56', 'Chemical', '-', (127, 132))	('bind', 'Interaction', (57, 61))	('interaction', 'Interaction', (183, 194))	('Tyr56', 'Var', (127, 132))	('Arg113', 'Chemical', '-', (137, 143))
24080	32051289	There have been several studies targeting the epidermal growth factor receptor variant III, a transmembrane tyrosine kinase receptor variant which is expressed in 24%-67% of GBM.	('GBM', 'Phenotype', 'HP:0012174', (174, 177))	('GBM', 'Disease', 'MESH:D005909', (174, 177))	('GBM', 'Disease', (174, 177))	('variant', 'Var', (79, 86))
24099	32051289	A study of the immune checkpoint inhibitor nivolumab is ongoing in patients with select rare CNS cancers (NCT03173950).	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('nivolumab', 'Chemical', 'MESH:D000077594', (43, 52))	('NCT03173950', 'Var', (106, 117))	('cancers', 'Disease', (97, 104))	('patients', 'Species', '9606', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
24110	32051289	The inhibitory immune checkpoint molecules PD-1 and CTLA-4 are under active investigation with a recent study suggesting efficacy from PD-1 inhibitors when given preoperatively.	('inhibitors', 'Var', (140, 150))	('rat', 'Species', '10116', (168, 171))	('PD-1', 'Gene', (135, 139))
24113	32051289	TIM-3 antibody blockade improves survival and, like 4-1BB and GITR, appears to have synergistic benefit with radiation in mice models.	('blockade', 'Var', (15, 23))	('survival', 'CPA', (33, 41))	('mice', 'Species', '10090', (122, 126))	('antibody', 'Protein', (6, 14))	('improves', 'PosReg', (24, 32))	('TIM-3', 'Gene', (0, 5))
24125	31745090	Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing inflammation and the display of potentially immunogenic neoantigens.	('inducing', 'PosReg', (83, 91))	('tumor', 'Disease', (28, 33))	('reactivation', 'Var', (12, 24))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('inflammation', 'Disease', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('TEs', 'Gene', (43, 46))
24129	31745090	Neoantigens stemming from point mutations in the coding exons alone, however, likely underestimate the true mutational burden in the tumor; other cancer-specific antigens might also exist and contribute to immune response against the tumor.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', (234, 239))	('point mutations', 'Var', (26, 41))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('underestimate', 'NegReg', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('contribute', 'Reg', (192, 202))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
24132	31745090	Although in normal tissue, much of TE activity is under tight epigenetic control, in cancer, we hypothesized that wide-spread TE expression occurs, particularly in those with extensive epigenetic dysregulation.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('epigenetic dysregulation', 'Var', (185, 209))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
24137	31745090	We show that tumor cells present potentially immunogenic peptides derived not only from HERVs, but also other classes of TE: long interspersed nuclear elements (LINE), short interspersed nuclear elements (SINE), and SINE-VNTR-Alu (SVA).	('tumor', 'Disease', (13, 18))	('short interspersed nuclear', 'Var', (168, 194))	('long interspersed nuclear elements', 'Var', (125, 159))	('HERVs', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
24143	31745090	Although these data cannot address transposition, our results suggest active gene expression by DNA transposons in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gene expression', 'MPA', (77, 92))	('active', 'PosReg', (70, 76))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('DNA transposons', 'Var', (96, 111))
24161	31745090	At the global level, we observed strong CpG demethylation of tumor tissue compared with normal in liver, head and neck, bladder and lung squamous and colon cancers (Supplementary Fig.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('CpG', 'Var', (40, 43))	('liver', 'Disease', (98, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (150, 162))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('bladder and lung squamous and colon cancers', 'Disease', 'MESH:D001749', (120, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('colon cancers', 'Phenotype', 'HP:0003003', (150, 163))	('tumor', 'Disease', (61, 66))
24162	31745090	3b), where the majority of differentially methylated CpGs (DMCs) in these cancer types were demethylated (Deltabeta < -0.1, FDR < 0.05, Fig.	('demethylated', 'MPA', (92, 104))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('CpGs', 'Chemical', 'MESH:C024660', (53, 57))	('differentially', 'Var', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
24163	31745090	However, in all 10 cancer types considered, we discovered a striking enrichment of demethylated DMCs located within TEs as compared with background level of DNA demethylation on the 450 K array (Fig.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('demethylated', 'Var', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('DMCs', 'Gene', (96, 100))
24181	31745090	MER75 (piggyBac DNA transposon), MER4A (ERV1 family), MER54A (ERV3), and MER67A (ERV1) were identified by the true TE model as top predictors for DDR activities (Fig.	('ERV1', 'Gene', (40, 44))	('ERV1', 'Gene', '2671', (40, 44))	('ERV3', 'Gene', '2086', (62, 66))	('ERV1', 'Gene', (81, 85))	('MER54A', 'Var', (54, 60))	('ERV1', 'Gene', '2671', (81, 85))	('ERV3', 'Gene', (62, 66))	('MER67A', 'Var', (73, 79))	('DDR activities', 'MPA', (146, 160))
24183	31745090	MamGypLTR2b (Gypsy), THE1C-int (ERVL), LTR21B (ERV1), and MER57F (ERV1) were identified as TEs with the strongest positive association to type I IFN response (Fig.	('positive', 'PosReg', (114, 122))	('MamGypLTR2b', 'Var', (0, 11))	('ERV1', 'Gene', (47, 51))	('type I IFN response', 'MPA', (138, 157))	('LTR21B', 'Var', (39, 45))	('ERV1', 'Gene', '2671', (47, 51))	('ERV1', 'Gene', (66, 70))	('THE1C-int', 'Var', (21, 30))	('ERV1', 'Gene', '2671', (66, 70))	('MER57F', 'Var', (58, 64))
24189	31745090	KIRC, a highly immunogenic type of tumor, was recently found to harbor the highest proportion of insertion-and-deletion tumor mutations compared with other TCGA cancer types.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', (120, 125))
24191	31745090	Somatic TE transposition events have been previously described in TCGA samples to lead to insertional mutations private to tumors and retrotransposition is known to create DNA double-strand breaks.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('lead', 'Reg', (82, 86))	('insertional mutations', 'Var', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TE transposition', 'Phenotype', 'HP:0011540', (8, 24))
24192	31745090	Although DDR is known to activate immune signaling and inflammation, more research is needed to elucidate the connection between TE expression, DDR and immunogenicity in cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('activate', 'PosReg', (25, 33))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('DDR', 'Var', (9, 12))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('immune', 'CPA', (34, 40))	('inflammation', 'Disease', (55, 67))
24197	31745090	Epigenetic de-repression by decitabine resulted in strong overexpression of TEs originating from intergenic and intronic regions in these GBM cell lines, particularly TEs from SVA (SVA_B, C, D, E, F), ERV1 (n = 27), L1 (n = 2), and Alu (n = 9) families (FDR < 0.05 and FC > 2, Fig.	('ERV1', 'Gene', '2671', (201, 205))	('decitabine', 'Chemical', 'MESH:C014347', (28, 38))	('Epigenetic', 'Var', (0, 10))	('overexpression', 'PosReg', (58, 72))	('decitabine', 'Gene', (28, 38))	('ERV1', 'Gene', (201, 205))
24199	31745090	Among the 39 MHC-I TE peptides, 16 (41%) were detected only in the decitabine-treated condition, suggesting increased presentation of possibly novel peptides induced by a 5-aza-2'.	('decitabine', 'Chemical', 'MESH:C014347', (67, 77))	("5-aza-2'", 'Chemical', 'MESH:D001372', (171, 179))	("5-aza-2'", 'Var', (171, 179))	('increased', 'PosReg', (108, 117))	('presentation', 'MPA', (118, 130))
24211	31745090	Synergistic effect between epigenetic therapy and immunotherapy have been observed in preclinical models, where induction of antiviral immunity to retroviral expression is proposed to be a mechanism of tumor regression.	('epigenetic therapy', 'Var', (27, 45))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('antiviral', 'MPA', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
24282	31745090	CGP RNA sequencing data have been deposited in the European genome-phenome archive under the following accession codes: small cell lung cancer screen, EGAS00001000334; colon cancer screen, EGAS00001000288; Exome sequencing, RNA Sequencing, SNP array profiling of gastric tumor samples and cell lines, EGAS00001000736 and non-clear cell renal cell carcinoma, EGAS00001000926.	('gastric tumor', 'Disease', (263, 276))	('colon cancer', 'Disease', (168, 180))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('small cell lung cancer', 'Disease', (120, 142))	('gastric tumor', 'Disease', 'MESH:D013274', (263, 276))	('gastric tumor', 'Phenotype', 'HP:0006753', (263, 276))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('non-clear', 'Disease', (321, 330))	('colon cancer', 'Phenotype', 'HP:0003003', (168, 180))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (336, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('EGAS00001000736', 'Var', (301, 316))	('CGP', 'Chemical', 'MESH:C428863', (0, 3))	('colon cancer', 'Disease', 'MESH:D015179', (168, 180))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (325, 356))	('cell renal cell carcinoma', 'Disease', 'MESH:D002292', (331, 356))	('small cell lung cancer', 'Disease', 'MESH:D055752', (120, 142))	('cell renal cell carcinoma', 'Disease', (331, 356))
24343	31164078	The fixed concentration of 0.67muM (Table 2) for Dis resulted in approximately 95% cell viability in the initial dose response experiment, while the same concentration resulted in approximately 10% cell viability in the main exhaustive experiment (Additional File 1: Figure S16).	('0.67muM', 'Var', (27, 34))	('cell viability', 'CPA', (83, 97))	('S16', 'Gene', (274, 277))	('S16', 'Gene', '6217', (274, 277))	('Dis', 'Chemical', 'MESH:D004221', (49, 52))
24364	31164078	Cells were seeded in poly-L-ornithine (P4957, Sigma-Aldrich) and laminin (L2020, Sigma-Aldrich) coated 384-well plates (164688, Thermo Fisher Scientific) at a density of 1000 cells/well using a BioMek 4000 (Beckman Coulter).	('poly-L-ornithine', 'Chemical', 'MESH:C008973', (21, 37))	('P4957', 'Var', (39, 44))	('L2020', 'Var', (74, 79))	('Cel', 'Chemical', 'MESH:D000068579', (0, 3))
24414	30984099	Traditional Kaplan-Meier curves showed that patients with reoperation had prolonged OS compared with those without reoperation (Figure 3).	('OS', 'Chemical', '-', (84, 86))	('reoperation', 'Var', (58, 69))	('prolonged', 'PosReg', (74, 83))	('patients', 'Species', '9606', (44, 52))
24421	30984099	When the timing of reoperation was ignored, reoperation was also associated with long PPS (HR = 0.70, 95% CI 0.57-0.88, p < 0.01, I2 = 70.2%, Figure 4B).	('PPS', 'Chemical', '-', (86, 89))	('long PPS', 'Disease', (81, 89))	('reoperation', 'Var', (44, 55))
24455	30984099	Fourth, the molecular marker profile, such as MGMT promoter methylation and IDH1 mutation, is associated with clinical outcomes of GBM patients.	('IDH1', 'Gene', (76, 80))	('patients', 'Species', '9606', (135, 143))	('MGMT', 'Gene', (46, 50))	('mutation', 'Var', (81, 89))	('MGMT', 'Gene', '4255', (46, 50))	('IDH1', 'Gene', '3417', (76, 80))	('associated', 'Reg', (94, 104))
24586	29988316	TOP2A/B differ in their catalytic sites; the etoposide binding site of hTOP2A contains a methionine (M762) residue while hTOP2B contains a Glutamine (Q778).	('M762', 'Var', (101, 105))	('etoposide', 'Chemical', 'MESH:D005047', (45, 54))	('hTOP2B', 'Gene', (121, 127))	('al', 'Chemical', 'MESH:D000535', (27, 29))	('TOP2A/B', 'Gene', '7153;7155', (0, 7))	('TOP2A/B', 'Gene', (0, 7))	('hTOP2A', 'Gene', (71, 77))	('methionine', 'Chemical', 'MESH:D008715', (89, 99))	('etoposide binding', 'MPA', (45, 62))	('Glutamine', 'Chemical', 'MESH:D005973', (139, 148))	('hTOP2B', 'Gene', '7155', (121, 127))	('hTOP2A', 'Gene', '7153', (71, 77))	('Q778', 'Var', (150, 154))
24622	29988316	Nanoliposomal topotecan in combination with pegylated liposomal doxorubicin administered through CED was found to be associated with a significantly increased median survival, and an additive effect was observed between these two agents in a rodent model.	('topotecan', 'Chemical', 'MESH:D019772', (14, 23))	('al', 'Chemical', 'MESH:D000535', (172, 174))	('median survival', 'CPA', (159, 174))	('al', 'Chemical', 'MESH:D000535', (11, 13))	('increased', 'PosReg', (149, 158))	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('Nanoliposomal', 'Var', (0, 13))	('al', 'Chemical', 'MESH:D000535', (61, 63))
24639	29988316	The first category, called "experimental" evidence, includes studies in which the gene was experimentally disrupted, leading to cancer cell resistance/susceptibility.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('al', 'Chemical', 'MESH:D000535', (21, 23))	('al', 'Chemical', 'MESH:D000535', (38, 40))	('disrupted', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('al', 'Chemical', 'MESH:D000535', (101, 103))	('leading to', 'Reg', (117, 127))	('cancer', 'Disease', (128, 134))
24640	29988316	The second category, "correlative" evidence, includes genes that are implicated as their natural disruption or variations of expression in some tumors correlates with susceptibility (Table 1).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('variations of', 'Var', (111, 124))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('al', 'Chemical', 'MESH:D000535', (94, 96))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
24650	29988316	The more important question is whether or not naturally occurring variations in TOP2A expression correlate with etoposide/doxorubicin susceptibility, which does not.	('al', 'Chemical', 'MESH:D000535', (51, 53))	('etoposide/doxorubicin susceptibility', 'MPA', (112, 148))	('variations', 'Var', (66, 76))	('TOP2A', 'Gene', (80, 85))	('doxorubicin', 'Chemical', 'MESH:D004317', (122, 133))	('expression', 'MPA', (86, 96))	('etoposide', 'Chemical', 'MESH:D005047', (112, 121))	('correlate', 'Reg', (97, 106))
24652	29988316	It is possible that there are other molecular factors limiting the effectiveness of these agents, and that even a small amount of TOP2A expression is sufficient to elicit DNA damage if other conditions are met.	('TOP2A', 'Gene', (130, 135))	('expression', 'Var', (136, 146))	('DNA damage', 'MPA', (171, 181))	('elicit', 'Reg', (164, 170))	('al', 'Chemical', 'MESH:D000535', (116, 118))
24654	29988316	Mutations in the KEAP1 (Kelch-like ECH-associated Protein-1) gene are common abnormalities in non-small cell lung cancer (NSCLC), gallbladder, liver, ovarian, endometrial, and lung papillary cancers.	('al', 'Chemical', 'MESH:D000535', (168, 170))	('liver', 'Disease', (143, 148))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('lung papillary cancers', 'Disease', (176, 198))	('gallbladder', 'Disease', (130, 141))	('SCLC', 'Phenotype', 'HP:0030357', (123, 127))	('KEAP1', 'Gene', '9817', (17, 22))	('endometrial', 'Disease', (159, 170))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('lung papillary cancers', 'Disease', 'MESH:D008175', (176, 198))	('KEAP1', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('al', 'Chemical', 'MESH:D000535', (100, 102))	('al', 'Chemical', 'MESH:D000535', (131, 133))	('Kelch-like ECH-associated Protein-1', 'Gene', (24, 59))	('ovarian', 'Disease', (150, 157))	('NSCLC', 'Disease', (122, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('non-small cell lung cancer', 'Disease', (94, 120))	('al', 'Chemical', 'MESH:D000535', (83, 85))	('Kelch-like ECH-associated Protein-1', 'Gene', '9817', (24, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))
24657	29988316	A systematic analysis of the KEAP1 genomic locus in NSCLC cell lines demonstrated bi-allelic inactivation in KEAP1 was associated with constitutive activation of Nrf2-mediated gene expression.	('al', 'Chemical', 'MESH:D000535', (15, 17))	('rat', 'Species', '10116', (76, 79))	('NSCLC', 'Disease', (52, 57))	('activation', 'PosReg', (148, 158))	('KEAP1', 'Gene', (109, 114))	('Nrf2', 'Gene', '4780', (162, 166))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('KEAP1', 'Gene', '9817', (29, 34))	('SCLC', 'Phenotype', 'HP:0030357', (53, 57))	('Nrf2', 'Gene', (162, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('al', 'Chemical', 'MESH:D000535', (85, 87))	('KEAP1', 'Gene', '9817', (109, 114))	('KEAP1', 'Gene', (29, 34))	('bi-allelic inactivation', 'Var', (82, 105))
24659	29988316	Amplifying alterations in KEAP1 are found in approximately 0.8% of GBM tumors.	('KEAP1', 'Gene', (26, 31))	('rat', 'Species', '10116', (15, 18))	('al', 'Chemical', 'MESH:D000535', (11, 13))	('GBM tumors', 'Disease', (67, 77))	('GBM tumors', 'Disease', 'MESH:D005910', (67, 77))	('found', 'Reg', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('KEAP1', 'Gene', '9817', (26, 31))	('Amplifying alterations', 'Var', (0, 22))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
24660	29988316	Mutations in the Keap1-Nrf2 pathway have been implicated in TOP2 poison resistance.	('TOP2 poison resistance', 'Disease', (60, 82))	('Nrf2', 'Gene', (23, 27))	('Keap1', 'Gene', (17, 22))	('implicated', 'Reg', (46, 56))	('Keap1', 'Gene', '9817', (17, 22))	('Mutations', 'Var', (0, 9))	('Nrf2', 'Gene', '4780', (23, 27))
24663	29988316	Also, a recent study used a genome wide knock down approach and demonstrated that KEAP1 mutations also confer resistance to TOP2 poisons by decreasing TOP2A expression levels (experimental evidence).	('KEAP1', 'Gene', (82, 87))	('TOP2A expression levels', 'MPA', (151, 174))	('resistance', 'MPA', (110, 120))	('rat', 'Species', '10116', (71, 74))	('decreasing', 'NegReg', (140, 150))	('al', 'Chemical', 'MESH:D000535', (186, 188))	('mutations', 'Var', (88, 97))	('KEAP1', 'Gene', '9817', (82, 87))	('al', 'Chemical', 'MESH:D000535', (98, 100))
24675	29988316	Alterations in C9orf82, predominantly deletions, are found in approximately between 6 and11% of GBM tumors.	('C9orf82', 'Gene', '79886', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('GBM tumors', 'Disease', (96, 106))	('GBM tumors', 'Disease', 'MESH:D005910', (96, 106))	('found', 'Reg', (53, 58))	('Alterations', 'Var', (0, 11))	('C9orf82', 'Gene', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('deletions', 'Var', (38, 47))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('rat', 'Species', '10116', (4, 7))
24676	29988316	A mutation in the C9orf82 gene was shown to confer resistance to TOP2 poisons (experimental evidence).	('C9orf82', 'Gene', (18, 25))	('mutation', 'Var', (2, 10))	('C9orf82', 'Gene', '79886', (18, 25))	('resistance to TOP2 poisons', 'MPA', (51, 77))	('al', 'Chemical', 'MESH:D000535', (89, 91))
24681	29988316	Alterations in individual components of the SWI/SNF complex are also seen in GBM, with mutation, fusion, deletion, or amplification occurring in between 0.25 and 3.5% of tumors depending on the subunit and the underlying gene.	('al', 'Chemical', 'MESH:D000535', (64, 66))	('deletion', 'Var', (105, 113))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('amplification', 'Var', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('GBM', 'Disease', (77, 80))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('fusion', 'Var', (97, 103))	('rat', 'Species', '10116', (4, 7))	('mutation', 'Var', (87, 95))	('al', 'Chemical', 'MESH:D000535', (23, 25))	('tumors', 'Disease', (170, 176))	('Alterations', 'Reg', (0, 11))
24698	29313975	Near-infrared photoimmunotherapy targeting EGFR:Shedding new light on glioblastoma treatment Glioblastomas (GBMs) are high-grade brain tumors, differentially driven by alterations (amplification, deletion or missense mutations) in the epidermal growth factor receptor (EGFR), that carry a poor prognosis of just 12-15 months following standard therapy.	('brain tumors', 'Disease', 'MESH:D001932', (129, 141))	('brain tumors', 'Phenotype', 'HP:0030692', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('brain tumor', 'Phenotype', 'HP:0030692', (129, 140))	('glioblastoma', 'Disease', (70, 82))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', '13649', (43, 47))	('Glioblastomas', 'Phenotype', 'HP:0012174', (93, 106))	('GBMs', 'Phenotype', 'HP:0012174', (108, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('Glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('deletion', 'Var', (196, 204))	('brain tumors', 'Disease', (129, 141))	('EGFR', 'Gene', (269, 273))	('EGFR', 'Gene', '13649', (269, 273))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('driven by alterations', 'Reg', (158, 179))	('Glioblastomas', 'Disease', 'MESH:D005909', (93, 106))	('Glioblastomas', 'Disease', (93, 106))	('missense mutations', 'Var', (208, 226))
24720	29313975	The dye is considerably less sensitive to photobleaching than many other fluorochromes, has excellent water solubility and can be covalently conjugated to a targeted molecule via an N-hydroxysuccinimide ester or maleimide.15 Recent in vitro studies have demonstrated that IR700DX-based mAb conjugates are highly specific for cells that express the target antigen, and have no effect on adjacent non-expressing cells.15, 18 It has been found that, when the conjugate selectively binds to a target on the cell membrane and is exposed to NIR light, it induces rapid alterations in the cell membrane that ultimately lead to cell death.18 These promising preclinical findings have resulted in clinical trial initiation for the IR700DX-cetuximab conjugate, currently in a Phase I study in inoperable squamous cell carcinomas of the head and neck [NCT02422979].	('IR700DX-cetuximab', 'Var', (722, 739))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (794, 818))	('squamous cell carcinomas', 'Disease', (794, 818))	('carcinomas', 'Phenotype', 'HP:0030731', (808, 818))	('cetuximab', 'Chemical', 'MESH:D000068818', (730, 739))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (794, 818))	('maleimide', 'Chemical', 'MESH:C043592', (212, 221))
24724	29313975	The hydrophilic IR700DX-maleimide used for affibody conjugation, IR700DX-NHS ester, IR700DX-carboxylate and IR800CW-maleimide were purchased from LI-COR Biosciences (Lincoln, NE).	('IR700DX-NHS ester', 'Chemical', '-', (65, 82))	('IR800CW-maleimide', 'Chemical', '-', (108, 125))	('IR800CW-maleimide', 'Var', (108, 125))	('IR700DX-carboxylate', 'Var', (84, 103))	('IR700DX-maleimide', 'Chemical', '-', (16, 33))	('IR700DX-NHS', 'Var', (65, 76))	('IR700DX-carboxylate', 'Chemical', '-', (84, 103))
24731	29313975	To test the specificity of conjugate binding, ZEGFR:03115-IR700DX (1 microM) or IR700DX alone (1 microM) were added to the medium and cells were incubated for 1, 3 or 6 h at 37 C. To analyse the penetration of the conjugate in comparison to an antibody-based conjugate, U87-MGvIII spheroids were incubated with either ZEGFR:03115-IR700DX (500 nM), anti-EGFR-targeted antibody-FITC (500 nM) or IR700DX-maleimide alone (500 nM).	('antibody-FITC (500 nM', 'Var', (367, 388))	('U87-MG', 'CellLine', 'CVCL:0022', (270, 276))	('anti-EGFR-targeted', 'Protein', (348, 366))	('IR700DX-maleimide', 'Chemical', '-', (393, 410))	('IR700DX-maleimide', 'Var', (393, 410))
24735	29313975	U87-MGvIII or MCF7 cells (4 x 103) were seeded in black 96-well plates with clear bottoms for 24 h. For 3D U87-MGvIII or WSz4 cultures, cells (4 x 103) were seeded in 96-well ultra-low attachment plates (Corning  Costar , Corning, NY) for 72 or 120 h (for WSz4).	('MCF7', 'CellLine', 'CVCL:0031', (14, 18))	('Corning  Costar', 'Disease', 'MESH:D002145', (204, 219))	('U87-MG', 'CellLine', 'CVCL:0022', (0, 6))	('Corning  Costar', 'Disease', (204, 219))	('U87-MG', 'CellLine', 'CVCL:0022', (107, 113))	('U87-MGvIII', 'Var', (107, 117))
24741	29313975	The corresponding densitometric analysis of protein bands indicated that EGFR expression level ranged from overexpression (U87-MGvIII, 1), through intermediate (WSz4, 0.18) to very low (U251, 0.06; U87-MG, 0.03) and negligible expression (MCF7, 0; Fig.	('U87-MG', 'CellLine', 'CVCL:0022', (123, 129))	('U251', 'Var', (186, 190))	('EGFR', 'Gene', (73, 77))	('expression', 'MPA', (227, 237))	('U251', 'CellLine', 'CVCL:0021', (186, 190))	('MCF7', 'CellLine', 'CVCL:0031', (239, 243))	('U87-MG', 'CellLine', 'CVCL:0022', (198, 204))	('U87-MGvIII', 'Var', (123, 133))	('overexpression', 'PosReg', (107, 121))
24743	29313975	Furthermore, confocal microscopy images showed intense binding of the conjugate to the cell membrane of U251 cells at 4 C, which further confirmed binding specificity of the ZEGFR03115-IR700DX to EGFR (Fig.	('U251', 'CellLine', 'CVCL:0021', (104, 108))	('ZEGFR03115-IR700DX', 'Var', (174, 192))	('binding', 'Interaction', (55, 62))
24750	29313975	2 a) post-continuous irradiation with the red LED L690-66-60 for 1,280 sec (16 J/cm2).	('L690-66-60', 'Var', (50, 60))	('sec', 'Gene', '65967', (71, 74))	('sec', 'Gene', (71, 74))
24755	29313975	To determine the phototoxicity of ZEGFR:03115-IR700DX, cells were incubated with the conjugate for 6 h and exposed to two different doses of NIR light.	('ZEGFR:03115-IR700DX', 'Var', (34, 53))	('toxicity', 'Disease', 'MESH:D064420', (22, 30))	('toxicity', 'Disease', (22, 30))
24759	29313975	As expected, there was no significant cytotoxicity associated with exposure to ZEGFR:03115-IR700DX without NIR irradiation, IR700DX or light irradiation alone.	('ZEGFR:03115-IR700DX', 'Var', (79, 98))	('cytotoxicity', 'Disease', (38, 50))	('cytotoxicity', 'Disease', 'MESH:D064420', (38, 50))
24768	29313975	The tumor signal intensity after ZEGFR:03115-IR700DX injection (6 mug) was calculated to be >6-fold higher than the signal measured for ZTaq-IR700DX, which confirmed the EGFR specificity of the affibody-based conjugate in vivo (Figs.	('tumor', 'Disease', (4, 9))	('ZEGFR:03115-IR700DX', 'Var', (33, 52))	('ZTaq', 'Chemical', '-', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('higher', 'PosReg', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
24776	29313975	Surprisingly, when we injected the equivalent to 18 microg ZEGFR:03115-IR700DX, of the highly hydrophilic IR700DX-maleimide, there was an intense tumor fluorescence that gradually increased over time and slow clearance was observed only after 24 h (Supporting Information Figs.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('increased', 'PosReg', (180, 189))	('tumor', 'Disease', (146, 151))	('ZEGFR:03115-IR700DX', 'Var', (59, 78))	('IR700DX-maleimide', 'Chemical', '-', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
24778	29313975	We hypothesized that this uptake was due to the reactive nature of the maleimide, so we compared the pharmacokinetics (PK) of IR700DX with three different functional groups: IR700DX-maleimide, IR700DX-NHS ester, IR700DX-carboxylate.	('IR700DX-carboxylate', 'Var', (212, 231))	('IR700DX-maleimide', 'Var', (174, 191))	('maleimide', 'Chemical', 'MESH:C043592', (182, 191))	('IR700DX-carboxylate', 'Chemical', '-', (212, 231))	('maleimide', 'Chemical', 'MESH:C043592', (71, 80))	('IR700DX-NHS ester', 'Chemical', '-', (193, 210))	('IR700DX-maleimide', 'Chemical', '-', (174, 191))
24779	29313975	Interestingly, tumor uptake was markedly lower when administering the IR700DX-NHS ester and IR700DX-carboxylate and was almost completely washed out after 3 h (Figs.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('IR700DX-NHS ester', 'Chemical', '-', (70, 87))	('lower', 'NegReg', (41, 46))	('tumor', 'Disease', (15, 20))	('IR700DX-NHS', 'Var', (70, 81))	('IR700DX-carboxylate', 'Var', (92, 111))	('IR700DX-carboxylate', 'Chemical', '-', (92, 111))
24780	29313975	4e), indicating that the functional group was affecting the PK of IR700DX and the dye itself has no preferential uptake in the tumor.	('tumor', 'Disease', (127, 132))	('IR700DX', 'Var', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
24783	29313975	We, therefore, postulated that the increased uptake of IR700DX-maleimide is due to an association with blood proteins, primarily blood serum albumin, via thiols which lead to longer systemic circulation and preferential accumulation in the tumor.	('increased', 'PosReg', (35, 44))	('longer', 'PosReg', (175, 181))	('tumor', 'Disease', (240, 245))	('IR700DX-maleimide', 'Chemical', '-', (55, 72))	('accumulation', 'MPA', (220, 232))	('IR700DX-maleimide', 'Var', (55, 72))	('association', 'Interaction', (86, 97))	('thiols', 'Chemical', 'MESH:D013438', (154, 160))	('preferential', 'PosReg', (207, 219))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('uptake', 'MPA', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
24784	29313975	To test our hypothesis, we analyzed mouse serum following administration of the respective dyes and discovered that the IR700DX-maleimide dyes appeared to have the highest affinity for the blood proteins based on the clear and intense fluorescent protein bands on the SDS-PAGE gel (Fig.	('SDS', 'Chemical', 'MESH:D012967', (268, 271))	('affinity', 'MPA', (172, 180))	('IR700DX-maleimide', 'Chemical', '-', (120, 137))	('mouse', 'Species', '10090', (36, 41))	('IR700DX-maleimide', 'Var', (120, 137))
24789	29313975	Although an equivalent dose of IR700DX-maleimide alone had higher tumor uptake (2.9 x 108 p/sec/cm2/sr/muW/cm2), the surrounding brain had large amounts of non-specific uptake and, therefore, only produced a mean tumor-to-brain ratio of 2.95 +- 1.07 (Supporting Information Fig.	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('IR700DX-maleimide', 'Chemical', '-', (31, 48))	('IR700DX-maleimide', 'Var', (31, 48))	('sec', 'Gene', '65967', (92, 95))	('sec', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('non-specific uptake', 'MPA', (156, 175))	('higher', 'PosReg', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
24791	29313975	Distinct receptor expression correlated well with the histological staining of the tumor, the fluorescence image and IHC staining of ZEGFR:03115-IR700DX distribution.	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ZEGFR:03115-IR700DX', 'Var', (133, 152))
24793	29313975	For the PIT studies, mice bearing subcutaneous U87-MGvIII tumors were randomized into four groups (as in the Material and Methods section) and injected with ZEGFR:03115-IR700DX or IR700DX-maleimide.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('IR700DX-maleimide', 'Chemical', '-', (180, 197))	('mice', 'Species', '10090', (21, 25))	('IR700DX-maleimide', 'Var', (180, 197))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('sec', 'Gene', '65967', (130, 133))	('sec', 'Gene', (130, 133))	('U87-MG', 'CellLine', 'CVCL:0022', (47, 53))
24796	29313975	Interestingly, the IR700DX-maleimide fluorescence intensity not only did not photobleach, but rather increased in the tissues surrounding the tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('increased', 'PosReg', (101, 110))	('tumor', 'Disease', (142, 147))	('IR700DX-maleimide', 'Chemical', '-', (19, 36))	('IR700DX-maleimide', 'Var', (19, 36))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
24797	29313975	This may be due to vessel dilation in response to irradiation with the NIR light and subsequent reaccumulation of the IR700DX in the tumor.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('vessel', 'MPA', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('IR700DX', 'Var', (118, 125))
24799	29313975	There was a significant inhibition of tumor growth in mice treated with the ZEGFR:03115-IR700DX-based PIT, as well as IR700DX-based PDT, in comparison to the control groups that received only light or each of the agents alone (p < 0.01; control groups vs.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ZEGFR:03115-IR700DX-based', 'Var', (76, 101))	('IR700DX-based', 'Var', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('inhibition', 'NegReg', (24, 34))	('mice', 'Species', '10090', (54, 58))
24801	29313975	The advantage of PIT over PDT was highlighted as mice treated with the IR700DX-based PDT started to developed skin necrosis on the treated lesion, as early as 1 day after the first light exposure, whereas in PIT-treated mice the normal tissue was spared (Fig.	('mice', 'Species', '10090', (220, 224))	('mice', 'Species', '10090', (49, 53))	('IR700DX-based', 'Var', (71, 84))	('skin necrosis', 'Disease', (110, 123))	('skin necrosis', 'Disease', 'MESH:D012871', (110, 123))
24807	29313975	Of note, IR700DX-mAb-based PIT targeting EGFR has been previously demonstrated to be effective in cancers such as breast, lung and bladder by Kobayashi and co-workers.30, 31, 32, 33, 34 We found that ZEGFR:03115-IR700DX has significant activity in inducing cell death selectively in EGFR+ve GBM cells both in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('GBM', 'Phenotype', 'HP:0012174', (291, 294))	('inducing', 'Reg', (248, 256))	('cell death', 'CPA', (257, 267))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('ZEGFR:03115-IR700DX', 'Var', (200, 219))
24809	29313975	No toxicity was observed when the cells were treated with the ZEGFR:03115-IR700DX or IR700DX alone.	('toxicity', 'Disease', 'MESH:D064420', (3, 11))	('IR700DX', 'Var', (85, 92))	('toxicity', 'Disease', (3, 11))
24814	29313975	Importantly, the in vivo PIT experiments showed significant differences in tumor growth between U87-MGvIII tumor-bearing mice treated with the conjugate and control groups: (i) mice that were optically irradiated only and (ii) mice that received ZEGFR:03115-IR700DX or saline only.	('i)', 'Chemical', 'MESH:D007455', (174, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('differences', 'Reg', (60, 71))	('U87-MG', 'CellLine', 'CVCL:0022', (96, 102))	('mice', 'Species', '10090', (227, 231))	('i)', 'Chemical', 'MESH:D007455', (224, 226))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('saline', 'Chemical', 'MESH:D012965', (269, 275))	('mice', 'Species', '10090', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mice', 'Species', '10090', (177, 181))	('tumor', 'Disease', (75, 80))	('U87-MGvIII', 'Var', (96, 106))
24818	29313975	administration of the conjugate.36  We also questioned whether IR700DX alone induces any antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IR700DX', 'Var', (63, 70))
24819	29313975	Surprisingly, and in contrast to our in vitro experiments, we showed that IR700DX rapidly penetrated into the tumor mass and, when exposed to NIR light, inhibited tumor growth.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('IR700DX', 'Var', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('inhibited', 'NegReg', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
24821	29313975	The IR700DX-NHS ester and IR700DX-carboxylate had their highest uptake in the U87-MGvIII tumor at 30 min post-injection and were cleared from the tumor faster than the IR700DX-maleimide.	('U87-MG', 'CellLine', 'CVCL:0022', (78, 84))	('IR700DX-NHS ester', 'Var', (4, 21))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('IR700DX-NHS ester', 'Chemical', '-', (4, 21))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('uptake', 'MPA', (64, 70))	('IR700DX-carboxylate', 'Var', (26, 45))	('IR700DX-carboxylate', 'Chemical', '-', (26, 45))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('IR700DX-maleimide', 'Chemical', '-', (168, 185))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
24824	29313975	These results were in agreement with previous evidence showing that the linker moiety can affect the PK of the probe.37 Even though the IR700DX-maleimide was highly effective and has the potential to be a useful non-targeted PS in vivo, its high non-specific binding to serum proteins, post-treatment skin toxicity and lack of tumor specificity will limit the probe's utility especially for intraoperative PDT of brain tumors.	('intraoperative PDT of brain tumors', 'Disease', (391, 425))	('brain tumors', 'Phenotype', 'HP:0030692', (413, 425))	('brain tumor', 'Phenotype', 'HP:0030692', (413, 424))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumor', 'Disease', (419, 424))	('tumor', 'Disease', 'MESH:D009369', (419, 424))	('intraoperative PDT of brain tumors', 'Disease', 'MESH:D001932', (391, 425))	('tumors', 'Phenotype', 'HP:0002664', (419, 425))	('tumor', 'Disease', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (419, 424))	('skin toxicity', 'Disease', (301, 314))	('skin toxicity', 'Disease', 'MESH:D012871', (301, 314))	('binding', 'Interaction', (259, 266))	('IR700DX-maleimide', 'Chemical', '-', (136, 153))	('IR700DX-maleimide', 'Var', (136, 153))	('tumor', 'Disease', 'MESH:D009369', (327, 332))
24866	29262591	GAMG, SW1783 and A172) an accumulation of Beva at the extracellular region (attached to the coverslip).	('accumulation', 'PosReg', (26, 38))	('SW1783', 'CellLine', 'CVCL:1722', (6, 12))	('SW1783', 'Var', (6, 12))	('Beva', 'Chemical', '-', (42, 46))	('A172', 'Var', (17, 21))
24933	29262591	Seven immortalized GBM cell lines were used: SW1088, SW1783, U-87 MG and A172 were obtained from ATCC (American Type Culture Collection), SNB-19 and GAMG were obtained from DSMZ (German Collection of Microorganisms and Cell Cultures) and U251 was kindly provided by Professor Joseph Costello.	('SNB-19', 'Disease', 'MESH:C567026', (138, 144))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('SNB-19', 'Disease', (138, 144))	('SW1088', 'CellLine', 'CVCL:1715', (45, 51))	('SW1088', 'Var', (45, 51))	('SW1783', 'CellLine', 'CVCL:1722', (53, 59))
24936	29262591	Authentication of cell lines was performed in our lab by short tandem repeat (STR) DNA typing according to the International Reference Standard for Authentication of Human Cell Lines using a panel of 8 (D5S818, D13S317, D7S820, D16S539, vWA, TH01, TPOX and CSF1P0) STR loci plus gender determination (AMEL).	('D13S317', 'Var', (211, 218))	('D16S539', 'Var', (228, 235))	('D7S820', 'Var', (220, 226))	('Human', 'Species', '9606', (166, 171))	('D5S818', 'Var', (203, 209))
25013	27530322	Median survival was significantly increased in CCL2-low subset patients in data encompassing all glioma grades (Figure 1A) as well as in data limited to GBM cases alone (Figure 1B) when compared to the CCL2-high subset (Affymetrix U133A: CCL2-low 479 days, CCL2-high 375 days, P < 0.001) (Illumina HiSeq: CCL2-low 485 days, CCL2-high 317 days, P = 0.003).	('CCL2-low subset', 'Var', (47, 62))	('glioma', 'Disease', (97, 103))	('Median survival', 'MPA', (0, 15))	('patients', 'Species', '9606', (63, 71))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('increased', 'PosReg', (34, 43))
25077	27530322	Ly-6G+ granulocytic MDSCs were unaffected by the absence of CCR2 in terms of trafficking to the brain tumor.	('brain tumor', 'Phenotype', 'HP:0030692', (96, 107))	('CCR2', 'Gene', '12772', (60, 64))	('Ly-6G', 'Gene', '546644', (0, 5))	('Ly-6G', 'Gene', (0, 5))	('CCR2', 'Gene', (60, 64))	('brain tumor', 'Disease', 'MESH:D001932', (96, 107))	('brain tumor', 'Disease', (96, 107))	('absence', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
25161	25980499	Additionally, no significant increase in the number of apoptotic or necrotic cells was observed in both cell lines following 24h treatment with IC50 and double-IC50 concentrations of BGB324 (Figure 5B).	('BGB324', 'Gene', (183, 189))	('necrotic', 'Disease', 'MESH:D009336', (68, 76))	('necrotic', 'Disease', (68, 76))	('double-IC50', 'Var', (153, 164))	('BGB324', 'Chemical', 'MESH:C548378', (183, 189))	('IC50', 'Var', (144, 148))
25162	25980499	In long-term cell growth experiments in 3D (soft agar assays), BGB324 significantly reduced colony formation at 0.75 muM in UP007 cells, and inhibition of SNB-19 colony formation was apparent at 2 muM of BGB324, with complete inhibition of colony growth without cell death achieved at 10 muM BGB324 (Figure 6).	('muM', 'Gene', (288, 291))	('BGB324', 'Chemical', 'MESH:C548378', (204, 210))	('inhibition', 'NegReg', (141, 151))	('SNB-19', 'Gene', (155, 161))	('colony formation', 'CPA', (92, 108))	('muM', 'Gene', '56925', (117, 120))	('reduced', 'NegReg', (84, 91))	('muM', 'Gene', '56925', (197, 200))	('agar', 'Chemical', 'MESH:D000362', (49, 53))	('BGB324', 'Chemical', 'MESH:C548378', (292, 298))	('BGB324', 'Chemical', 'MESH:C548378', (63, 69))	('muM', 'Gene', '56925', (288, 291))	('muM', 'Gene', (117, 120))	('BGB324', 'Var', (204, 210))	('BGB324', 'Gene', (63, 69))	('muM', 'Gene', (197, 200))	('colony formation', 'CPA', (162, 178))
25191	25980499	Furthermore, inhibition of Akt was observed in both cell lines following treatment with BGB324 even in the presence of Gas6, indicating that BGB324 is effective in inhibiting basal Axl activity and downstream signalling in a dose-dependent manner, irrespective of the ligand.	('BGB324', 'Chemical', 'MESH:C548378', (88, 94))	('Axl', 'Gene', '558', (181, 184))	('Gas6', 'Gene', '2621', (119, 123))	('inhibiting', 'NegReg', (164, 174))	('BGB324', 'Var', (141, 147))	('Akt', 'Gene', '207', (27, 30))	('downstream signalling', 'MPA', (198, 219))	('Axl', 'Gene', (181, 184))	('BGB324', 'Chemical', 'MESH:C548378', (141, 147))	('Gas6', 'Gene', (119, 123))	('Akt', 'Gene', (27, 30))
25274	23641361	Several primary oncogenic events including, mutational activation of the Ras (Grugel et al.,) and Wnt (Zhang et al.,) pathways, also upregulate VEGF expression and VEGF is known to be overexpressed in many types of cancer including colon cancer, non-squamous non-small cell lung cancer (NSCLC), kidney cancer, and brain cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('cancer', 'Disease', (320, 326))	('VEGF', 'Gene', '7422', (164, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('brain cancers', 'Disease', 'MESH:D001932', (314, 327))	('mutational', 'Var', (44, 54))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (259, 285))	('cancer', 'Disease', (279, 285))	('VEGF', 'Gene', (164, 168))	('cancer', 'Disease', (302, 308))	('Wnt', 'Pathway', (98, 101))	('kidney cancer', 'Disease', 'MESH:D007680', (295, 308))	('colon cancer', 'Phenotype', 'HP:0003003', (232, 244))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('overexpressed', 'PosReg', (184, 197))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (263, 285))	('upregulate', 'PosReg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('kidney cancer', 'Phenotype', 'HP:0009726', (295, 308))	('kidney cancer', 'Disease', (295, 308))	('VEGF', 'Gene', '7422', (144, 148))	('colon cancer', 'Disease', 'MESH:D015179', (232, 244))	('expression', 'MPA', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('VEGF', 'Gene', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('NSCLC', 'Disease', 'MESH:D002289', (287, 292))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('non-squamous non-small cell lung cancer', 'Disease', 'MESH:D002289', (246, 285))	('colon cancer', 'Disease', (232, 244))	('non-squamous non-small cell lung cancer', 'Disease', (246, 285))	('NSCLC', 'Disease', (287, 292))	('brain cancers', 'Disease', (314, 327))	('cancers', 'Phenotype', 'HP:0002664', (320, 327))	('Ras', 'Pathway', (73, 76))
25277	23641361	Thus, molecular inhibition of VEGF is an attractive model for targeting tumor growth and spread.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('molecular inhibition', 'Var', (6, 26))	('VEGF', 'Gene', '7422', (30, 34))	('tumor', 'Disease', (72, 77))	('VEGF', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
25389	23641361	reported a 2-year-old with GSD who continued to have progressive osteolysis with massive pleural effusions despite PEG-interferon-alpha-2b, bisphosphonates, and imatinib.	('PEG-interferon-alpha-2b', 'Var', (115, 138))	('bisphosphonates', 'Chemical', 'MESH:D004164', (140, 155))	('pleural effusion', 'Phenotype', 'HP:0002202', (89, 105))	('pleural effusions', 'Disease', (89, 106))	('osteolysis', 'Disease', 'MESH:D010014', (65, 75))	('GSD', 'Disease', 'MESH:D016098', (27, 30))	('GSD', 'Disease', (27, 30))	('pleural effusions', 'Disease', 'MESH:D010996', (89, 106))	('osteolysis', 'Phenotype', 'HP:0002797', (65, 75))	('pleural effusions', 'Phenotype', 'HP:0002202', (89, 106))	('imatinib', 'Chemical', 'MESH:D000068877', (161, 169))	('osteolysis', 'Disease', (65, 75))
25449	33976133	Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (alphaGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('promotes', 'PosReg', (116, 124))	('Treg', 'Chemical', '-', (129, 133))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('alleviates', 'NegReg', (182, 192))	('CD4', 'Var', (125, 128))	('induces', 'PosReg', (259, 266))	('Treg', 'Chemical', '-', (193, 197))	('Treg', 'Chemical', '-', (65, 69))	('GBM', 'Phenotype', 'HP:0012174', (303, 306))	('tumor', 'Disease', (232, 237))	('Treg cell-mediated suppression', 'CPA', (193, 223))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
25464	33976133	Anti-GITR agonistic antibody therapy has been shown to cause tumor regression in a number of preclinical non-CNS tumor models and is under evaluation as monotherapy (NCT01239134) and in combination with aPD1 therapy in a number of clinical trials (NCT04021043, NCT02740270, NCT02628574, NCT02598960, and NCT04225039).	('tumor', 'Disease', (113, 118))	('CNS tumor', 'Phenotype', 'HP:0100006', (109, 118))	('NCT02628574', 'Var', (274, 285))	('NCT02740270', 'Var', (261, 272))	('NCT02598960', 'Var', (287, 298))	('NCT04021043', 'Var', (248, 259))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('NCT04225039', 'Var', (304, 315))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (61, 66))
25487	33976133	A high ratio of CD4 to CD8 T cells has been reported to correlate with poor prognosis in GBM, similar to the observation in a limited number of patients (n = 6), where two patients who survived for more than 2 years demonstrated a relatively high proportion of intratumoral CD8 T cells (Supplementary Fig.	('CD8', 'Gene', (23, 26))	('GBM', 'Phenotype', 'HP:0012174', (89, 92))	('CD8', 'Gene', '925', (23, 26))	('CD8', 'Gene', '925', (274, 277))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('patients', 'Species', '9606', (144, 152))	('CD4', 'Var', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('patients', 'Species', '9606', (172, 180))	('GBM', 'Disease', (89, 92))	('CD8', 'Gene', (274, 277))
25511	33976133	The expression of markers of Treg cell anergy substantially increased with alphaPD1 therapy (Fig.	('expression', 'MPA', (4, 14))	('Treg', 'Chemical', '-', (29, 33))	('alphaPD1 therapy', 'Var', (75, 91))	('increased', 'PosReg', (60, 69))
25516	33976133	3a), the ratio of FR4hiCD73hi/FR4loCD73lo was higher compared to non-tumor-bearing mice (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('higher', 'PosReg', (46, 52))	('tumor', 'Disease', (69, 74))	('mice', 'Species', '10090', (83, 87))	('FR4hiCD73hi/FR4loCD73lo', 'Var', (18, 41))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
25534	33976133	However, the addition of alphaPD1 to alphaCTLA4 reversed the reduction in Treg cell anergy conferred by alphaCTLA4 (Supplementary Fig.	('Treg', 'Chemical', '-', (74, 78))	('alphaCTLA4', 'Var', (104, 114))	('reduction', 'NegReg', (61, 70))	('Treg cell anergy', 'CPA', (74, 90))	('alphaCTLA4', 'Chemical', '-', (104, 114))	('alphaCTLA4', 'Chemical', '-', (37, 47))
25542	33976133	Therefore, we reasoned that inducing GITR signaling in Treg cells may be a promising immunotherapeutic strategy to overcome resistance to ICBs in GBM as it would not only reduce suppression of antitumor immunity but also activate potential antitumor effector functions of reprogrammed Treg cells.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (244, 249))	('reduce', 'NegReg', (171, 177))	('inducing', 'Var', (28, 36))	('ICBs', 'Chemical', '-', (138, 142))	('suppression', 'MPA', (178, 189))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Treg', 'Chemical', '-', (285, 289))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))	('Treg', 'Chemical', '-', (55, 59))	('activate', 'PosReg', (221, 229))	('tumor', 'Disease', (197, 202))
25550	33976133	1e), alphaPD1 monotherapy enhanced Treg cells anergy (Fig.	('monotherapy', 'Var', (14, 25))	('Treg cells anergy', 'CPA', (35, 52))	('enhanced', 'PosReg', (26, 34))	('Treg', 'Chemical', '-', (35, 39))
25556	33976133	Therapeutic administration of alphaGITR to established GBM tumors (GL261-MGH, CT2A, and 005GSC) (Fig.	('GBM tumors', 'Disease', (55, 65))	('GBM tumors', 'Disease', 'MESH:D005910', (55, 65))	('CT2A', 'Mutation', 'c.2CT>A', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('GL261', 'Chemical', '-', (67, 72))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('GL261-MGH', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
25570	33976133	We found that, in contrast to CD8 T cells from mice treated with IgG2a or alphaPD1 alone, CD8 T cells harvested from mice treated with alphaGITR alone or combined alphaPD1 + alphaGITR gained an ability to resist Treg cell suppression and therefore were significantly more proliferative and exhibited increased IFNgamma expression (Supplementary Fig.	('expression', 'MPA', (319, 329))	('alphaPD1', 'Var', (163, 171))	('CD8', 'Gene', (30, 33))	('more', 'PosReg', (267, 271))	('IgG2a', 'Gene', (65, 70))	('CD8', 'Gene', '925', (30, 33))	('CD8', 'Gene', '925', (90, 93))	('resist Treg cell suppression', 'CPA', (205, 233))	('increased', 'PosReg', (300, 309))	('gained', 'PosReg', (184, 190))	('Treg', 'Chemical', '-', (212, 216))	('mice', 'Species', '10090', (117, 121))	('CD8', 'Gene', (90, 93))	('IgG2a', 'Gene', '668478', (65, 70))	('IFNgamma', 'Protein', (310, 318))	('mice', 'Species', '10090', (47, 51))	('proliferative', 'CPA', (272, 285))
25586	33976133	We found that modulation of Treg cells (depletion + conversion) along with the reduction of TAMs enhanced the survival in both GL261-MGH (~2-fold increase) and CT2A (~3.5-fold) challenged mice (Supplementary Fig.	('mice', 'Species', '10090', (188, 192))	('GL261', 'Chemical', '-', (127, 132))	('CT2A', 'Mutation', 'c.2CT>A', (160, 164))	('modulation', 'Var', (14, 24))	('enhanced', 'PosReg', (97, 105))	('survival', 'CPA', (110, 118))	('Treg', 'Chemical', '-', (28, 32))	('TAMs', 'Chemical', '-', (92, 96))
25597	33976133	Consistent with the upregulation of genes associated with the Th1-like phenotype by GBM Treg cells, treatment with alphaPD1 + alphaGITR in mice displayed reduced Treg cell anergy (Fig.	('GBM', 'Phenotype', 'HP:0012174', (84, 87))	('alphaPD1 + alphaGITR', 'Var', (115, 135))	('Treg', 'Chemical', '-', (88, 92))	('mice', 'Species', '10090', (139, 143))	('reduced', 'NegReg', (154, 161))	('Treg', 'Chemical', '-', (162, 166))	('Treg cell anergy', 'CPA', (162, 178))
25600	33976133	alphaPD1 + alphaGITR, but not alphaPD1 monotherapy, reduced Treg-mediated suppression of CD8 T cells ex vivo (Supplementary Fig.	('CD8', 'Gene', (89, 92))	('Treg', 'Chemical', '-', (60, 64))	('reduced', 'NegReg', (52, 59))	('CD8', 'Gene', '925', (89, 92))	('alphaPD1 + alphaGITR', 'Var', (0, 20))	('Treg-mediated', 'CPA', (60, 73))
25623	33976133	We first investigated the anti-GBM cytotoxicity of Treg cells, CD8 T cells, or both, by co-culturing them with GBM tumor cells in the presence of alphaPD1 + alphaGITR or control IgG2a antibodies.	('alphaPD1', 'Var', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IgG2a', 'Gene', (178, 183))	('GBM tumor', 'Disease', 'MESH:D005910', (111, 120))	('alphaGITR', 'Protein', (157, 166))	('cytotoxicity', 'Disease', (35, 47))	('GBM tumor', 'Disease', (111, 120))	('CD8', 'Gene', (63, 66))	('GBM', 'Phenotype', 'HP:0012174', (31, 34))	('CD8', 'Gene', '925', (63, 66))	('Treg', 'Chemical', '-', (51, 55))	('IgG2a', 'Gene', '668478', (178, 183))	('cytotoxicity', 'Disease', 'MESH:D064420', (35, 47))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
25624	33976133	We found that a combination of CD8 T cells and Treg cells reprogrammed with alphaPD1 + alphaGITR was most effective for killing tumor cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Treg', 'Chemical', '-', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('alphaPD1 +', 'Var', (76, 86))	('CD8', 'Gene', (31, 34))	('CD8', 'Gene', '925', (31, 34))	('tumor', 'Disease', (128, 133))
25634	33976133	In line with our in vitro findings, alphaPD1 and alphaGITR selectively upregulated MHC I and MHC II, respectively.	('alphaPD1', 'Var', (36, 44))	('MHC II', 'Gene', (93, 99))	('MHC II', 'Gene', '111364', (93, 99))	('MHC I', 'Gene', (83, 88))	('upregulated', 'PosReg', (71, 82))
25645	33976133	Importantly, in vivo blockade of IFNgamma abrogated the antitumor effect of alphaGITR + alphaPD1 in mice (Fig.	('abrogated', 'NegReg', (42, 51))	('IFNgamma', 'Protein', (33, 41))	('mice', 'Species', '10090', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('blockade', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
25647	33976133	Neither GzmB blockade nor TNFalpha blockade was able to abrogate the therapeutic efficacy of alphaPD1 + alphaGITR in both mouse and human cell settings (Supplementary Fig.	('TNFalpha', 'Gene', (26, 34))	('TNFalpha', 'Gene', '21926', (26, 34))	('human', 'Species', '9606', (132, 137))	('alphaPD1', 'Var', (93, 101))	('mouse', 'Species', '10090', (122, 127))
25663	33976133	Upon alphaPD1 treatment, Treg cells not only suppress CTL function (Supplementary Fig.	('suppress', 'NegReg', (45, 53))	('alphaPD1', 'Var', (5, 13))	('CTL function', 'MPA', (54, 66))	('Treg', 'Chemical', '-', (25, 29))
25678	33976133	In our study, the therapeutic benefit of the alphaPD1 + alphaGITR combination is predominantly mediated by this conversion of Treg cells rather than by re-activating CD8 T cells alone (Fig.	('CD8', 'Gene', (166, 169))	('CD8', 'Gene', '925', (166, 169))	('alphaPD1 +', 'Var', (45, 55))	('Treg', 'Chemical', '-', (126, 130))
25684	33976133	In addition, increased expression of T-bet and Stat4 after alphaPD1 + alphaGITR treatment (Fig.	('T-bet', 'Gene', (37, 42))	('Stat4', 'Gene', (47, 52))	('T-bet', 'Gene', '57765', (37, 42))	('alphaPD1 +', 'Var', (59, 69))	('Stat4', 'Gene', '20849', (47, 52))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
25685	33976133	Molecular changes in Treg cells associated with alphaPD1 + alphaGITR treatment, therefore, can lead to dedifferentiation of Treg cells into effector T cells without reduction of FoxP3 expression.	('lead to', 'Reg', (95, 102))	('FoxP3', 'Gene', (178, 183))	('FoxP3', 'Gene', '20371', (178, 183))	('alphaPD1 +', 'Var', (48, 58))	('Treg', 'Chemical', '-', (21, 25))	('Treg', 'Chemical', '-', (124, 128))	('dedifferentiation', 'CPA', (103, 120))
25698	33976133	Given that alphaGITR antibodies are currently being evaluated in a number of clinical trials (NCT04021043, NCT02740270, NCT02628574, NCT02598960, and NCT04225039), our study provides mechanistic insights and compelling preclinical data in support of testing the combination of alphaGITR with alphaPD1/PDL1:with or without the SoC therapy:in GBM patients with a high intratumoral accumulation of Treg cells.	('PDL1', 'Gene', (301, 305))	('tumor', 'Disease', (371, 376))	('NCT02628574', 'Var', (120, 131))	('NCT02740270', 'Var', (107, 118))	('NCT04021043', 'Var', (94, 105))	('Treg', 'Chemical', '-', (395, 399))	('NCT02598960', 'Var', (133, 144))	('NCT04225039', 'Var', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('PDL1', 'Gene', '29126', (301, 305))	('GBM', 'Phenotype', 'HP:0012174', (341, 344))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('patients', 'Species', '9606', (345, 353))
25708	33976133	The GL261-MGH and CT2A cell lines expressing secreted Gaussia luciferase (GLUC) were generated by transducing cells with a lentiviral vector co-expressing GLUC and GFP, provided by the MGH vector core, followed by sorting.	('GLUC', 'Var', (155, 159))	('secreted Gaussia luciferase', 'Disease', (45, 72))	('secreted Gaussia luciferase', 'Disease', 'MESH:D002640', (45, 72))	('GL261', 'Chemical', '-', (4, 9))	('CT2A', 'Mutation', 'c.2CT>A', (18, 22))
25720	33976133	For survival studies, C57BL/6 mice bearing GL261-MGH-GFP-GLUC, CT2A-GFP-GLUC, or 005GSC-GFP-GLUC were treated every 3 days with total six doses of (i) IgG2a; (ii) alphaPD1 (Bioxcell, RMP1-14); (iii) alphaGITR (Bioxcell, DTA-1); or (iv) alphaPD1 + alphaGITR.	('mice', 'Species', '10090', (30, 34))	('RMP1-14', 'Gene', '104168;104225;109970;109961', (183, 190))	('IgG2a', 'Gene', (151, 156))	('RMP1-14', 'Gene', (183, 190))	('GL261-MGH-GFP-GLUC', 'Var', (43, 61))	('GL261', 'Chemical', '-', (43, 48))	('IgG2a', 'Gene', '668478', (151, 156))	('CT2A', 'Mutation', 'c.2CT>A', (63, 67))	('CT2A-GFP-GLUC', 'Var', (63, 76))
25738	33976133	Patient records were reviewed for age, sex, medical history, surgical intervention, therapeutic regimens, IDH1 mutation status, MGMT promotor methylation, cytogenetics and overall survival.	('MGMT', 'Gene', '4255', (128, 132))	('MGMT', 'Gene', (128, 132))	('IDH1', 'Gene', (106, 110))	('mutation', 'Var', (111, 119))	('Patient', 'Species', '9606', (0, 7))
25761	32894165	Bioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of ISL2, miR-342-3p, circRNA ARF1 (cARF1), U2AF2, and VEGFA.	('miR-342-3p', 'Var', (125, 135))	('miR-342-3p', 'Chemical', '-', (125, 135))	('VEGFA', 'Gene', (170, 175))	('ISL2', 'Gene', (119, 123))	('VEGFA', 'Gene', '7422', (170, 175))
25768	32894165	Furthermore, U2AF2 bound to and promoted the stability and expression of cARF1, while ISL2 induced the expression of U2AF2, which formed a feedback loop in GSCs.	('promoted', 'PosReg', (32, 40))	('expression', 'MPA', (103, 113))	('stability', 'MPA', (45, 54))	('GSCs', 'Chemical', '-', (156, 160))	('expression', 'MPA', (59, 69))	('bound', 'Interaction', (19, 24))	('U2AF2', 'Var', (117, 122))	('cARF1', 'Gene', (73, 78))
25770	32894165	Our study identified a novel feedback loop among U2AF2, cARF1, miR-342-3p, and ISL2 in GSCs.	('miR-342-3p', 'Var', (63, 73))	('U2AF2', 'Gene', (49, 54))	('miR-342-3p', 'Chemical', '-', (63, 73))	('GSCs', 'Chemical', '-', (87, 91))	('cARF1', 'Gene', (56, 61))	('GSCs', 'Disease', (87, 91))
25778	32894165	It has been reported that ISL2 is essential for acquisition of motor neuron identity, and it contributes to the restriction of motor neurons within the neural tube via slit and semaphorin signaling, while ISL2 inhibition impairs peripheral axonal outgrowth in embryonic zebrafish.	('ISL2', 'Gene', (205, 209))	('restriction', 'MPA', (112, 123))	('peripheral axonal outgrowth', 'CPA', (229, 256))	('semaphorin signaling', 'MPA', (177, 197))	('inhibition', 'Var', (210, 220))	('zebrafish', 'Species', '7955', (270, 279))	('impairs', 'NegReg', (221, 228))
25789	32894165	MiR-342-3p is reported to exert tumor inhibiting effects in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MiR-342-3p', 'Chemical', '-', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancers', 'Disease', (68, 75))	('MiR-342-3p', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
25798	32894165	Six patient-derived primary glioma stem cells from WHO grade II to IV (grade II: GSC205 and GSC207; grade III: GSC306 and GSC307; grade IV: GSC406 and GSC408) were isolated, and neurosphere cultures were obtained as previously described.	('GSC307', 'Var', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('glioma', 'Disease', (28, 34))	('patient', 'Species', '9606', (4, 11))	('GSC306', 'Var', (111, 117))	('GSC406', 'Var', (140, 146))	('GSC205', 'Chemical', '-', (81, 87))	('GSC408', 'Var', (151, 157))	('GSC207', 'Var', (92, 98))
25837	32894165	Gene set enrichment analysis (GSEA, http://www.broadinstitute.org/gsea/index.jsp) was used to analyze enrichment of a biological process or signal pathway with high versus low ISL2 expressions.	('high', 'Var', (160, 164))	('expressions', 'MPA', (181, 192))	('low', 'NegReg', (172, 175))	('GSEA', 'Chemical', '-', (30, 34))	('ISL2', 'Gene', (176, 180))
25840	32894165	ISL2 was also highly enriched in the IDH wildtype glioma, and was associated with decreased survival rates among different WHO grade glioma in the CGGA datasets (Fig.	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('glioma', 'Disease', (50, 56))	('survival rates', 'CPA', (92, 106))	('glioma', 'Disease', (133, 139))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('IDH', 'Gene', (37, 40))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('ISL2', 'Var', (0, 4))	('decreased', 'NegReg', (82, 91))	('IDH', 'Gene', '3417', (37, 40))
25849	32894165	Both qPCR and western blotting showed that ISL2 was expressed highest in WHO grade IV GSCs (GSC406 and GSC408), followed with WHO grade III GSCs (GSC306 and GSC307), and lowest in WHO grade II GSCs (GSC205 and GSC207) (Figure S2d, e).	('GSC408', 'Var', (103, 109))	('GSC205', 'Chemical', '-', (199, 205))	('GSCs', 'Chemical', '-', (140, 144))	('GSC406', 'Var', (92, 98))	('GSCs', 'Chemical', '-', (86, 90))	('GSC306', 'Var', (146, 152))	('GSCs', 'Chemical', '-', (193, 197))
25853	32894165	The results showed there was a positive association with "GO_POSITIVE_REGULATION_OF_VASCULAR_ENDOTHELIAL_ GROWTH_FACTOR_PRODUCTION" signatures in ISL2 high expression glioma.	('ISL2', 'Gene', (146, 150))	('glioma', 'Disease', (167, 173))	('high expression', 'Var', (151, 166))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioma', 'Disease', 'MESH:D005910', (167, 173))
25855	32894165	All qPCR, western blotting, and ELISA assays showed that the expression and secretion of VEGFA decreased after ISL2 silencing of GSC406, while it increased in ISL2 overexpressing GSC205 (Fig.	('decreased', 'NegReg', (95, 104))	('GSC205', 'Chemical', '-', (179, 185))	('expression', 'MPA', (61, 71))	('GSC406', 'Gene', (129, 135))	('VEGFA', 'Gene', '7422', (89, 94))	('silencing', 'Var', (116, 125))	('secretion', 'MPA', (76, 85))	('VEGFA', 'Gene', (89, 94))
25857	32894165	A luciferase plasmid with the top 2000 nucleotides of the promoter domain of the VEGFA gene (pGl3-wt) and a luciferase plasmid with mutant sequences in both binding sites of the promoter domain (pGL3-mt) were generated (Fig.	('pGl3', 'Gene', '6391', (93, 97))	('VEGFA', 'Gene', '7422', (81, 86))	('pGL3', 'Gene', '6391', (195, 199))	('mutant', 'Var', (132, 138))	('pGl3', 'Gene', (93, 97))	('VEGFA', 'Gene', (81, 86))	('pGL3', 'Gene', (195, 199))
25859	32894165	ChIP assays also revealed that the enrichment of VEGFA was decreased in ISL2 silencing GSC406 and increased in ISL2 overexpressing GSC205 (Fig.	('GSC406', 'Var', (87, 93))	('ISL2', 'Gene', (72, 76))	('VEGFA', 'Gene', (49, 54))	('decreased', 'NegReg', (59, 68))	('silencing', 'NegReg', (77, 86))	('GSC205', 'Chemical', '-', (131, 137))	('increased', 'PosReg', (98, 107))	('enrichment', 'MPA', (35, 45))	('VEGFA', 'Gene', '7422', (49, 54))
25862	32894165	The results showed that treatment with the conditioned medium from ISL2-silenced GSC406 decreased cell viability and the rates of EDU-positive hBMECs, while ISL2-overexpressed GSC205-GCM increased the cell viability and the rates of EDU-positive hBMECs (Figure S4a-d).	('EDU', 'Chemical', '-', (233, 236))	('EDU', 'Chemical', '-', (130, 133))	('GSC205-GCM', 'Var', (176, 186))	('GSC406', 'Gene', (81, 87))	('rates', 'MPA', (121, 126))	('GSC205', 'Chemical', '-', (176, 182))	('cell viability', 'CPA', (201, 215))	('increased', 'PosReg', (187, 196))	('decreased', 'NegReg', (88, 97))	('cell viability', 'CPA', (98, 112))
25863	32894165	Transwell assays showed that treatment with ISL2-silenced GSC406-GCM decreased the invading cell numbers of hBMECs, whereas treatment with ISL2-overexpressed GSC205-GCM increased its invasive cell numbers (Figure S4e, f).	('increased', 'PosReg', (169, 178))	('invasive cell numbers', 'CPA', (183, 204))	('decreased', 'NegReg', (69, 78))	('GSC205', 'Chemical', '-', (158, 164))	('invading cell numbers of hBMECs', 'CPA', (83, 114))	('GSC406-GCM', 'Var', (58, 68))
25864	32894165	Moreover, tube formation assays showed that ISL2-silenced GSC406-GCM treatment decreased the number of branches and tubule lengths of hBMECs, while the opposite results were obtained after treatment with ISL2-overexpressed GSC205-GCM (Figure S4g-i).	('decreased', 'NegReg', (79, 88))	('GSC205', 'Chemical', '-', (223, 229))	('GSC406-GCM', 'Var', (58, 68))
25866	32894165	Therefore, human recombinant VEGFA or VEGFA-neutralizing antibody were combined with treatment of ISL2-silenced GSC406-GCM or ISL2-overexpressed GSC205-GCM, respectively.	('VEGFA', 'Gene', (38, 43))	('VEGFA', 'Gene', '7422', (29, 34))	('human', 'Species', '9606', (11, 16))	('VEGFA', 'Gene', (29, 34))	('GSC406-GCM', 'Var', (112, 122))	('GSC205', 'Chemical', '-', (145, 151))	('VEGFA', 'Gene', '7422', (38, 43))
25872	32894165	The results showed that miR-342-3p was the only intersection among these four datasets that bound to the 3'-UTR of ISL2 (Fig.	('miR-342-3p', 'Var', (24, 34))	('bound', 'Reg', (92, 97))	('miR-342-3p', 'Chemical', '-', (24, 34))	('ISL2', 'Gene', (115, 119))
25874	32894165	We therefore designed luciferase reporter assays and found that miR-342-3p mimic treatment decreased the luciferase activity of the luciferase reporter plasmid with the wildtype ISL2 mRNA 3'-UTR in GSC406 (Fig.	('luciferase', 'Enzyme', (105, 115))	('activity', 'MPA', (116, 124))	('miR-342-3p', 'Var', (64, 74))	('miR-342-3p', 'Chemical', '-', (64, 74))	('decreased', 'NegReg', (91, 100))
25875	32894165	3d), while the luciferase activity of wildtype ISL2 mRNA 3'-UTR was increased after miR-342-3p inhibitor treatment in GSC205 (Fig.	('luciferase', 'Enzyme', (15, 25))	('miR-342-3p', 'Var', (84, 94))	('miR-342-3p', 'Chemical', '-', (84, 94))	('GSC205', 'Chemical', '-', (118, 124))	('activity', 'MPA', (26, 34))	('increased', 'PosReg', (68, 77))
25876	32894165	We then detected the expression of miR-342-3p in our clinical glioma specimens and found its expression was negatively correlated with ISL2 expression in each WHO grade of glioma (Fig.	('miR-342-3p', 'Var', (35, 45))	('miR-342-3p', 'Chemical', '-', (35, 45))	('expression', 'MPA', (140, 150))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('ISL2', 'Gene', (135, 139))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('negatively', 'NegReg', (108, 118))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('expression', 'MPA', (93, 103))	('glioma', 'Disease', (172, 178))	('glioma', 'Disease', (62, 68))
25877	32894165	Both qPCR and western blotting showed the expression of ISL2 was significantly decreased after miR-342-3p mimic treatment in GSC406, while it was upregulated after miR-342-3p inhibitor treatment in GSC205 (Fig.	('miR-342-3p', 'Chemical', '-', (164, 174))	('miR-342-3p mimic', 'Var', (95, 111))	('decreased', 'NegReg', (79, 88))	('expression', 'MPA', (42, 52))	('GSC205', 'Chemical', '-', (198, 204))	('miR-342-3p', 'Chemical', '-', (95, 105))	('upregulated', 'PosReg', (146, 157))	('ISL2', 'Gene', (56, 60))
25878	32894165	Based on these results, miR-342-3p was a possible upstream regulatory factor, which negatively regulated ISL2 expression by binding with the ISL2 3'-UTR.	('ISL2', 'Gene', (105, 109))	('binding', 'Interaction', (124, 131))	('negatively regulated', 'NegReg', (84, 104))	('expression', 'MPA', (110, 120))	('miR-342-3p', 'Var', (24, 34))	('miR-342-3p', 'Chemical', '-', (24, 34))
25879	32894165	We detected the possible functions of miR-342-3p expression of GSCs in hBMECs.	('hBMECs', 'Disease', (71, 77))	('GSCs', 'Chemical', '-', (63, 67))	('GSCs', 'Gene', (63, 67))	('miR-342-3p', 'Var', (38, 48))	('miR-342-3p', 'Chemical', '-', (38, 48))
25880	32894165	The MTS, EDU, Transwell, and tube formation assay results showed the proliferation, invasion, and angiogenesis of hBMECs were decreased after miR-342-3p mimic-transfected GSC406-GCM treatment (Fig.	('decreased', 'NegReg', (126, 135))	('invasion', 'CPA', (84, 92))	('angiogenesis of hBMECs', 'CPA', (98, 120))	('miR-342-3p', 'Chemical', '-', (142, 152))	('EDU', 'Chemical', '-', (9, 12))	('GSC406-GCM', 'Var', (171, 181))	('miR-342-3p mimic-transfected GSC406-GCM', 'Var', (142, 181))
25881	32894165	The qPCR and ELISA assays also showed that the expression and secretion of VEGFA were decreased in GSC406 after transfection with the miR-342-3p mimic (Fig.	('VEGFA', 'Gene', '7422', (75, 80))	('GSC406', 'Var', (99, 105))	('secretion', 'MPA', (62, 71))	('decreased', 'NegReg', (86, 95))	('miR-342-3p', 'Chemical', '-', (134, 144))	('VEGFA', 'Gene', (75, 80))	('expression', 'MPA', (47, 57))
25883	32894165	To further determine whether miR-342-3p inhibited these biological functions by downregulating ISL2 expression, rescued experiments were performed with additional transfection with ISL2 overexpression or knockdown on the basis of the miR-342-3p mimic or inhibitor treatment, respectively.	('overexpression', 'PosReg', (186, 200))	('miR-342-3p', 'Chemical', '-', (234, 244))	('knockdown', 'Var', (204, 213))	('inhibited', 'NegReg', (40, 49))	('downregulating', 'NegReg', (80, 94))	('miR-342-3p', 'Var', (29, 39))	('expression', 'MPA', (100, 110))	('miR-342-3p', 'Chemical', '-', (29, 39))	('ISL2', 'Gene', (95, 99))
25884	32894165	Compared with miR-342-3p mimic-transfected GSC406-GCM treatment alone, additional ISL2 overexpression-transfected GSC406-GCM increased the cell viability and the rates of EDU-positive hBMECs, the invading cell numbers of hBMECs, and the number of branches and tubule lengths of hBMECs as measured by MTS, EDU, Transwell, and tube formation assays, respectively (Fig.	('EDU', 'Chemical', '-', (171, 174))	('increased', 'PosReg', (125, 134))	('GSC406-GCM', 'Var', (114, 124))	('EDU-positive hBMECs', 'CPA', (171, 190))	('miR-342-3p', 'Chemical', '-', (14, 24))	('invading cell numbers of hBMECs', 'CPA', (196, 227))	('ISL2', 'Gene', (82, 86))	('cell viability', 'CPA', (139, 153))	('EDU', 'Chemical', '-', (305, 308))	('tube formation', 'CPA', (325, 339))
25885	32894165	The qPCR and ELISA also showed VEGFA expression in GSC406 was increased after additional transfection with ISL2 overexpression (Fig.	('increased', 'PosReg', (62, 71))	('VEGFA', 'Gene', '7422', (31, 36))	('VEGFA', 'Gene', (31, 36))	('GSC406', 'Var', (51, 57))
25887	32894165	Together, these data suggested that miR-342-3p suppressed the proliferation, invasion, and angiogenesis of hBMECs by inhibiting ISL2 and VEGFA expression in GSCs.	('suppressed', 'NegReg', (47, 57))	('expression', 'MPA', (143, 153))	('angiogenesis', 'CPA', (91, 103))	('proliferation', 'CPA', (62, 75))	('GSCs', 'Chemical', '-', (157, 161))	('invasion', 'CPA', (77, 85))	('VEGFA', 'Gene', '7422', (137, 142))	('inhibiting', 'NegReg', (117, 127))	('miR-342-3p', 'Var', (36, 46))	('miR-342-3p', 'Chemical', '-', (36, 46))	('ISL2', 'Protein', (128, 132))	('VEGFA', 'Gene', (137, 142))
25889	32894165	To confirm the possibility that miR-342-3p directly bound to cARF1, we constructed full-length cARF1 sequences (cARF1-wt) and cARF1 sequences with mutant binding sites (cARF1-mt) (Fig.	('mutant', 'Var', (147, 153))	('binding', 'Interaction', (154, 161))	('cARF1', 'Gene', (95, 100))	('cARF1', 'Gene', (126, 131))	('miR-342-3p', 'Chemical', '-', (32, 42))
25890	32894165	The results showed that the miR-342-3p mimic significantly decreased the activity of cARF1-wt vector and miR-342-3p inhibitor increased the activity of the cARF1-wt vector, while there was no change in the activity of the cARF1-mt vector group (Fig.	('miR-342-3p', 'Chemical', '-', (28, 38))	('activity', 'MPA', (73, 81))	('decreased', 'NegReg', (59, 68))	('cARF1-wt vector', 'MPA', (85, 100))	('miR-342-3p', 'Var', (105, 115))	('miR-342-3p', 'Chemical', '-', (105, 115))	('activity', 'MPA', (140, 148))	('increased', 'PosReg', (126, 135))
25894	32894165	The qPCR also showed that the expression of cARF1 was decreased after miR-342-3p mimic treatment in GSC406, while it increased after miR-342-3p inhibitor treatment in GSC205 (Fig.	('miR-342-3p', 'Chemical', '-', (70, 80))	('expression', 'MPA', (30, 40))	('cARF1', 'Gene', (44, 49))	('increased', 'PosReg', (117, 126))	('decreased', 'NegReg', (54, 63))	('miR-342-3p mimic', 'Var', (70, 86))	('miR-342-3p', 'Chemical', '-', (133, 143))	('GSC205', 'Chemical', '-', (167, 173))
25895	32894165	Overexpression or knockdown of cARF1 led to downregulation or upregulation of miR-342-3p, respectively (Fig.	('knockdown', 'Var', (18, 27))	('miR-342-3p', 'MPA', (78, 88))	('downregulation', 'NegReg', (44, 58))	('cARF1', 'Gene', (31, 36))	('miR-342-3p', 'Chemical', '-', (78, 88))	('upregulation', 'PosReg', (62, 74))
25901	32894165	MTS, EDU, Transwell, and tube formation assays results showed that the proliferation, invasion, and angiogenesis of hBMECs were decreased after cARF1-silenced GSC406-GCM treatment (Fig.	('cARF1-silenced', 'Gene', (144, 158))	('GSC406-GCM', 'Var', (159, 169))	('decreased', 'NegReg', (128, 137))	('angiogenesis of hBMECs', 'CPA', (100, 122))	('EDU', 'Chemical', '-', (5, 8))	('invasion', 'CPA', (86, 94))
25902	32894165	The qPCR and ELISA assays showed that the expression and secretion of VEGFA were also decreased in GSC406 after cARF1 knockdown (Fig.	('secretion', 'MPA', (57, 66))	('cARF1', 'Gene', (112, 117))	('VEGFA', 'Gene', (70, 75))	('knockdown', 'Var', (118, 127))	('expression', 'MPA', (42, 52))	('GSC406', 'Var', (99, 105))	('decreased', 'NegReg', (86, 95))	('VEGFA', 'Gene', '7422', (70, 75))
25905	32894165	Comparing cARF1-silenced GSC406-GCM treatment alone, additional treatment of the miR-342-3p inhibitor promoted the proliferation, invasion, and angiogenesis of hBMECs, and expression and secretion of VEGFA of GSC406 (Fig.	('promoted', 'PosReg', (102, 110))	('invasion', 'CPA', (130, 138))	('VEGFA', 'Gene', (200, 205))	('expression', 'MPA', (172, 182))	('angiogenesis of hBMECs', 'CPA', (144, 166))	('GSC406', 'Var', (209, 215))	('proliferation', 'CPA', (115, 128))	('miR-342-3p', 'Chemical', '-', (81, 91))	('secretion', 'MPA', (187, 196))	('VEGFA', 'Gene', '7422', (200, 205))
25908	32894165	Since miR-342-3p can inhibit ISL2 expression via binding to its 3'-UTR and cARF1 acts as a sponge of miR-342-3p, we further determined whether cARF1 regulated the expression of ISL2 via the miR-342-3p-mediated ceRNA mechanism in GSCs.	('miR-342-3p', 'Chemical', '-', (6, 16))	('expression', 'MPA', (34, 44))	('ISL2', 'Gene', (29, 33))	('ISL2', 'Gene', (177, 181))	('miR-342-3p', 'Chemical', '-', (190, 200))	('binding', 'Interaction', (49, 56))	('miR-342-3p', 'Chemical', '-', (101, 111))	('inhibit', 'NegReg', (21, 28))	('expression', 'MPA', (163, 173))	('GSCs', 'Chemical', '-', (229, 233))	('miR-342-3p', 'Var', (6, 16))
25909	32894165	Both western blotting and qPCR showed that ISL2 expression was overexpressed after cARF1 overexpression in GSC205 and decreased after cARF1 knockdown in GSC406 (Fig.	('overexpressed', 'PosReg', (63, 76))	('GSC205', 'Chemical', '-', (107, 113))	('expression', 'MPA', (48, 58))	('ISL2', 'Gene', (43, 47))	('cARF1', 'Gene', (83, 88))	('decreased', 'NegReg', (118, 127))	('knockdown', 'Var', (140, 149))	('overexpression', 'Var', (89, 103))
25914	32894165	The qPCR and ELISA assays also showed that VEGFA expression and secretion were increased in GSC406 after cARF1 knockdown combined with ISL2 overexpression (Fig.	('increased', 'PosReg', (79, 88))	('knockdown', 'Var', (111, 120))	('cARF1', 'Gene', (105, 110))	('VEGFA', 'Gene', '7422', (43, 48))	('secretion', 'MPA', (64, 73))	('expression', 'MPA', (49, 59))	('VEGFA', 'Gene', (43, 48))
25915	32894165	However, the opposite results were also obtained after ISL2 knockdown combined with cARF1 overexpression in GSC205 (Fig.	('ISL2', 'Gene', (55, 59))	('GSC205', 'Chemical', '-', (108, 114))	('knockdown', 'Var', (60, 69))	('cARF1', 'Gene', (84, 89))	('overexpression', 'PosReg', (90, 104))
25918	32894165	We searched Starbase and found that U2AF2 was the most probable RBP with the highest "Clip Exp Num" which could interact with cARF1.	('RBP', 'Gene', '27303', (64, 67))	('U2AF2', 'Var', (36, 41))	('RBP', 'Gene', (64, 67))
25920	32894165	U2AF2 knockdown decreased the enrichment of cARF1 in GSC406, while U2AF2 overexpression further increased the enrichment of cARF1 in GSC205 (Fig.	('increased', 'PosReg', (96, 105))	('enrichment', 'MPA', (30, 40))	('cARF1', 'Gene', (44, 49))	('U2AF2', 'Gene', (67, 72))	('enrichment', 'MPA', (110, 120))	('knockdown', 'Var', (6, 15))	('U2AF2', 'Gene', (0, 5))	('decreased', 'NegReg', (16, 25))	('GSC205', 'Chemical', '-', (133, 139))
25921	32894165	Together, these results suggested that as a type of RBP, U2AF2 directly promoted the stability and expression of cARF1.	('expression', 'MPA', (99, 109))	('stability', 'MPA', (85, 94))	('cARF1', 'Gene', (113, 118))	('RBP', 'Gene', '27303', (52, 55))	('U2AF2', 'Var', (57, 62))	('RBP', 'Gene', (52, 55))	('promoted', 'PosReg', (72, 80))
25924	32894165	U2AF2 was also highly enriched in IDH wildtype gliomas, and was associated with decreased survival rates in both TCGA and CGGA datasets (Fig.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('IDH', 'Gene', (34, 37))	('IDH', 'Gene', '3417', (34, 37))	('survival rates', 'CPA', (90, 104))	('gliomas', 'Disease', (47, 54))	('decreased', 'NegReg', (80, 89))	('U2AF2', 'Var', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (47, 54))	('gliomas', 'Phenotype', 'HP:0009733', (47, 54))
25927	32894165	Kaplan-Meier survival analyses also showed that the median survival time of higher U2AF2 expression patients was shorter than those patients with lower U2AF2 expression levels (Fig.	('U2AF2', 'Gene', (83, 88))	('survival time', 'CPA', (59, 72))	('patients', 'Species', '9606', (100, 108))	('higher', 'Var', (76, 82))	('shorter', 'NegReg', (113, 120))	('patients', 'Species', '9606', (132, 140))
25929	32894165	To determine whether U2AF2 promotes glioma angiogenesis, we performed MTS, EDU, Transwell, and tube formation assays and found that the proliferation, invasion, and angiogenesis of hBMECs were decreased after U2AF2-knockdown GSC406-GCM treatment (Fig.	('U2AF2-knockdown', 'Gene', (209, 224))	('glioma', 'Disease', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('invasion', 'CPA', (151, 159))	('GSC406-GCM', 'Var', (225, 235))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('angiogenesis of hBMECs', 'CPA', (165, 187))	('EDU', 'Chemical', '-', (75, 78))	('decreased', 'NegReg', (193, 202))	('proliferation', 'CPA', (136, 149))
25930	32894165	The qPCR and ELISA assay results showed the expression and secretion of VEGFA were also decreased in GSC406 after U2AF2 knockdown (Fig.	('expression', 'MPA', (44, 54))	('GSC406', 'Var', (101, 107))	('VEGFA', 'Gene', (72, 77))	('secretion', 'MPA', (59, 68))	('U2AF2', 'Gene', (114, 119))	('knockdown', 'Var', (120, 129))	('decreased', 'NegReg', (88, 97))	('VEGFA', 'Gene', '7422', (72, 77))
25932	32894165	The qPCR and ELISA assays also showed that VEGFA expression and secretion were increased in GSC406 after U2AF2 knockdown when combined with cARF1 overexpression (Fig.	('increased', 'PosReg', (79, 88))	('knockdown', 'Var', (111, 120))	('VEGFA', 'Gene', '7422', (43, 48))	('secretion', 'MPA', (64, 73))	('GSC406', 'Var', (92, 98))	('expression', 'MPA', (49, 59))	('VEGFA', 'Gene', (43, 48))	('U2AF2', 'Gene', (105, 110))
25933	32894165	However, U2AF2 overexpression combined with cARF1 knockdown in GSC205 showed the opposite results (Fig.	('overexpression', 'PosReg', (15, 29))	('cARF1', 'Gene', (44, 49))	('knockdown', 'Var', (50, 59))	('GSC205', 'Chemical', '-', (63, 69))	('U2AF2', 'Protein', (9, 14))
25934	32894165	Taken together, these results suggested that U2AF2 promoted glioma angiogenesis via upregulating cARF1 expression in GSCs.	('upregulating', 'PosReg', (84, 96))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('expression', 'MPA', (103, 113))	('glioma', 'Disease', (60, 66))	('promoted', 'PosReg', (51, 59))	('GSCs', 'Chemical', '-', (117, 121))	('cARF1', 'Gene', (97, 102))	('U2AF2', 'Var', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
25936	32894165	Luciferase reporter assays were then performed to show that ISL2 overexpression enhanced the luciferase activity of pGL3-U2AF2-wt, and ISL2 knockdown decreased the luciferase activity of pGL3-U2AF2-wt, but not that of pGL3-U2AF2-mt (Fig.	('luciferase', 'Enzyme', (93, 103))	('pGL3', 'Gene', (187, 191))	('ISL2', 'Gene', (135, 139))	('activity', 'MPA', (104, 112))	('enhanced', 'PosReg', (80, 88))	('pGL3', 'Gene', (218, 222))	('luciferase', 'Enzyme', (164, 174))	('activity', 'MPA', (175, 183))	('pGL3', 'Gene', '6391', (187, 191))	('pGL3', 'Gene', (116, 120))	('knockdown', 'Var', (140, 149))	('pGL3', 'Gene', '6391', (218, 222))	('decreased', 'NegReg', (150, 159))	('pGL3', 'Gene', '6391', (116, 120))
25937	32894165	ChIP assays also showed that the enrichment of U2AF2 was decreased in ISL2-knockdown GSC406 and increased in ISL2-overexpressed GSC205 (Fig.	('increased', 'PosReg', (96, 105))	('ISL2-knockdown', 'Gene', (70, 84))	('ISL2-knockdown', 'Var', (70, 84))	('GSC205', 'Chemical', '-', (128, 134))	('decreased', 'NegReg', (57, 66))	('U2AF2', 'Protein', (47, 52))	('enrichment', 'MPA', (33, 43))
25940	32894165	Compared to the control group, the tumor volumes were enlarged in the ISL2 overexpression and U2AF2 overexpression groups, and decreased in the miR-342-3p-mimic and cARF1-knockdown groups (Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('miR-342-3p', 'Chemical', '-', (144, 154))	('decreased', 'NegReg', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('miR-342-3p-mimic', 'Var', (144, 160))	('enlarged', 'PosReg', (54, 62))
25941	32894165	Moreover, ISL2 overexpression combined with the miR-342-3p mimic group also showed enlarged tumor volumes, while it was decreased in the U2AF2-overexpression combined with the cARF1-knockdown group (Fig.	('miR-342-3p', 'Chemical', '-', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('enlarged', 'PosReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR-342-3p mimic', 'Var', (48, 64))	('tumor', 'Disease', (92, 97))
25947	32894165	A schematic diagram showing that the U2AF2/cARF1/miR-342-3p/ISL2 feedback loop promotes glioma tumorigenesis and angiogenesis through VEGFA-mediated ERK signaling pathway is presented in Fig.	('ERK', 'Gene', (149, 152))	('miR-342-3p', 'Chemical', '-', (49, 59))	('glioma tumorigenesis', 'Disease', (88, 108))	('VEGFA', 'Gene', '7422', (134, 139))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('ERK', 'Gene', '5594', (149, 152))	('angiogenesis', 'CPA', (113, 125))	('glioma tumorigenesis', 'Disease', 'MESH:D063646', (88, 108))	('promotes', 'PosReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('VEGFA', 'Gene', (134, 139))	('U2AF2/cARF1/miR-342-3p/ISL2', 'Var', (37, 64))
25955	32894165	Our study revealed that ISL2 transcriptionally regulated VEGFA expression and promoted VEGFA secretion in GSCs, and that ISL2-mediated GCM promoted the proliferation, invasion, and angiogenesis of hBMECs via ERK signaling.	('VEGFA', 'Gene', '7422', (57, 62))	('promoted', 'PosReg', (139, 147))	('VEGFA', 'Gene', (87, 92))	('ISL2-mediated', 'Var', (121, 134))	('ERK', 'Gene', '5594', (208, 211))	('GSCs', 'Chemical', '-', (106, 110))	('proliferation', 'CPA', (152, 165))	('ERK', 'Gene', (208, 211))	('promoted', 'PosReg', (78, 86))	('expression', 'MPA', (63, 73))	('invasion', 'CPA', (167, 175))	('VEGFA', 'Gene', (57, 62))	('VEGFA', 'Gene', '7422', (87, 92))	('angiogenesis', 'CPA', (181, 193))
25958	32894165	Accumulating evidence has recently indicated that there are numerous circRNAs expressed in neuronal tissues, and that dysregulation of circRNAs can lead to diseases of the nervous system, including glioma.	('diseases', 'Disease', (156, 164))	('glioma', 'Disease', (198, 204))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('dysregulation', 'Var', (118, 131))	('lead to', 'Reg', (148, 155))
25961	32894165	Circular RNA MAPK4 (circ-MAPK4) inhibits glioma cell apoptosis via the MAPK signaling pathway by sponging miR-125a-3p in glioma.	('MAPK4', 'Gene', (25, 30))	('circ-MAPK4', 'Gene', '5596', (20, 30))	('MAPK4', 'Gene', '5596', (25, 30))	('circ-MAPK4', 'Gene', (20, 30))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('sponging', 'Var', (97, 105))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Disease', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('-3p', 'Chemical', '-', (114, 117))	('MAPK4', 'Gene', (13, 18))	('inhibits', 'NegReg', (32, 40))	('MAPK signaling pathway', 'Pathway', (71, 93))	('MAPK4', 'Gene', '5596', (13, 18))	('glioma', 'Disease', (121, 127))
25962	32894165	Circ_002136 can bind to a RBP, FUS, and this regulates angiogenesis via the miR-138-5p/SOX13 axis in glioma.	('RBP', 'Gene', (26, 29))	('FUS', 'Gene', '2521', (31, 34))	('SOX13', 'Gene', (87, 92))	('glioma', 'Disease', (101, 107))	('SOX13', 'Gene', '9580', (87, 92))	('bind', 'Interaction', (16, 20))	('regulates', 'Reg', (45, 54))	('Circ_002136', 'Var', (0, 11))	('RBP', 'Gene', '27303', (26, 29))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('angiogenesis', 'CPA', (55, 67))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('FUS', 'Gene', (31, 34))
25965	32894165	MiR-342-3p was the only candidate miRNA that we predicted could target the 3'-UTR of ISL2, based on four datasets including microRNA, miRDB, TargetScan, and Starbase.	('MiR-342-3p', 'Chemical', '-', (0, 10))	('ISL2', 'Gene', (85, 89))	('MiR-342-3p', 'Var', (0, 10))
25966	32894165	Although there has been no previous study on the regulation between miR-342-3p and ISL2, miR-342-3p has been reported to play an anti-tumor role in several cancers including glioma.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('cancers', 'Disease', (156, 163))	('miR-342-3p', 'Chemical', '-', (68, 78))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('glioma', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('miR-342-3p', 'Var', (89, 99))	('miR-342-3p', 'Chemical', '-', (89, 99))	('tumor', 'Disease', (134, 139))
25967	32894165	For example, miR-342-3p expression levels have been negatively correlated with advanced WHO grades and inhibit the progression of glioma by directly targeting PAK4.	('PAK4', 'Gene', (159, 163))	('negatively', 'NegReg', (52, 62))	('progression', 'CPA', (115, 126))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('glioma', 'Disease', (130, 136))	('miR-342-3p', 'Var', (13, 23))	('targeting', 'Reg', (149, 158))	('PAK4', 'Gene', '10298', (159, 163))	('inhibit', 'NegReg', (103, 110))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('miR-342-3p', 'Chemical', '-', (13, 23))
25968	32894165	MiR-342-3p can also inhibit the malignant biological behaviors of glioblastoma cells via Zic4.	('MiR-342-3p', 'Var', (0, 10))	('glioblastoma', 'Disease', (66, 78))	('Zic4', 'Gene', '84107', (89, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('inhibit', 'NegReg', (20, 27))	('MiR-342-3p', 'Chemical', '-', (0, 10))	('Zic4', 'Gene', (89, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))
25969	32894165	Our study further showed that miR-342-3p exerted anti-glioma effects by inhibiting GSC-GCM-mediated angiogenesis in hBMECs.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('inhibiting', 'NegReg', (72, 82))	('miR-342-3p', 'Var', (30, 40))	('glioma', 'Disease', (54, 60))	('miR-342-3p', 'Chemical', '-', (30, 40))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
25970	32894165	Moreover, we also showed that miR-342-3p downregulated ISL2 expression in GSCs and inhibited the angiogenesis mediated by ISL2.	('expression', 'MPA', (60, 70))	('angiogenesis', 'CPA', (97, 109))	('downregulated', 'NegReg', (41, 54))	('miR-342-3p', 'Var', (30, 40))	('inhibited', 'NegReg', (83, 92))	('GSCs', 'Chemical', '-', (74, 78))	('miR-342-3p', 'Chemical', '-', (30, 40))	('ISL2', 'Gene', (55, 59))
25972	32894165	It was reported that ARF1 gene promoter methylation is associated with EGFR gene amplification and can promote the distinct tumor infiltration in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('methylation', 'Var', (40, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('associated', 'Reg', (55, 65))	('tumor', 'Disease', (124, 129))	('ARF1', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (71, 75))	('promote', 'PosReg', (103, 110))	('glioblastoma', 'Disease', (146, 158))	('EGFR', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
25973	32894165	ARF1 promotes cancer stem cell viability via lipid metabolism, and its ablation induces anti-tumor immune responses in mice.	('cancer', 'Disease', (14, 20))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', (93, 98))	('ablation', 'Var', (71, 79))	('lipid', 'Chemical', 'MESH:D008055', (45, 50))	('ARF1', 'Gene', (0, 4))	('lipid metabolism', 'MPA', (45, 61))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('promotes', 'PosReg', (5, 13))	('induces', 'Reg', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
25983	32894165	Our study showed that U2AF2 binds to and promotes the stability and expression of cARF1 in GSCs, while there was no effect on the expression of its ARF1 linear form.	('binds', 'Interaction', (28, 33))	('cARF1', 'Gene', (82, 87))	('GSCs', 'Chemical', '-', (91, 95))	('U2AF2', 'Var', (22, 27))	('expression', 'MPA', (68, 78))	('promotes', 'PosReg', (41, 49))	('stability', 'MPA', (54, 63))
25989	32894165	Furthermore, U2AF2 can also lead to the proliferation, invasion, and angiogenesis of hBMECs via upregulating cARF1 in GSCs.	('cARF1', 'Gene', (109, 114))	('upregulating', 'PosReg', (96, 108))	('U2AF2', 'Var', (13, 18))	('GSCs', 'Chemical', '-', (118, 122))	('invasion', 'CPA', (55, 63))	('lead to', 'Reg', (28, 35))	('angiogenesis', 'CPA', (69, 81))	('proliferation', 'CPA', (40, 53))
25993	32894165	Mechanistically, cARF1 upregulated ISL2 expression in GSCs via miR-342-3p sponging.	('expression', 'MPA', (40, 50))	('ISL2', 'Gene', (35, 39))	('miR-342-3p', 'Var', (63, 73))	('upregulated', 'PosReg', (23, 34))	('miR-342-3p', 'Chemical', '-', (63, 73))	('cARF1', 'Gene', (17, 22))	('GSCs', 'Chemical', '-', (54, 58))
26042	32804262	Treatment of R1-R3 was performed in a dose-escalation manner with an administered activity of 0.0192, 0.0246, and 0.0161 GBq in R1-R3, respectively.	('0.0161 GBq', 'Var', (114, 124))	('0.0192', 'Var', (94, 100))	('0.0246', 'Var', (102, 108))	('GBq', 'Chemical', '-', (121, 124))
26045	32804262	The infused 90Y activity on treatment day was 0.0183, 0.0478, 0.0351, 0.0414, and 0.0486 GBq in dogs P1-P5, respectively.	('GBq', 'Chemical', '-', (89, 92))	('0.0183', 'Var', (46, 52))	('0.0486 GBq', 'Var', (82, 92))	('dogs', 'Species', '9615', (96, 100))	('0.0351', 'Var', (62, 68))	('0.0478', 'Var', (54, 60))	('0.0414', 'Var', (70, 76))
26094	32804262	P1-P3 displayed focal cerebral cortical deficits at 1 day post-treatment, including circling to the side of the lesion and contralateral visual deficit, proprioceptive delay, and weakness (P1-P2 only).	('contralateral visual deficit', 'Disease', 'MESH:D014786', (123, 151))	('weakness', 'Disease', (179, 187))	('contralateral visual deficit', 'Disease', (123, 151))	('P2', 'Chemical', 'MESH:C020845', (192, 194))	('weakness', 'Disease', 'MESH:D018908', (179, 187))	('cerebral cortical deficits', 'Disease', (22, 48))	('circling to the', 'CPA', (84, 99))	('proprioceptive delay', 'CPA', (153, 173))	('P1-P3', 'Var', (0, 5))	('cerebral cortical deficits', 'Disease', 'MESH:D054220', (22, 48))	('cerebral cortical deficits', 'Phenotype', 'HP:0100704', (22, 48))
26095	32804262	On post-treatment days 33, 20, and 29 in dogs P1-P3, respectively, neurological exams normalized (Fig.	('neurological exams normalized', 'MPA', (67, 96))	('dogs', 'Species', '9615', (41, 45))	('P1-P3', 'Var', (46, 51))
26098	32804262	P1-P4 demonstrated improvement in clinical status by their 1 month follow-up visit, with no new seizures or neurologic deficits (Fig.	('clinical status', 'MPA', (34, 49))	('P1-P4', 'Var', (0, 5))	('seizures', 'Disease', 'MESH:D012640', (96, 104))	('neurologic deficits', 'Phenotype', 'HP:0000707', (108, 127))	('improvement', 'PosReg', (19, 30))	('seizures', 'Phenotype', 'HP:0001250', (96, 104))	('seizures', 'Disease', (96, 104))	('neurologic deficits', 'Disease', 'MESH:D009461', (108, 127))	('seizure', 'Phenotype', 'HP:0001250', (96, 103))	('neurologic deficits', 'Disease', (108, 127))
26105	32804262	At 1 month post-therapy, MRI of P1 showed a 94% reduction in mass size, resolution of perilesional edema, and falx shift as well as the absence of contrast enhancement.	('perilesional edema', 'Disease', 'MESH:D004487', (86, 104))	('MRI', 'Var', (25, 28))	('mass size', 'MPA', (61, 70))	('edema', 'Phenotype', 'HP:0000969', (99, 104))	('falx', 'MPA', (110, 114))	('reduction', 'NegReg', (48, 57))	('perilesional edema', 'Disease', (86, 104))
26123	32804262	However, this should be interpreted in the context that the tissue-dependent biological effect of 90Y-RE may be reduced compared to EBRT owing to the absorbed dose non-uniformity at the microscopic scale.	('tissue-dependent biological', 'CPA', (60, 87))	('EBRT', 'Chemical', '-', (132, 136))	('90Y-RE', 'Var', (98, 104))	('reduced', 'NegReg', (112, 119))
26125	32804262	At the time of treatment, diagnosis in P1-P5 was based on clinical symptomatology and an imaging appearance suggestive of cancer (Table 2), although no diagnoses were biopsy-proven.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('P1-P5', 'Var', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
26131	32804262	90Y-RE has two potential modes of toxicity to normal brain tissue: (1) radiation toxicity and (2) ischemic toxicity.	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('toxicity', 'Disease', (81, 89))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('radiation toxicity', 'Disease', 'MESH:D004194', (71, 89))	('radiation toxicity', 'Disease', (71, 89))	('toxicity', 'Disease', (34, 42))	('90Y-RE', 'Var', (0, 6))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('toxicity', 'Disease', (107, 115))
26133	32804262	In the liver, the greatly decreased toxicity of 90Y-RE compared to EBRT has been attributed to this micro-scale heterogeneity.	('EBRT', 'Chemical', '-', (67, 71))	('90Y-RE', 'Var', (48, 54))	('toxicity', 'Disease', 'MESH:D064420', (36, 44))	('toxicity', 'Disease', (36, 44))	('decreased', 'NegReg', (26, 35))
26149	32804262	In future attempts, acute post-treatment neurologic abnormalities may be reduced with selective 90Y-RE delivery and with a treatment day closer to the microsphere calibration date.	('neurologic abnormalities', 'Disease', (41, 65))	('90Y-RE delivery', 'Var', (96, 111))	('reduced', 'NegReg', (73, 80))	('neurologic abnormalities', 'Disease', 'MESH:D009422', (41, 65))	('neurologic abnormalities', 'Phenotype', 'HP:0000707', (41, 65))
26150	32804262	While preliminary, initial data on the efficacy of 90Y-RE as a potential treatment for brain cancer is encouraging, however, additional investigation is needed to further evaluate both safety and efficacy.	('brain cancer', 'Disease', (87, 99))	('brain cancer', 'Phenotype', 'HP:0030692', (87, 99))	('brain cancer', 'Disease', 'MESH:D001932', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('90Y-RE', 'Var', (51, 57))
26153	31530567	N6-methyladenosine Modulates Nonsense-mediated mRNA Decay in Human Glioblastoma The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined.	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (84, 102))	('N6-methyladenosine', 'Var', (84, 102))	('Human', 'Species', '9606', (61, 66))	('modification', 'Var', (109, 121))	('influences', 'Reg', (122, 132))	('m6A', 'Gene', '56339', (104, 107))	('Glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (275, 289))	('Glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('carcinogenesis', 'Disease', (275, 289))	('mRNA metabolic events', 'MPA', (141, 162))	('tumor', 'Disease', (167, 172))	('Glioblastoma', 'Disease', (67, 79))	('m6A', 'Gene', (104, 107))
26157	31530567	Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs.	('GSC', 'Chemical', '-', (122, 125))	('METTL3', 'Gene', (23, 29))	('METTL3', 'Gene', '56339', (73, 79))	('METTL3', 'Gene', (73, 79))	('suppressed', 'NegReg', (80, 90))	('METTL3', 'Gene', '56339', (23, 29))	('silencing', 'Var', (13, 22))
26159	31530567	Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms.	('METTL3', 'Gene', (40, 46))	('NCOR2', 'Gene', (102, 107))	('BCL-X', 'Gene', '598', (93, 98))	('BCL-X', 'Gene', (93, 98))	('NCOR2', 'Gene', '9612', (102, 107))	('downregulating', 'NegReg', (78, 92))	('METTL3', 'Gene', '56339', (40, 46))	('deficiency', 'Var', (47, 57))
26162	31530567	N6-Methyladenosine (m6A) represents the most abundant methylation modification of mRNAs in eukaryotes, and it regulates almost every aspect of mRNA metabolism, including RNA processing, transport from the nucleus to cytoplasm, translation, and decay.	('N6-Methyladenosine', 'Var', (0, 18))	('N6-Methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('m6A', 'Gene', '56339', (20, 23))	('m6A', 'Gene', (20, 23))	('transport from the nucleus to cytoplasm', 'MPA', (186, 225))	('mRNA metabolism', 'MPA', (143, 158))	('RNA processing', 'MPA', (170, 184))	('translation', 'MPA', (227, 238))	('regulates', 'Reg', (110, 119))	('decay', 'MPA', (244, 249))
26166	31530567	Recent studies have revealed that m6A methylation of mRNA results in diverse regulatory functions in cancer initiation and progression.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('m6A', 'Gene', '56339', (34, 37))	('progression', 'CPA', (123, 134))	('methylation', 'Var', (38, 49))	('cancer', 'Disease', (101, 107))	('results in', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mRNA', 'Gene', (53, 57))	('regulatory functions', 'MPA', (77, 97))	('m6A', 'Gene', (34, 37))
26167	31530567	In addition, dysregulated m6A methylation is closely related to various types of cancers.	('methylation', 'Var', (30, 41))	('related', 'Reg', (53, 60))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('m6A', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('m6A', 'Gene', '56339', (26, 29))	('dysregulated', 'Var', (13, 25))
26170	31530567	Although evidence is emerging, linking m6A modulators and tumorigenesis, it remains to be determined whether m6A modifications on different regions of mRNA, recognized by distinct readers, will lead to different cell fates.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lead to', 'Reg', (194, 201))	('m6A', 'Gene', (39, 42))	('m6A', 'Gene', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('m6A', 'Gene', '56339', (39, 42))	('m6A', 'Gene', '56339', (109, 112))	('modifications', 'Var', (113, 126))
26172	31530567	Controversially, another research group found knockdown (KD) of METTL3 dramatically promoted GSC self-renewal and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('METTL3', 'Gene', (64, 70))	('promoted', 'PosReg', (84, 92))	('knockdown', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('GSC', 'Chemical', '-', (93, 96))	('tumor', 'Disease', (114, 119))	('METTL3', 'Gene', '56339', (64, 70))	('GSC self-renewal', 'CPA', (93, 109))
26174	31530567	These findings have raised questions about whether m6A methylation modifications that affect GBM progression are dependent on the RNA sequence and are dynamically regulated.	('GBM', 'Gene', (93, 96))	('affect', 'Reg', (86, 92))	('m6A', 'Gene', '56339', (51, 54))	('methylation', 'Var', (55, 66))	('m6A', 'Gene', (51, 54))
26177	31530567	Moreover, we found that silencing of METTL3 led to reduced aggressive and tumorigenic capabilities, as well as diminished GSC phenotypes in GBM cells.	('GSC', 'Chemical', '-', (122, 125))	('reduced', 'NegReg', (51, 58))	('GSC phenotypes', 'CPA', (122, 136))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('METTL3', 'Gene', '56339', (37, 43))	('METTL3', 'Gene', (37, 43))	('diminished', 'NegReg', (111, 121))	('silencing', 'Var', (24, 33))
26203	31530567	Previous studies have suggested that glioma stem cells (GSCs) are derived from mutated neural progenitor cells (NPCs), which are critical for GBM tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutated', 'Var', (79, 86))	('glioma', 'Disease', (37, 43))	('tumor', 'Disease', (146, 151))	('GSC', 'Chemical', '-', (56, 59))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
26213	31530567	Western blot analysis also showed higher METTL3 protein levels in GBMs compared to that in normal brain tissues (Supp.	('GBMs', 'Var', (66, 70))	('higher', 'PosReg', (34, 40))	('METTL3', 'Gene', '56339', (41, 47))	('METTL3', 'Gene', (41, 47))
26226	31530567	As expected, depletion of METTL3 also led to significantly reduced m6A modification levels of mRNAs in both GBM cell lines (Supp.	('METTL3', 'Gene', (26, 32))	('reduced', 'NegReg', (59, 66))	('m6A', 'Gene', (67, 70))	('depletion', 'Var', (13, 22))	('m6A', 'Gene', '56339', (67, 70))	('METTL3', 'Gene', '56339', (26, 32))
26232	31530567	Conversely, overexpression of the METTL3 dominant-negative mutant in GBMs inhibited cell migration and invasion (Supp.	('inhibited', 'NegReg', (74, 83))	('overexpression', 'PosReg', (12, 26))	('METTL3', 'Gene', '56339', (34, 40))	('METTL3', 'Gene', (34, 40))	('mutant', 'Var', (59, 65))
26238	31530567	Compared with the control shRNA, both shMETTL3 sequences significantly decreased stem cell size (Supp.	('METTL3', 'Gene', (40, 46))	('sequences', 'Var', (47, 56))	('stem cell size', 'CPA', (81, 95))	('decreased', 'NegReg', (71, 80))	('METTL3', 'Gene', '56339', (40, 46))
26240	31530567	Whereas overexpression of WT METTL3 promoted U87MG and U251 neurosphere formation and stem cell frequency, the METTL3 mutant inhibited these phenotypes (Fig.	('METTL3', 'Gene', '56339', (111, 117))	('U87MG', 'CPA', (45, 50))	('U251', 'CellLine', 'CVCL:0021', (55, 59))	('METTL3', 'Gene', (111, 117))	('METTL3', 'Gene', '56339', (29, 35))	('stem cell frequency', 'CPA', (86, 105))	('mutant', 'Var', (118, 124))	('U251 neurosphere formation', 'CPA', (55, 81))	('inhibited', 'NegReg', (125, 134))	('METTL3', 'Gene', (29, 35))	('U87MG', 'CellLine', 'CVCL:0022', (45, 50))	('promoted', 'PosReg', (36, 44))
26243	31530567	To map m6A modification sites and unveil potential METTL3 functions in GBM, we performed MeRIP-seq on U87MG cells with silenced METTL3 (Supp.	('m6A', 'Gene', '56339', (7, 10))	('METTL3', 'Gene', '56339', (51, 57))	('U87MG', 'CellLine', 'CVCL:0022', (102, 107))	('METTL3', 'Gene', '56339', (128, 134))	('METTL3', 'Gene', (51, 57))	('METTL3', 'Gene', (128, 134))	('m6A', 'Gene', (7, 10))	('silenced', 'Var', (119, 127))
26244	31530567	Consistent with previous studies, we demonstrated that m6A peaks in GBMs were enriched in the RGACH motif (R = G/A; H = A/C/U) (Fig.	('R = G/A;', 'Var', (107, 115))	('m6A', 'Gene', (55, 58))	('m6A', 'Gene', '56339', (55, 58))
26248	31530567	4D), suggesting a role for METTL3-mediated m6A modifications in GBM tumorigenesis.	('tumor', 'Disease', (68, 73))	('m6A', 'Gene', '56339', (43, 46))	('METTL3', 'Gene', '56339', (27, 33))	('METTL3', 'Gene', (27, 33))	('m6A', 'Gene', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('modifications', 'Var', (47, 60))	('GBM', 'Disease', (64, 67))
26253	31530567	Next, we randomly selected several splicing factors regulated by METTL3 and found that KD of these genes impaired the proliferation of GBM cells (Fig.	('impaired', 'NegReg', (105, 113))	('METTL3', 'Gene', '56339', (65, 71))	('genes', 'Var', (99, 104))	('proliferation of GBM cells', 'CPA', (118, 144))	('METTL3', 'Gene', (65, 71))
26260	31530567	By comparing the m6A modification of SRSFs in NPCs and GSCs, we found that m6A modifications around start codon of splicing factor transcripts (e.g., SRSFs) were elevated (Fig.	('modifications', 'Var', (79, 92))	('GSC', 'Chemical', '-', (55, 58))	('m6A', 'Gene', (75, 78))	('m6A', 'Gene', (17, 20))	('m6A', 'Gene', '56339', (75, 78))	('m6A', 'Gene', '56339', (17, 20))
26262	31530567	Importantly, on the basis of the markedly decreased m6A modification peaks, premature termination (i.e., stop) codons (PTCs) in the mRNAs of SRSFs were generated via exon inclusion or skipping upon METTL3 depletion (Fig.	('exon inclusion', 'Var', (166, 180))	('decreased', 'NegReg', (42, 51))	('m6A', 'Gene', (52, 55))	('m6A', 'Gene', '56339', (52, 55))	('skipping', 'Var', (184, 192))	('METTL3', 'Gene', '56339', (198, 204))	('METTL3', 'Gene', (198, 204))
26263	31530567	Silencing METTL3 significantly reduced protein-coding mRNAs (mRNAs without PTCs) of SRSFs (Fig.	('reduced', 'NegReg', (31, 38))	('METTL3', 'Gene', '56339', (10, 16))	('METTL3', 'Gene', (10, 16))	('Silencing', 'Var', (0, 9))	('protein-coding mRNAs', 'MPA', (39, 59))
26265	31530567	Moreover, protein-coding mRNAs of SRSFs were significantly decreased, upon overexpression of mutant METTL3 (Fig.	('overexpression', 'PosReg', (75, 89))	('decreased', 'NegReg', (59, 68))	('protein-coding mRNAs', 'MPA', (10, 30))	('METTL3', 'Gene', '56339', (100, 106))	('METTL3', 'Gene', (100, 106))	('SRSFs', 'Gene', (34, 39))	('mutant', 'Var', (93, 99))
26272	31530567	In addition, we mutated the A with G to inactivate the m6A modification-mediated exon inclusion.	('m6A', 'Gene', (55, 58))	('m6A', 'Gene', '56339', (55, 58))	('inactivate', 'NegReg', (40, 50))	('mutated', 'Var', (16, 23))	('modification-mediated', 'Reg', (59, 80))
26275	31530567	However, no significant change of luciferase activity occurred in the reporter with the mutation in m6A modification (Fig.	('activity', 'MPA', (45, 53))	('mutation', 'Var', (88, 96))	('m6A', 'Gene', '56339', (100, 103))	('luciferase', 'Enzyme', (34, 44))	('m6A', 'Gene', (100, 103))
26276	31530567	Similarly, a lack of luciferase activity increase has also been observed with addition of the METTL3 mutant in GBM cells, compared with addition of the WT METTL3 (Fig.	('METTL3', 'Gene', '56339', (155, 161))	('METTL3', 'Gene', '56339', (94, 100))	('activity', 'MPA', (32, 40))	('mutant', 'Var', (101, 107))	('luciferase', 'Enzyme', (21, 31))	('METTL3', 'Gene', (94, 100))	('METTL3', 'Gene', (155, 161))
26283	31530567	To generate m6A site mutation in the SRSFs gene of interest in U87MG cells, we transduced the base editor construct and guide RNA targeting the SRSF3 m6A modification site around start codon (Fig.	('SRSFs', 'Gene', (37, 42))	('m6A', 'Gene', (12, 15))	('m6A', 'Gene', (150, 153))	('mutation', 'Var', (21, 29))	('SRSF3', 'Gene', (144, 149))	('U87MG', 'CellLine', 'CVCL:0022', (63, 68))	('m6A', 'Gene', '56339', (12, 15))	('m6A', 'Gene', '56339', (150, 153))	('SRSF3', 'Gene', '6428', (144, 149))
26284	31530567	We next found the NMD RNA of SRSF3 significantly increased in m6A mutant U87MG cells compared to WT control (Fig.	('SRSF3', 'Gene', (29, 34))	('U87MG', 'CellLine', 'CVCL:0022', (73, 78))	('mutant', 'Var', (66, 72))	('increased', 'PosReg', (49, 58))	('SRSF3', 'Gene', '6428', (29, 34))	('m6A', 'Gene', (62, 65))	('NMD', 'MPA', (18, 21))	('m6A', 'Gene', '56339', (62, 65))
26285	31530567	These results support that m6A modifications around start codon mediate repression of NMD in GBM.	('m6A', 'Gene', '56339', (27, 30))	('GBM', 'Gene', (93, 96))	('modifications', 'Var', (31, 44))	('NMD', 'Gene', (86, 89))	('m6A', 'Gene', (27, 30))
26286	31530567	YTHDC1 has been reported as an m6A modification reader that mediates mRNA splicing, and mutating either W377 or W428 to alanine completely disrupts its binding to m6A RNA.	('alanine', 'Chemical', 'MESH:D000409', (120, 127))	('YTHDC1', 'Gene', (0, 6))	('m6A', 'Gene', (163, 166))	('m6A', 'Gene', '56339', (31, 34))	('YTHDC1', 'Gene', '91746', (0, 6))	('W428', 'Var', (112, 116))	('W377', 'Var', (104, 108))	('mutating', 'Var', (88, 96))	('m6A', 'Gene', '56339', (163, 166))	('binding', 'Interaction', (152, 159))	('mediates', 'Reg', (60, 68))	('mRNA splicing', 'MPA', (69, 82))	('disrupts', 'NegReg', (139, 147))	('m6A', 'Gene', (31, 34))
26287	31530567	KO of YTHDC1 reduced sphere number substantially in METTL3 overexpression cells but not in control cells (Supp.	('YTHDC1', 'Gene', (6, 12))	('METTL3', 'Gene', '56339', (52, 58))	('overexpression', 'Var', (59, 73))	('YTHDC1', 'Gene', '91746', (6, 12))	('METTL3', 'Gene', (52, 58))	('reduced', 'NegReg', (13, 20))	('sphere number', 'CPA', (21, 34))
26288	31530567	Overexpressing mutant YTHDC1 (m6A binding activity loss) failed to enhance the sphere formation capacity of U87MG cells (Supp.	('U87MG', 'CellLine', 'CVCL:0022', (108, 113))	('sphere formation capacity', 'CPA', (79, 104))	('m6A', 'Gene', (30, 33))	('YTHDC1', 'Gene', (22, 28))	('enhance', 'PosReg', (67, 74))	('m6A', 'Gene', '56339', (30, 33))	('mutant', 'Var', (15, 21))	('YTHDC1', 'Gene', '91746', (22, 28))	('loss', 'NegReg', (51, 55))
26296	31530567	We compared the alterative splicing events in METTL3 KD U87MG cells compared with U87MG control cells.	('U87MG', 'Var', (56, 61))	('U87MG', 'CellLine', 'CVCL:0022', (82, 87))	('METTL3', 'Gene', '56339', (46, 52))	('METTL3', 'Gene', (46, 52))	('U87MG', 'CellLine', 'CVCL:0022', (56, 61))
26301	31530567	BCL-X is a well-known example of genes critical for cancer that has splicing variants that can function as cancer biomarkers and therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BCL-X', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BCL-X', 'Gene', '598', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('splicing variants', 'Var', (68, 85))	('cancer', 'Disease', (107, 113))
26307	31530567	This phenotypic rescue suggests that METTL3 maintains the tumorigenicity of GBM cells, at least partially, through the splicing of BCL-X.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('BCL-X', 'Gene', '598', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('splicing', 'Var', (119, 127))	('BCL-X', 'Gene', (131, 136))	('METTL3', 'Gene', '56339', (37, 43))	('METTL3', 'Gene', (37, 43))
26314	31530567	In this study, we established a novel mechanism for m6A modifications around start codon of mRNA splicing factors in modulating NMD of these splicing factors.	('NMD of these splicing factors', 'MPA', (128, 157))	('m6A', 'Gene', (52, 55))	('modifications', 'Var', (56, 69))	('modulating', 'Reg', (117, 127))	('m6A', 'Gene', '56339', (52, 55))
26316	31530567	Unlike previous studies, reporting that m6A modifications at 3'-terminal ends are destabilizers of mRNA, our study revealed that m6A modifications around start codon stabilize the mRNAs of SRSFs by preventing NMD.	('m6A', 'Gene', (40, 43))	('preventing', 'NegReg', (198, 208))	('NMD', 'MPA', (209, 212))	('modifications', 'Var', (133, 146))	('m6A', 'Gene', (129, 132))	('mRNAs', 'MPA', (180, 185))	('m6A', 'Gene', '56339', (129, 132))	('m6A', 'Gene', '56339', (40, 43))
26317	31530567	By preventing NMD and promoting mRNA degradation, m6A modifications act as a molecular rheostat to finely adjust the transcript levels of SRSFs in order to influence alternative splicing events.	('modifications', 'Var', (54, 67))	('m6A', 'Gene', (50, 53))	('mRNA degradation', 'MPA', (32, 48))	('alternative splicing events', 'MPA', (166, 193))	('m6A', 'Gene', '56339', (50, 53))	('promoting', 'PosReg', (22, 31))	('preventing', 'NegReg', (3, 13))	('NMD', 'MPA', (14, 17))	('influence', 'Reg', (156, 165))
26320	31530567	The reasons for these opposite conclusions may depend on the patients from whom the GBM cells originated and other compensatory genetic mutations and epigenetic changes in GBM cells.	('mutations', 'Var', (136, 145))	('epigenetic changes', 'Var', (150, 168))	('patients', 'Species', '9606', (61, 69))
26329	31530567	In glioma, the mutation of isocitrate dehydrogenase 1 (IDH1) occurs frequently, which results in accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG).	('mutation', 'Var', (15, 23))	('IDH1', 'Gene', '3417', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('2-HG', 'Chemical', 'MESH:C019417', (158, 162))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (138, 156))	('accumulation', 'PosReg', (97, 109))	('isocitrate dehydrogenase 1', 'Gene', (27, 53))	('glioma', 'Disease', (3, 9))	('isocitrate dehydrogenase 1', 'Gene', '3417', (27, 53))	('IDH1', 'Gene', (55, 59))
26331	31530567	In the late stage of glioma, high m6A modification levels may increase epigenetic reprogramming of non-GSCs into GSCs, whereas KD METTL3 may reduce the proportion of GSCs in GBM.	('high', 'Var', (29, 33))	('METTL3', 'Gene', (130, 136))	('m6A', 'Gene', '56339', (34, 37))	('epigenetic', 'MPA', (71, 81))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('GSC', 'Chemical', '-', (103, 106))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('GSC', 'Chemical', '-', (166, 169))	('GSC', 'Chemical', '-', (113, 116))	('reduce', 'NegReg', (141, 147))	('glioma', 'Disease', (21, 27))	('METTL3', 'Gene', '56339', (130, 136))	('m6A', 'Gene', (34, 37))	('increase', 'PosReg', (62, 70))
26334	31530567	The prevailing goal of understanding the regulatory roles of m6A modifications in RNA processing has been mainly focused on the regulation of mRNA translation or mRNA stability.	('modifications', 'Var', (65, 78))	('mRNA stability', 'MPA', (162, 176))	('m6A', 'Gene', (61, 64))	('mRNA translation', 'MPA', (142, 158))	('m6A', 'Gene', '56339', (61, 64))
26338	31530567	We have presented a number of findings supporting the notion that m6A modifications modulate the NMD of splicing factors.	('m6A', 'Gene', '56339', (66, 69))	('NMD of splicing factors', 'MPA', (97, 120))	('modifications', 'Var', (70, 83))	('modulate', 'Reg', (84, 92))	('m6A', 'Gene', (66, 69))
26342	31530567	Consistently, a large number of cancer-relevant genes have undergone splice alterations in GBM.	('splice alterations', 'Var', (69, 87))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('GBM', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
26344	31530567	This subsequently results in the creation of cancer-specific alternative splicing patterns, such as the preferential expression of the anti-apoptotic transcript variant of BCL-X and the GSC-promoting transcript variant of NCOR2 (Fig.	('BCL-X', 'Gene', '598', (172, 177))	('NCOR2', 'Gene', (222, 227))	('preferential', 'PosReg', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('expression', 'MPA', (117, 127))	('NCOR2', 'Gene', '9612', (222, 227))	('BCL-X', 'Gene', (172, 177))	('anti-apoptotic', 'PosReg', (135, 149))	('variant', 'Var', (161, 168))	('GSC', 'Chemical', '-', (186, 189))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
26376	31083655	Similarly, meningioma cells expressing PROM1 revealed a higher proliferation rate and the formation of tumorspheres.	('meningioma', 'Disease', 'MESH:D008577', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('proliferation rate', 'CPA', (63, 81))	('tumors', 'Disease', (103, 109))	('meningioma', 'Disease', (11, 21))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('meningioma', 'Phenotype', 'HP:0002858', (11, 21))	('higher', 'PosReg', (56, 62))	('PROM1', 'Var', (39, 44))
26414	31083655	A meta-analysis on 12 studies revealed that high PODXL expression is significantly associated with worse overall survival in different cancer types.	('high', 'Var', (44, 48))	('cancer', 'Disease', (135, 141))	('overall survival', 'MPA', (105, 121))	('expression', 'MPA', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PODXL', 'Gene', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('worse', 'NegReg', (99, 104))
26416	31083655	Furthermore, high PODXL expression was identified to be an independent factor for unfavorable prognosis in breast cancer patients.	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('PODXL', 'Protein', (18, 23))	('patients', 'Species', '9606', (121, 129))
26423	31083655	In astrocytomas, high expression of PODXL is associated with unfavorable prognosis.	('astrocytomas', 'Disease', (3, 15))	('high', 'Var', (17, 21))	('PODXL', 'Gene', (36, 41))	('astrocytomas', 'Disease', 'MESH:D001254', (3, 15))
26434	31083655	TOP2A and HER2 gene amplifications frequently coincide with a number of malignancies including breast, ovarian, pancreatic, and esophageal/gastroesophageal cancer.	('TOP2A', 'Gene', (0, 5))	('coincide', 'Reg', (46, 54))	('pancreatic', 'Disease', 'MESH:D010195', (112, 122))	('HER2', 'Gene', (10, 14))	('amplifications', 'Var', (20, 34))	('ovarian', 'Disease', (103, 110))	('esophageal/gastroesophageal cancer', 'Disease', (128, 162))	('esophageal/gastroesophageal cancer', 'Disease', 'MESH:D004938', (128, 162))	('pancreatic', 'Disease', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('HER2', 'Gene', '2064', (10, 14))	('TOP2A', 'Gene', '7153', (0, 5))	('malignancies', 'Disease', (72, 84))	('breast', 'Disease', (95, 101))
26450	31083655	In a xenograft mouse model, LGR4 silencing in prostate cancer cells led to a delay of metastases and reduced expression of EMT markers.	('prostate cancer', 'Disease', (46, 61))	('metastases', 'Disease', (86, 96))	('expression', 'MPA', (109, 119))	('metastases', 'Disease', 'MESH:D009362', (86, 96))	('EMT markers', 'CPA', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('delay', 'NegReg', (77, 82))	('silencing', 'Var', (33, 42))	('reduced', 'NegReg', (101, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('mouse', 'Species', '10090', (15, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))	('LGR4', 'Gene', (28, 32))
26452	31083655	Reduced expression of BRINP1 caused by different mechanisms, such as promoter hypermethylation, has been revealed in a number of tumor types including lymphoproliferative malignancies, non-small cell lung carcinomas, and astrocytomas.	('tumor', 'Disease', (129, 134))	('astrocytomas', 'Disease', (221, 233))	('lymphoproliferative malignancies', 'Disease', (151, 183))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('lymphoproliferative malignancies', 'Phenotype', 'HP:0005523', (151, 183))	('expression', 'MPA', (8, 18))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (189, 215))	('promoter hypermethylation', 'Var', (69, 94))	('BRINP1', 'Gene', '1620', (22, 28))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (185, 215))	('Reduced', 'NegReg', (0, 7))	('lymphoproliferative malignancies', 'Disease', 'MESH:D008232', (151, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('astrocytomas', 'Disease', 'MESH:D001254', (221, 233))	('BRINP1', 'Gene', (22, 28))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (185, 215))	('non-small cell lung carcinomas', 'Disease', (185, 215))
26470	31083655	OLFML3 may constitute a target for antiangiogenic therapy as further in vivo experiments demonstrated that anti-Olfml3 antibodies impaired tumor growth and angiogenesis.	('angiogenesis', 'CPA', (156, 168))	('antibodies', 'Var', (119, 129))	('impaired tumor', 'Disease', 'MESH:D015417', (130, 144))	('OLFML3', 'Gene', '56944', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('impaired tumor', 'Disease', (130, 144))	('OLFML3', 'Gene', (0, 6))	('anti-Olfml3 antibodies', 'Var', (107, 129))
26477	31083655	In vitro and in vivo experiments indicated that NCAM1 is necessary for EMT induction and maintenance and furthermore, high NCAM1 expression level was found to be associated with tumor invasion.	('high', 'Var', (118, 122))	('NCAM1', 'Gene', '4684', (48, 53))	('NCAM1', 'Gene', '4684', (123, 128))	('tumor', 'Disease', (178, 183))	('NCAM1', 'Gene', (123, 128))	('NCAM1', 'Gene', (48, 53))	('associated', 'Reg', (162, 172))	('expression level', 'MPA', (129, 145))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
26479	31083655	Furthermore, blood-brain-barrier permeability was decreased in Tlr2 knockout mice compared with wild type mice.	('blood-brain-barrier', 'CPA', (13, 32))	('mice', 'Species', '10090', (77, 81))	('mice', 'Species', '10090', (106, 110))	('knockout', 'Var', (68, 76))	('Tlr2', 'Gene', (63, 67))	('decreased', 'NegReg', (50, 59))
26522	31119110	NO induced by iNOS expression downregulates IDO1 expression transcriptionally, translationally, and posttranslationally (Alberati-Giani et al.,; Daubener et al.,).	('iNOS', 'Gene', '4843', (14, 18))	('iNOS', 'Gene', (14, 18))	('c', 'Chemical', 'MESH:D002244', (7, 8))	('expression', 'Var', (19, 29))	('downregulates', 'NegReg', (30, 43))	('expression', 'MPA', (49, 59))	('IDO1', 'Gene', '3620', (44, 48))	('c', 'Chemical', 'MESH:D002244', (65, 66))	('IDO1', 'Gene', (44, 48))
26535	31119110	T. gondii numbers were significantly reduced in the presence of aminoguanidine (Figure 2C) in the brain cell lines tested.	('c', 'Chemical', 'MESH:D002244', (30, 31))	('aminoguanidine', 'Chemical', 'MESH:C004479', (64, 78))	('c', 'Chemical', 'MESH:D002244', (58, 59))	('c', 'Chemical', 'MESH:D002244', (41, 42))	('c', 'Chemical', 'MESH:D002244', (104, 105))	('aminoguanidine', 'Var', (64, 78))	('reduced', 'NegReg', (37, 44))	('T. gondii', 'Species', '5811', (0, 9))
26543	31119110	Parasite numbers in the GRA15-KO Pru T. gondii co-cultures with human brain cell lines and THP-1 cells were significantly lower than those that included wild-type Pru T. gondii-infected THP-1 (Figure 3A).	('Parasite numbers', 'CPA', (0, 16))	('lower', 'NegReg', (122, 127))	('c', 'Chemical', 'MESH:D002244', (181, 182))	('human', 'Species', '9606', (64, 69))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('c', 'Chemical', 'MESH:D002244', (146, 147))	('GRA15-KO', 'Var', (24, 32))	('THP-1', 'Gene', (186, 191))	('c', 'Chemical', 'MESH:D002244', (115, 116))	('T. gondii', 'Species', '5811', (37, 46))	('c', 'Chemical', 'MESH:D002244', (47, 48))	('THP-1', 'Gene', '2736', (186, 191))	('T. gondii', 'Species', '5811', (167, 176))	('c', 'Chemical', 'MESH:D002244', (50, 51))	('THP-1', 'Gene', '2736', (91, 96))	('THP-1', 'Gene', (91, 96))
26554	31119110	Moreover, GRA15-dependent proparasitic functions were observed with the type II strain infection but not the type I or type III strain infections (Figure 4C).	('c', 'Chemical', 'MESH:D002244', (42, 43))	('type III strain infections', 'Disease', (119, 145))	('observed', 'Reg', (54, 62))	('infection', 'Disease', (87, 96))	('proparasitic functions', 'CPA', (26, 48))	('type III strain infections', 'Disease', 'MESH:D013180', (119, 145))	('infection', 'Disease', 'MESH:D007239', (87, 96))	('type II', 'Var', (72, 79))	('infection', 'Disease', (135, 144))	('c', 'Chemical', 'MESH:D002244', (139, 140))	('infection', 'Disease', 'MESH:D007239', (135, 144))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('c', 'Chemical', 'MESH:D002244', (91, 92))
26560	31119110	The number of GRA15-KO parasites in the co-cultures was significantly lower than the number of wild-type parasites (Figure 5C).	('c', 'Chemical', 'MESH:D002244', (63, 64))	('lower', 'NegReg', (70, 75))	('GRA15-KO', 'Var', (14, 22))	('c', 'Chemical', 'MESH:D002244', (43, 44))	('c', 'Chemical', 'MESH:D002244', (40, 41))
26578	31119110	Although we found a virulent role of GRA15 to suppress immune response in the co-culture of human monocytes and neurons is found in this study, we failed to find such an immune-suppressive function in the single culture of neurons.	('suppress immune response', 'Phenotype', 'HP:0002721', (46, 70))	('GRA15', 'Var', (37, 42))	('c', 'Chemical', 'MESH:D002244', (192, 193))	('c', 'Chemical', 'MESH:D002244', (212, 213))	('suppress', 'NegReg', (46, 54))	('c', 'Chemical', 'MESH:D002244', (81, 82))	('c', 'Chemical', 'MESH:D002244', (164, 165))	('c', 'Chemical', 'MESH:D002244', (78, 79))	('immune response', 'MPA', (55, 70))	('human', 'Species', '9606', (92, 97))	('c', 'Chemical', 'MESH:D002244', (102, 103))
26580	31119110	In the present study, we demonstrated that primary neurons exhibit the GRA15-dependent iNOS expression and IDO1 reduction in a manner similar to various neuronal cell lines that tend to be considered to be distinct from physiological neurons and therefore underestimated as fibroblasts with neuronal cell markers such as GFAP.	('iNOS', 'Gene', '4843', (87, 91))	('c', 'Chemical', 'MESH:D002244', (315, 316))	('c', 'Chemical', 'MESH:D002244', (230, 231))	('c', 'Chemical', 'MESH:D002244', (189, 190))	('c', 'Chemical', 'MESH:D002244', (212, 213))	('GFAP', 'Gene', (321, 325))	('iNOS', 'Gene', (87, 91))	('c', 'Chemical', 'MESH:D002244', (300, 301))	('IDO1', 'Gene', (107, 111))	('reduction', 'NegReg', (112, 121))	('c', 'Chemical', 'MESH:D002244', (162, 163))	('GRA15-dependent', 'Var', (71, 86))	('IDO1', 'Gene', '3620', (107, 111))	('c', 'Chemical', 'MESH:D002244', (116, 117))	('GFAP', 'Gene', '2670', (321, 325))	('expression', 'MPA', (92, 102))
26588	31119110	Obviously, further investigations to examine whether the presence of type II GRA15 affects bradyzoite transformation in the co-culture system may be of interest in the future.	('c', 'Chemical', 'MESH:D002244', (127, 128))	('c', 'Chemical', 'MESH:D002244', (63, 64))	('c', 'Chemical', 'MESH:D002244', (87, 88))	('c', 'Chemical', 'MESH:D002244', (124, 125))	('GRA15', 'Gene', (77, 82))	('presence', 'Var', (57, 65))	('bradyzoite transformation', 'CPA', (91, 116))	('affects', 'Reg', (83, 90))
26589	31119110	In summary, we demonstrated that the T. gondii effector, GRA15, plays an important role in inhibiting IFN-gamma-inducible IDO1-dependent anti-T. gondii responses in human brain and liver cells when co-cultured with human monocytes.	('inhibiting', 'NegReg', (91, 101))	('IDO1', 'Gene', (122, 126))	('human', 'Species', '9606', (165, 170))	('T. gondii', 'Species', '5811', (142, 151))	('GRA15', 'Var', (57, 62))	('c', 'Chemical', 'MESH:D002244', (51, 52))	('c', 'Chemical', 'MESH:D002244', (225, 226))	('IDO1', 'Gene', '3620', (122, 126))	('c', 'Chemical', 'MESH:D002244', (187, 188))	('c', 'Chemical', 'MESH:D002244', (201, 202))	('T. gondii', 'Species', '5811', (37, 46))	('c', 'Chemical', 'MESH:D002244', (198, 199))	('IFN-gamma', 'Gene', '3458', (102, 111))	('IFN-gamma', 'Gene', (102, 111))	('human', 'Species', '9606', (215, 220))	('c', 'Chemical', 'MESH:D002244', (116, 117))
26606	31119110	Purified anti-human IL-1beta (511601) and biotin anti-human IL-1beta antibodies (511703) were obtained from BioLegend.	('511703', 'Var', (81, 87))	('IL-1beta', 'Gene', (60, 68))	('human', 'Species', '9606', (14, 19))	('IL-1beta', 'Gene', '3553', (60, 68))	('biotin', 'Chemical', 'MESH:D001710', (42, 48))	('IL-1beta', 'Gene', '3553', (20, 28))	('IL-1beta', 'Gene', (20, 28))	('511601', 'Var', (30, 36))	('human', 'Species', '9606', (54, 59))
26622	31119110	5 x 105 A172, T98G, or 1 x 106 IMR-32 were untreated or treated with 10 ng/mL IFN-gamma and/or 20 ng/mL IL-1beta for 24 h, then the luciferase-expressing T. gondii were infected (MOI = 0.5).	('T. gondii', 'Species', '5811', (154, 163))	('c', 'Chemical', 'MESH:D002244', (134, 135))	('c', 'Chemical', 'MESH:D002244', (173, 174))	('IFN-gamma', 'Gene', '3458', (78, 87))	('IL-1beta', 'Gene', (104, 112))	('IFN-gamma', 'Gene', (78, 87))	('IL-1beta', 'Gene', '3553', (104, 112))	('T98G', 'Var', (14, 18))
26625	31119110	5 x 105 A172, T98G, 1 x 106 IMR-32, or 1 x 105 primary human neurons were cultured in 12- or 24-well plates for 24 h and washed twice with PBS before co-culture.	('c', 'Chemical', 'MESH:D002244', (150, 151))	('human', 'Species', '9606', (55, 60))	('c', 'Chemical', 'MESH:D002244', (131, 132))	('c', 'Chemical', 'MESH:D002244', (153, 154))	('A172', 'Var', (8, 12))	('c', 'Chemical', 'MESH:D002244', (74, 75))	('T98G', 'Var', (14, 18))
26630	31119110	5 x 105 A172 or T98G and 1 x 106 IMR-32 were treated with 10 ng/mL IFN-gamma and/or aminoguanidine hydrochloride (500 muM) for 24 h and then infected or uninfected with T. gondii as described above.	('c', 'Chemical', 'MESH:D002244', (185, 186))	('T98G', 'Var', (16, 20))	('c', 'Chemical', 'MESH:D002244', (145, 146))	('c', 'Chemical', 'MESH:D002244', (159, 160))	('c', 'Chemical', 'MESH:D002244', (104, 105))	('T. gondii', 'Species', '5811', (169, 178))	('IFN-gamma', 'Gene', '3458', (67, 76))	('IFN-gamma', 'Gene', (67, 76))	('aminoguanidine hydrochloride', 'Chemical', 'MESH:C004479', (84, 112))
26659	28659432	Initial feasibility studies showed MMP-14-specific cleavage, efficient drug delivery and therapeutic efficacy in murine mammary adenocarcinomas.	('therapeutic efficacy', 'CPA', (89, 109))	('drug delivery', 'MPA', (71, 84))	('murine', 'Species', '10090', (113, 119))	('adenocarcinomas', 'Disease', (128, 143))	('adenocarcinomas', 'Disease', 'MESH:D000230', (128, 143))	('MMP-14-specific cleavage', 'Var', (35, 59))
26661	28659432	Thus, we hypothesized that CLIO-ICT will induce significant apoptosis of GBM tumor cells and GIC, and thereby, prolong survival of GBM bearing mice.	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('survival', 'CPA', (119, 127))	('CLIO-ICT', 'Chemical', '-', (27, 35))	('GBM tumor', 'Disease', 'MESH:D005910', (73, 82))	('prolong', 'PosReg', (111, 118))	('GBM tumor', 'Disease', (73, 82))	('apoptosis', 'CPA', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CLIO-ICT', 'Var', (27, 35))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('mice', 'Species', '10090', (143, 147))
26676	28659432	U87-MG, U138, A172 cells were grown in DMEM (Life Technologies) containing 10% FBS and 1% Penicillin/Streptomycin (Life Technologies).	('U87-MG', 'CellLine', 'CVCL:0022', (0, 6))	('Streptomycin', 'Chemical', 'MESH:D013307', (101, 113))	('FBS', 'Disease', 'MESH:D005198', (79, 82))	('U87-MG', 'Var', (0, 6))	('Penicillin', 'Chemical', 'MESH:D010406', (90, 100))	('DMEM', 'Chemical', '-', (39, 43))	('FBS', 'Disease', (79, 82))
26687	28659432	For characterization of GICs, pcGBM39 and pcGBM2 were stained for cancer stem cell markers using anti-CD133-Biotin (Miltenyi Biotech), CD15-FITC (BD Biosciences) and CD49F-PE-Texas red (Biolegend) and analyzed with flow cytometry Immunofluorescence staining for alpha-tubulin (Cell Signaling Technology) at 1:25 dilution was conducted as previously described.	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('pcGBM2', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Biotec', 'Chemical', '-', (125, 131))	('CD15', 'Gene', '14345', (135, 139))	('FITC', 'Chemical', 'MESH:D016650', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('anti-CD133-Biotin', 'Var', (97, 114))	('GBM', 'Phenotype', 'HP:0012174', (32, 35))	('CD15', 'Gene', (135, 139))	('cancer', 'Disease', (66, 72))
26702	28659432	The following dilutions were used: MMP-14 (1:200, Abcam), Nestin (1:200, Abcam), cleaved Caspase-3 (1:300, Cell Signaling Technology), CD133 (1:10, Miltenyi Biotec), and CD15 (1:200, Abcam).	('CD15', 'Gene', (170, 174))	('Biotec', 'Chemical', '-', (157, 163))	('CD15', 'Gene', '14345', (170, 174))	('cleaved', 'Var', (81, 88))	('Nestin', 'Gene', '18008', (58, 64))	('Nestin', 'Gene', (58, 64))
26745	28659432	In apoptosis assays, GBM cells expressing high MMP-14 showed higher signal for both active caspase-3 fluorescence and Annexin-V/PI staining after incubation with CLIO-ICT and ICT (Fig.	('active caspase-3 fluorescence', 'MPA', (84, 113))	('Annexin-V', 'Gene', (118, 127))	('ICT', 'Chemical', 'MESH:C000595447', (175, 178))	('ICT', 'Chemical', 'MESH:C000595447', (167, 170))	('CLIO-ICT', 'Disease', (162, 170))	('Annexin-V', 'Gene', '11747', (118, 127))	('higher', 'PosReg', (61, 67))	('CLIO-ICT', 'Chemical', '-', (162, 170))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('high MMP-14', 'Var', (42, 53))
26754	28659432	2) by a combination of established cell surface markers, CD133, CD15 and CD49F.	('CD49F', 'Gene', '16403', (73, 78))	('CD15', 'Gene', (64, 68))	('CD133', 'Var', (57, 62))	('CD15', 'Gene', '14345', (64, 68))	('CD49F', 'Gene', (73, 78))
26760	28659432	Further, CD133+, CD15+ and CD49F+ cells from CLIO-ICT-treated pcGBM39 showed significant apoptosis as detected by Annexin-V/DAPI staining (p < 0.005; Fig.	('Annexin-V', 'Gene', '11747', (114, 123))	('CD15', 'Gene', (17, 21))	('Annexin-V', 'Gene', (114, 123))	('CLIO-ICT', 'Chemical', '-', (45, 53))	('apoptosis', 'CPA', (89, 98))	('DAPI', 'Chemical', 'MESH:C007293', (124, 128))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('CD49F', 'Gene', (27, 32))	('CD133+', 'Var', (9, 15))	('CD49F', 'Gene', '16403', (27, 32))	('pcGBM39', 'Gene', (62, 69))	('CD15', 'Gene', '14345', (17, 21))
26801	28659432	We observed that CLIO-ICTs triggers GBM cell apoptosis in vivo, as GBM cells (GFP-positive) from CLIO-ICT-treated mice presented higher levels of Annexin-V and DAPI staining compared to glioblastoma cells from vehicle-treated mice (Fig.	('CLIO-ICT', 'Chemical', '-', (17, 25))	('mice', 'Species', '10090', (226, 230))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('CLIO-ICT-treated', 'Var', (97, 113))	('higher', 'PosReg', (129, 135))	('GBM cell apoptosis', 'CPA', (36, 54))	('DAPI staining', 'MPA', (160, 173))	('CLIO-ICTs', 'Var', (17, 26))	('DAPI', 'Chemical', 'MESH:C007293', (160, 164))	('CLIO-ICT', 'Chemical', '-', (97, 105))	('mice', 'Species', '10090', (114, 118))	('levels', 'MPA', (136, 142))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))	('glioblastoma', 'Disease', (186, 198))	('Annexin-V', 'Gene', '11747', (146, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('Annexin-V', 'Gene', (146, 155))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
26804	28659432	The percentage of CD15+ GICs was significantly reduced in presence of CLIO-ICTs whereas apoptosis staining in CD15+ GICs from CLIO-ICT-treated mice was significantly increased (p < 0.05; Fig.	('CLIO-ICT', 'Chemical', '-', (126, 134))	('CD15', 'Gene', '14345', (110, 114))	('CD15', 'Gene', '14345', (18, 22))	('increased', 'PosReg', (166, 175))	('CLIO-ICT', 'Chemical', '-', (70, 78))	('CLIO-ICTs', 'Var', (70, 79))	('CD15', 'Gene', (110, 114))	('CD15', 'Gene', (18, 22))	('apoptosis staining', 'CPA', (88, 106))	('reduced', 'NegReg', (47, 54))	('mice', 'Species', '10090', (143, 147))
26824	28659432	We further demonstrate for the first time that CLIO-ICT is capable of inducing apoptosis in GBM initiating cells (GICs).	('CLIO-ICT', 'Chemical', '-', (47, 55))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('CLIO-ICT', 'Var', (47, 55))	('inducing', 'Reg', (70, 78))	('apoptosis', 'CPA', (79, 88))
26861	28303220	In traditional Chinese medicine (TCM) and folk medicine, Anemone is used in heat-clearing and detoxification [traditional remedy index (TRI) 424, distribution density of ethnopharmacological use (beta) 30], wind-dispersing and damp-eliminating (TRI 476, beta 35), warming and orifice-opening (TRI 700, beta 15), pesticide (TRI 400, beta 30), dysentery (TRI 1 051, beta 46), malaria (TRI 356, beta 30), tinea (TRI 445, beta 46), ulcers and sores (TRI 1 932, beta 84), arthritis (TRI 896, beta 76), traumatic injury (TRI 930, beta 53), pharyngolaryngitis (TRI 327, beta 7), parasitic disease (TRI 424, beta 30), and hepatitis (TRI 445, beta 7).	('arthritis', 'Phenotype', 'HP:0001369', (467, 476))	('malaria', 'Disease', 'MESH:D008288', (374, 381))	('ulcers', 'Disease', (428, 434))	('hepatitis', 'Disease', 'MESH:D056486', (614, 623))	('parasitic disease', 'Phenotype', 'HP:0030885', (572, 589))	('TRI', 'Var', (323, 326))	('tinea', 'Disease', (402, 407))	('TRI 424', 'Var', (591, 598))	('hepatitis', 'Disease', (614, 623))	('TRI 930', 'Var', (515, 522))	('ulcers', 'Disease', 'MESH:D014456', (428, 434))	('traumatic injury', 'Disease', (497, 513))	('parasitic disease', 'Disease', (572, 589))	('arthritis', 'Disease', 'MESH:D001168', (467, 476))	('parasitic disease', 'Disease', 'MESH:D010272', (572, 589))	('TRI 896', 'Var', (478, 485))	('arthritis', 'Disease', (467, 476))	('tinea', 'Disease', 'MESH:D014005', (402, 407))	('dysentery', 'Disease', (342, 351))	('TRI 356', 'Var', (383, 390))	('pharyngolaryngitis', 'Disease', 'None', (534, 552))	('TRI 1', 'Var', (353, 358))	('TRI', 'Var', (293, 296))	('TRI 327', 'Var', (554, 561))	('traumatic injury', 'Disease', 'MESH:D000070642', (497, 513))	('Anemone', 'Species', '416981', (57, 64))	('hepatitis', 'Phenotype', 'HP:0012115', (614, 623))	('TRI 1 932', 'Var', (446, 455))	('pharyngolaryngitis', 'Disease', (534, 552))	('malaria', 'Disease', (374, 381))
26943	28303220	Eleutheroside K (EK) and Rd10 significantly enhanced fMLP-induced superoxide generation in low concentration (0.5-0.75 mumol/L), while these compounds more efficiently suppressed superoxide generation than the other four compounds in other concentrations.	('superoxide generation', 'MPA', (179, 200))	('Eleutheroside K', 'Chemical', '-', (0, 15))	('Rd10', 'Var', (25, 29))	('suppressed', 'NegReg', (168, 178))	('EK', 'Chemical', '-', (17, 19))	('fMLP', 'Gene', '2357', (53, 57))	('superoxide', 'Chemical', 'MESH:D013481', (179, 189))	('fMLP', 'Gene', (53, 57))	('enhanced', 'PosReg', (44, 52))	('superoxide', 'Chemical', 'MESH:D013481', (66, 76))
26944	28303220	Rd12 dose-dependently inhibited fMLP-induced tyrosyl phosphorylation of 123.0, 79.4, 60.3, 56.2 and 50.1 kDa proteins in human neutrophil, while Rd10 and EK enhanced the tyrosyl phosphorylation of these proteins at a low concentration range.	('tyrosyl phosphorylation', 'MPA', (170, 193))	('inhibited', 'NegReg', (22, 31))	('fMLP', 'Gene', '2357', (32, 36))	('Rd12', 'Var', (0, 4))	('EK', 'Chemical', '-', (154, 156))	('tyrosyl phosphorylation', 'MPA', (45, 68))	('tyrosyl', 'Chemical', '-', (45, 52))	('fMLP', 'Gene', (32, 36))	('human', 'Species', '9606', (121, 126))	('Rd10', 'Var', (145, 149))	('tyrosyl', 'Chemical', '-', (170, 177))
26953	28303220	fMLP- and PMA-induced tyrosyl or serine/threonine phosphorylation, and fMLP-, PMA- and AA-induced translocation of p67 (phox), p47 (phox) and Rac to plasma membrane were in parallel with the suppression of the stimulus-induced superoxide generation.	('fMLP', 'Gene', (0, 4))	('translocation', 'MPA', (98, 111))	('fMLP', 'Gene', '2357', (0, 4))	('tyrosyl', 'MPA', (22, 29))	('serine', 'Chemical', 'MESH:D012694', (33, 39))	('fMLP', 'Gene', '2357', (71, 75))	('p67', 'Var', (115, 118))	('p47', 'Var', (127, 130))	('PMA', 'Chemical', 'MESH:D013755', (78, 81))	('fMLP', 'Gene', (71, 75))	('threonine', 'Chemical', 'MESH:D013912', (40, 49))	('PMA', 'Chemical', 'MESH:D013755', (10, 13))	('superoxide', 'Chemical', 'MESH:D013481', (227, 237))	('tyrosyl', 'Chemical', '-', (22, 29))
27063	27582126	Thus, EV communications between cancer cells and immune cells seem to provide the advantage of evasion from immune surveillance and cancer progression.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('EV communications', 'Var', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('evasion', 'MPA', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
27075	27582126	Instability of the PD-L1 3'-untranslated region (UTR) was recently reported to be associated with aberrant PD-L1 expression in cancer cells.	('expression', 'MPA', (113, 123))	('aberrant', 'Var', (98, 106))	('associated', 'Reg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('PD-L1', 'Gene', (107, 112))
27084	27582126	Similarly, nasopharyngeal cancer-derived EVs contained intercellular adhesion molecule-1 (ICAM-1) and CD44 variant isoform 5 (CD44v5), which significantly increase the migration, invasion, and tubulogenesis of endothelial cells.	('migration', 'CPA', (168, 177))	('increase', 'PosReg', (155, 163))	('ICAM-1', 'Gene', '3383', (90, 96))	('variant', 'Var', (107, 114))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('CD44', 'Gene', '960', (102, 106))	('ICAM-1', 'Gene', (90, 96))	('intercellular adhesion molecule-1', 'Gene', (55, 88))	('CD44', 'Gene', '960', (126, 130))	('invasion', 'CPA', (179, 187))	('rat', 'Species', '10116', (171, 174))	('CD44', 'Gene', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (11, 32))	('CD44', 'Gene', (126, 130))	('tubulogenesis of endothelial cells', 'CPA', (193, 227))	('intercellular adhesion molecule-1', 'Gene', '3383', (55, 88))
27090	27582126	The functional role of EVs containing miR-135 and miR-210 in tumor angiogenesis is also observed in multiple myeloma and leukemia, respectively.	('multiple myeloma', 'Phenotype', 'HP:0006775', (100, 116))	('multiple myeloma', 'Disease', 'MESH:D009101', (100, 116))	('multiple myeloma', 'Disease', (100, 116))	('observed', 'Reg', (88, 96))	('miR-210', 'Gene', (50, 57))	('miR-210', 'Gene', '406992', (50, 57))	('leukemia', 'Disease', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('leukemia', 'Disease', 'MESH:D007938', (121, 129))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-135', 'Var', (38, 45))	('tumor', 'Disease', (61, 66))
27091	27582126	Interestingly, hypoxic conditions promote the secretion of EVs containing miR-135 and miR-210 in cancer cells.	('hypoxic', 'Disease', 'MESH:D000860', (15, 22))	('cancer', 'Disease', (97, 103))	('miR-135', 'Var', (74, 81))	('secretion', 'MPA', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('promote', 'PosReg', (34, 41))	('hypoxic', 'Disease', (15, 22))	('miR-210', 'Gene', (86, 93))	('miR-210', 'Gene', '406992', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
27105	27582126	reported that metastatic breast cancer-derived EVs also contain miR-105 that directly inhibits tight junction protein 1 (ZO-1) expression in endothelial cells and destroys the tight junction to promote metastasis.	('promote', 'PosReg', (194, 201))	('ZO-1', 'Gene', '7082', (121, 125))	('expression', 'MPA', (127, 137))	('miR-105', 'Var', (64, 71))	('inhibits', 'NegReg', (86, 94))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('tight junction protein 1', 'Gene', (95, 119))	('destroys', 'NegReg', (163, 171))	('breast cancer', 'Disease', (25, 38))	('miR-105', 'Chemical', '-', (64, 71))	('tight junction protein 1', 'Gene', '7082', (95, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tight junction', 'MPA', (176, 190))	('metastasis', 'CPA', (202, 212))	('ZO-1', 'Gene', (121, 125))
27106	27582126	It appears that miR-181c is included in the EVs that preferentially accumulate in brain endothelial cells, but EVs that contain miR-105 may affect endothelial cells throughout the body.	('miR-181c', 'Gene', '406957', (16, 24))	('miR-105', 'Chemical', '-', (128, 135))	('affect', 'Reg', (140, 146))	('miR-105', 'Var', (128, 135))	('miR-181c', 'Gene', (16, 24))
27132	27582126	For instance, the epithelial growth factor receptor (EGFR) truncated mutant, EGFR variant III (EGFRvIII), is closely associated with cancer progression and poor patient prognosis of glioblastoma (GBM), which is most common brain malignancy in adults.	('brain malignancy', 'Disease', 'MESH:D001932', (223, 239))	('brain malignancy', 'Disease', (223, 239))	('patient', 'Species', '9606', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('glioblastoma', 'Disease', (182, 194))	('associated with', 'Reg', (117, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (182, 194))	('GBM', 'Phenotype', 'HP:0012174', (196, 199))	('cancer', 'Disease', (133, 139))	('variant', 'Var', (82, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('EGFR', 'Gene', (77, 81))	('brain malignancy', 'Phenotype', 'HP:0030692', (223, 239))
27137	27582126	This miR-200 transfer induces the mesenchymal to epithelial transition (MET) by altering the expression of genes, including zeb2 and sec23a, in non-metastatic breast cancer cell lines.	('zeb2', 'Gene', '9839', (124, 128))	('sec23a', 'Gene', '10484', (133, 139))	('miR-200 transfer', 'Var', (5, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('sec23a', 'Gene', (133, 139))	('expression of', 'MPA', (93, 106))	('zeb2', 'Gene', (124, 128))	('induces', 'PosReg', (22, 29))	('altering', 'Reg', (80, 88))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('mesenchymal to epithelial transition', 'CPA', (34, 70))
27141	27582126	In particular, during cancer initiation, aberrant cells bearing genetic or epigenetic mutations will conflict with the surrounding non-aberrant normal cells to eliminate them from the cell population.	('eliminate', 'NegReg', (160, 169))	('cancer initiation', 'Disease', 'MESH:D009369', (22, 39))	('epigenetic mutations', 'Var', (75, 95))	('cancer initiation', 'Disease', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
27142	27582126	If these aberrant cells eliminate normal cells from tissue, it may lead to cancer formation and progression.	('lead to', 'Reg', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('progression', 'CPA', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('aberrant cells', 'Var', (9, 23))
27185	25356585	Data is deposited in NCBI's Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) - series GSE26283 (samples GSM645515, GSM645519 and GSM645523) for U87-MG cells and series GSE59634 (samples GSM1440969, GSM1440973 and GSM1440977) for U373 cells.	('GSM1440969', 'Var', (201, 211))	('GSM645519', 'Var', (130, 139))	('GSM645515', 'Var', (119, 128))	('GSM1440977', 'Var', (228, 238))	('GSM1440969', 'Chemical', '-', (201, 211))	('U87-MG', 'CellLine', 'CVCL:0022', (159, 165))	('GSM1440973', 'Var', (213, 223))	('GSM645523', 'Var', (144, 153))	('U373', 'CellLine', 'CVCL:2219', (244, 248))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('GSM1440977', 'Chemical', '-', (228, 238))	('GSM645515', 'Chemical', '-', (119, 128))
27188	25356585	We used raw data of samples GSM309429, GSM309431 and GSM309432 from GEO series GSE12305 (NHA); samples GSM247617, GSM247618 and GSM247619 from GEO series GSE9834 (NHA); samples GSM460681, GSM460682 and GSM460683 from GEO series GSE18494 (U87-MG); samples U373D-1, U373D-2 and U373D-4 from ArrayExpress series E-MEXP-903 (U373); and GBM tissue (24 samples) and unmatched control brain tissue (10 samples) obtained from the TCGA Data Portal.	('N', 'Chemical', 'MESH:D009584', (89, 90))	('U373', 'CellLine', 'CVCL:2219', (321, 325))	('U373', 'CellLine', 'CVCL:2219', (255, 259))	('U373', 'CellLine', 'CVCL:2219', (264, 268))	('U373D-2', 'Var', (264, 271))	('GSM247619', 'Var', (128, 137))	('U87-MG', 'CellLine', 'CVCL:0022', (238, 244))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('GSM247618', 'Var', (114, 123))	('U373', 'CellLine', 'CVCL:2219', (276, 280))
27201	25356585	Gene expression (RT-qPCR) analyses were performed using TaqMan Gene Expression Assays (Applied Biosystems): Hs00951083_m1 (for TFRC), Hs00166156_m1 (for CTSK), Hs01049561_m1 (for GFPT2), Hs01073631_m1 (for ERAP2), Hs00173754_m1 (for GPR56), Hs00269961_m1 (for CD74), Hs00160066_m1 (for PI3), and human GAPD (GAPDH) as a reference (No.	('Hs00269961_m1', 'Var', (241, 254))	('human', 'Species', '9606', (296, 301))	('Hs01073631_m1', 'Var', (187, 200))	('GAPD', 'Gene', '2597', (302, 306))	('Hs01049561_m1', 'Var', (160, 173))	('GAPD', 'Gene', '2597', (308, 312))	('GFPT2', 'Gene', (179, 184))	('GPR56', 'Gene', '9289', (233, 238))	('Hs00166156_m1', 'Var', (134, 147))	('GAPDH', 'Gene', '2597', (308, 313))	('TFRC', 'Gene', '7037', (127, 131))	('PI3', 'Gene', '5266', (286, 289))	('TFRC', 'Gene', (127, 131))	('Hs00173754_m1', 'Var', (214, 227))	('CTSK', 'Gene', (153, 157))	('CD74', 'Gene', '972', (260, 264))	('ERAP2', 'Gene', (206, 211))	('Hs00160066_m1', 'Var', (267, 280))	('GAPD', 'Gene', (302, 306))	('GAPD', 'Gene', (308, 312))	('GAPDH', 'Gene', (308, 313))	('GPR56', 'Gene', (233, 238))	('Hs00951083_m1', 'Var', (108, 121))	('PI3', 'Gene', (286, 289))	('CTSK', 'Gene', '1513', (153, 157))	('ERAP2', 'Gene', '64167', (206, 211))	('GFPT2', 'Gene', '9945', (179, 184))	('N', 'Chemical', 'MESH:D009584', (331, 332))	('CD74', 'Gene', (260, 264))
27271	25356585	Altered expression of the ERAP2 gene may favor escape of cancer cells from immune surveillance.	('ERAP2', 'Gene', (26, 31))	('escape', 'CPA', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('favor', 'PosReg', (41, 46))	('ERAP2', 'Gene', '64167', (26, 31))	('cancer', 'Disease', (57, 63))	('Altered', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('expression', 'MPA', (8, 18))
27277	25356585	showed increased expression of stefin B in the nucleus of T98G astrocytoma cells that was associated with delay in cell cycle progression and stefin B was also found to inactivate caspase-3/7 in the nucleus.	('caspase-3', 'Gene', (180, 189))	('delay', 'NegReg', (106, 111))	('increased', 'PosReg', (7, 16))	('astrocytoma', 'Disease', 'MESH:D001254', (63, 74))	('astrocytoma', 'Disease', (63, 74))	('expression', 'MPA', (17, 27))	('stefin B', 'Gene', '13014', (31, 39))	('cell cycle progression', 'CPA', (115, 137))	('stefin B', 'Gene', (31, 39))	('stefin B', 'Gene', '13014', (142, 150))	('caspase-3', 'Gene', '836', (180, 189))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('stefin B', 'Gene', (142, 150))	('T98G', 'Var', (58, 62))	('inactivate', 'NegReg', (169, 179))
27300	33198244	However, most conventional BBB opening strategies are difficult to apply in the clinical setting due to their broad, non-specific modulation of the BBB, which can result in damage to normal brain tissue.	('modulation', 'Var', (130, 140))	('rat', 'Species', '10116', (41, 44))	('damage', 'MPA', (173, 179))	('result', 'Reg', (163, 169))
27320	33198244	Such strategies can often lead to broad drug distribution in the brain, which can result in damage to the non-diseased tissue.	('damage', 'MPA', (92, 98))	('strategies', 'Var', (5, 15))	('lead to', 'Reg', (26, 33))	('broad drug distribution', 'MPA', (34, 57))	('result in', 'Reg', (82, 91))	('rat', 'Species', '10116', (7, 10))
27321	33198244	For example, while osmotic disruption has met partial clinical success for the treatment of GBM, non-selective opening of the BBB induced by mannitol can also result in various complications including epilepsy and brain edema.	('mannitol', 'Chemical', 'MESH:D008353', (141, 149))	('brain edema', 'Phenotype', 'HP:0002181', (214, 225))	('brain edema', 'Disease', (214, 225))	('result in', 'Reg', (159, 168))	('non-selective', 'Var', (97, 110))	('brain edema', 'Disease', 'MESH:D001929', (214, 225))	('epilepsy', 'Disease', 'MESH:D004827', (201, 209))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('epilepsy', 'Phenotype', 'HP:0001250', (201, 209))	('epilepsy', 'Disease', (201, 209))	('edema', 'Phenotype', 'HP:0000969', (220, 225))
27346	33198244	P1C10, the lead candidate, specifically accumulated in regions of orthotopic GBM tumors with disrupted tumor BBB, with minimal uptake in normal brain or peripheral organs.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('P1C10', 'Var', (0, 5))	('accumulated', 'PosReg', (40, 51))	('GBM tumors', 'Disease', (77, 87))	('tumor BBB', 'Disease', 'MESH:C538387', (103, 112))	('tumor BBB', 'Disease', (103, 112))	('GBM tumors', 'Disease', 'MESH:D005910', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
27347	33198244	Importantly, P1C10-targeted doxorubicin-loaded liposomes selectively accumulated in tumor BBB-disrupted regions, significantly improving survival over mock-targeted controls, indicating the value of targeting and retention in the disrupted regions.	('tumor BBB', 'Disease', (84, 93))	('P1C10-targeted', 'Var', (13, 27))	('survival', 'CPA', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('improving', 'PosReg', (127, 136))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('tumor BBB', 'Disease', 'MESH:C538387', (84, 93))
27370	33198244	Similarly, intravenous injection of NS1619, an agonist of calcium-activated potassium (KCa) channels, can selectively enhance tumor BBB permeability in glioma, but not BBB permeability in the normal brain tissue (Figure 2).	('NS1619', 'Var', (36, 42))	('NS1619', 'Chemical', 'MESH:C086491', (36, 42))	('glioma', 'Disease', (152, 158))	('tumor BBB', 'Disease', 'MESH:C538387', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor BBB', 'Disease', (126, 135))	('enhance', 'PosReg', (118, 125))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
27376	33198244	In addition, when co-administered with NS1619 via intravenous injection, temozolomide (TMZ) and trastuzumab (anti-HER2 antibody) led to increased survival of mice bearing glioma.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('NS1619', 'Var', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('TMZ', 'Chemical', 'MESH:D000077204', (87, 90))	('NS1619', 'Chemical', 'MESH:C086491', (39, 45))	('HER2', 'Gene', (114, 118))	('mice', 'Species', '10090', (158, 162))	('temozolomide', 'Chemical', 'MESH:D000077204', (73, 85))	('trastuzumab', 'Chemical', 'MESH:D000068878', (96, 107))	('glioma', 'Disease', (171, 177))	('HER2', 'Gene', '13866', (114, 118))	('increased', 'PosReg', (136, 145))	('survival', 'CPA', (146, 154))
27377	33198244	The underlying mechanism responsible for NS1619-mediated tumor BBB permeability increases in glioma appears to depend on increased endocytotic, transcellular processes.	('tumor BBB', 'Disease', 'MESH:C538387', (57, 66))	('tumor BBB', 'Disease', (57, 66))	('glioma', 'Disease', (93, 99))	('endocytotic', 'MPA', (131, 142))	('increased', 'PosReg', (121, 130))	('NS1619', 'Chemical', 'MESH:C086491', (41, 47))	('increases', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('NS1619-mediated', 'Var', (41, 56))
27379	33198244	It was found that NS1619 could selectively modulate the protein expression of caveolin-1 through ROS/PI3K/PKB/FoxO1 signaling in brain capillary endothelial cells in tumor area of rat brain glioma (C6) model in a time dependent fashion, resulting in increased caveolae-mediated cholera toxin subunit B endocytosis into tumor microvessels (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('brain glioma', 'Disease', 'MESH:C564230', (184, 196))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('caveolin-1', 'Gene', (78, 88))	('NS1619', 'Chemical', 'MESH:C086491', (18, 24))	('modulate', 'Reg', (43, 51))	('increased', 'PosReg', (250, 259))	('tumor', 'Disease', (319, 324))	('rat', 'Species', '10116', (180, 183))	('protein expression', 'MPA', (56, 74))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('NS1619', 'Var', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('FoxO1', 'Gene', (110, 115))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('brain glioma', 'Disease', (184, 196))	('FoxO1', 'Gene', '84482', (110, 115))	('caveolin-1', 'Gene', '25404', (78, 88))
27393	33198244	RI-BK could increase the accumulation of coumarin-6-loaded micelles in glioma, but not in normal brain tissue, thus enhancing the anti-glioma effects in mice.	('coumarin-6-loaded', 'Protein', (41, 58))	('enhancing', 'PosReg', (116, 125))	('glioma', 'Disease', (135, 141))	('mice', 'Species', '10090', (59, 63))	('coumarin', 'Chemical', 'MESH:C030123', (41, 49))	('glioma', 'Disease', (71, 77))	('increase', 'PosReg', (12, 20))	('accumulation', 'MPA', (25, 37))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('RI-BK', 'Var', (0, 5))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('mice', 'Species', '10090', (153, 157))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('RI-BK', 'Chemical', '-', (0, 5))
27394	33198244	The transient BBB opening in the tumor volume mediated by RI-BK was size dependent, with gold nanoparticles of 70 nm having the maximal tumor uptake.	('RI-BK', 'Chemical', '-', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('BBB opening', 'MPA', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (33, 38))	('RI-BK', 'Var', (58, 63))	('tumor', 'Disease', (136, 141))
27401	33198244	A significantly enhanced expression of caveolin-1 was found after 15, 30 and 60 min RI-BK intra-arterial infusion, suggesting an increase in transcellular transport.	('RI-BK', 'Var', (84, 89))	('transcellular transport', 'MPA', (141, 164))	('expression', 'MPA', (25, 35))	('caveolin-1', 'Gene', (39, 49))	('caveolin-1', 'Gene', '25404', (39, 49))	('RI-BK', 'Chemical', '-', (84, 89))	('increase', 'PosReg', (129, 137))	('enhanced', 'PosReg', (16, 24))
27407	33198244	For example, the BK analog, R523, could increase the penetration of various hydrophilic macromolecular agents across the tumor BBB, and the increased permeability could be inhibited by an inhibitor of nitric oxide (NO) synthase, L-NA, suggesting a complex underlying mechanism.	('nitric oxide', 'Chemical', 'MESH:D009569', (201, 213))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('permeability', 'MPA', (150, 162))	('R523', 'Chemical', '-', (28, 32))	('increase', 'PosReg', (40, 48))	('R523', 'Var', (28, 32))	('tumor BBB', 'Disease', 'MESH:C538387', (121, 130))	('rat', 'Species', '10116', (58, 61))	('tumor BBB', 'Disease', (121, 130))	('inhibited', 'NegReg', (172, 181))
27409	33198244	Decreased cGMP formation induced by an inhibitor of soluble guanylate cyclase (sGC), LY83583, could block BK- induced BBB permeability.	('sGC', 'Gene', (79, 82))	('block', 'NegReg', (100, 105))	('cGMP', 'Chemical', 'MESH:D006152', (10, 14))	('LY83583', 'Var', (85, 92))	('cGMP formation', 'MPA', (10, 24))	('sGC', 'Gene', '497757', (79, 82))	('LY83583', 'Chemical', 'MESH:C041715', (85, 92))	('BK- induced', 'CPA', (106, 117))
27411	33198244	Furthermore, NO-producing agents, including L-arginine and hydroxyurea, could increase tumor permeability in rats bearing 9 L gliosarcoma, and involved the change of eNOS and cGMP levels in the tumor region.	('cGMP levels', 'MPA', (175, 186))	('eNOS', 'Gene', (166, 170))	('gliosarcoma', 'Disease', 'MESH:D018316', (126, 137))	('cGMP', 'Chemical', 'MESH:D006152', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('eNOS', 'Gene', '24600', (166, 170))	('L-arginine', 'Chemical', 'MESH:D001120', (44, 54))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('increase', 'PosReg', (78, 86))	('gliosarcoma', 'Disease', (126, 137))	('hydroxyurea', 'Chemical', 'MESH:D006918', (59, 70))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('rats', 'Species', '10116', (109, 113))	('change', 'Reg', (156, 162))	('L-arginine', 'Var', (44, 54))
27424	33198244	In particular, miR-132-3p expression was found to be upregulated in glioma endothelial cells, and therefore could be a novel target for selective tumor BBB modulation in brain tumors.	('expression', 'MPA', (26, 36))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('brain tumors', 'Disease', 'MESH:D001932', (170, 182))	('brain tumors', 'Phenotype', 'HP:0030692', (170, 182))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('brain tumors', 'Disease', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('brain tumor', 'Phenotype', 'HP:0030692', (170, 181))	('miR-132-3p', 'Chemical', '-', (15, 25))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor BBB', 'Disease', 'MESH:C538387', (146, 155))	('tumor BBB', 'Disease', (146, 155))	('glioma', 'Disease', (68, 74))	('miR-132-3p', 'Var', (15, 25))	('upregulated', 'PosReg', (53, 64))
27425	33198244	Researchers have further identified miR-132-3p as an important miRNA in selectively increasing tumor BBB permeability in glioma and overexpression of this miRNA yielded increased uptake of doxorubicin in rat C6 glioma tumors.	('glioma', 'Disease', (211, 217))	('glioma tumors', 'Disease', 'MESH:D005910', (211, 224))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('uptake', 'MPA', (179, 185))	('glioma', 'Disease', 'MESH:D005910', (211, 217))	('glioma', 'Disease', (121, 127))	('increasing', 'PosReg', (84, 94))	('overexpression', 'PosReg', (132, 146))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('glioma', 'Phenotype', 'HP:0009733', (211, 217))	('C6 glioma', 'Disease', (208, 217))	('miR-132-3p', 'Chemical', '-', (36, 46))	('miR-132-3p', 'Var', (36, 46))	('increased', 'PosReg', (169, 178))	('rat', 'Species', '10116', (204, 207))	('tumor BBB', 'Disease', (95, 104))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('doxorubicin', 'Chemical', 'MESH:D004317', (189, 200))	('C6 glioma', 'Disease', 'MESH:C567307', (208, 217))	('tumor BBB', 'Disease', 'MESH:C538387', (95, 104))	('glioma tumors', 'Disease', (211, 224))
27426	33198244	In vitro studies indicated that endocytosis of cholera toxin subunit B and FITC-bovine serum albumin were significantly increased by miR-132-3p, via PTEN/PI3K/PKB/Src/Caveolin-1 signaling pathways (Figure 2).	('Caveolin-1', 'Gene', (167, 177))	('PTEN', 'Gene', '50557', (149, 153))	('serum albumin', 'Gene', (87, 100))	('endocytosis of cholera toxin subunit B', 'MPA', (32, 70))	('miR-132-3p', 'Var', (133, 143))	('PTEN', 'Gene', (149, 153))	('Caveolin-1', 'Gene', '25404', (167, 177))	('FITC', 'Chemical', 'MESH:D016650', (75, 79))	('serum albumin', 'Gene', '24186', (87, 100))	('Src', 'Gene', '83805', (163, 166))	('Src', 'Gene', (163, 166))	('increased', 'PosReg', (120, 129))	('miR-132-3p', 'Chemical', '-', (133, 143))
27452	33198244	Despite the aforementioned evidence that MRT can lead to a selective increase in tumor BBB permeability, the strategy has yet to be combined with co-administration of a chemotherapeutic and efficacy demonstrated in a brain tumor model.	('rat', 'Species', '10116', (111, 114))	('increase', 'PosReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor BBB', 'Disease', 'MESH:C538387', (81, 90))	('brain tumor', 'Disease', 'MESH:D001932', (217, 228))	('brain tumor', 'Disease', (217, 228))	('tumor BBB', 'Disease', (81, 90))	('rat', 'Species', '10116', (157, 160))	('MRT', 'Var', (41, 44))	('rat', 'Species', '10116', (206, 209))	('brain tumor', 'Phenotype', 'HP:0030692', (217, 228))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
27457	33198244	FUS can also increase tumor uptake of biologicals and complex nanostructures such as IgG and gold particles, and has been shown to be a relatively safe, well-tolerated approach for healthy BBB and tumor BBB opening in preclinical animal models, and in clinical trials where improved drug efficacy was observed.	('tumor BBB opening', 'Disease', (197, 214))	('rat', 'Species', '10116', (162, 165))	('tumor BBB opening', 'Disease', 'MESH:C538387', (197, 214))	('FUS', 'Chemical', '-', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('healthy BBB', 'CPA', (181, 192))	('improved drug efficacy', 'Phenotype', 'HP:0020173', (274, 296))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('increase', 'PosReg', (13, 21))	('tumor', 'Disease', (22, 27))	('FUS', 'Var', (0, 3))	('tumor', 'Disease', (197, 202))
27461	33198244	However, microbubble oscillation induces mechanical shear forces that might still be of potential risk, and cause excessive immune reactions and brain hemorrhage.	('mechanical shear forces', 'MPA', (41, 64))	('brain hemorrhage', 'Disease', (145, 161))	('immune reactions', 'CPA', (124, 140))	('brain hemorrhage', 'Disease', 'MESH:D020300', (145, 161))	('microbubble', 'Var', (9, 20))	('brain hemorrhage', 'Phenotype', 'HP:0001342', (145, 161))	('cause', 'Reg', (108, 113))	('induces', 'Reg', (33, 40))
27463	33198244	In terms of mechanism, FUS can lead to upregulation of cellular machinery in charge of transcellular transport, including caveolin-1 showing a peak value at 1 h after sonication, with a commensurate downregulation of TJ proteins such as claudin-1, claudin-5 and occludin.	('claudin-5', 'Gene', '65131', (248, 257))	('claudin-1', 'Gene', '65129', (237, 246))	('TJ proteins', 'Protein', (217, 228))	('occludin', 'Gene', (262, 270))	('rat', 'Species', '10116', (194, 197))	('occludin', 'Gene', '83497', (262, 270))	('downregulation', 'NegReg', (199, 213))	('upregulation', 'PosReg', (39, 51))	('FUS', 'Var', (23, 26))	('claudin-5', 'Gene', (248, 257))	('claudin-1', 'Gene', (237, 246))	('caveolin-1', 'Gene', (122, 132))	('FUS', 'Chemical', '-', (23, 26))	('caveolin-1', 'Gene', '25404', (122, 132))	('cellular machinery in', 'MPA', (55, 76))
27510	33178687	Astrocyte-derived EVs containing Cox2 small interfering RNA was capable of restoring microglial phagocytic activity after being up-taken by microglial cells in morphine-mediate neurodegenerative mice model.	('mice', 'Species', '10090', (195, 199))	('small interfering RNA', 'Var', (38, 59))	('Cox2', 'Gene', (33, 37))	('rat', 'Species', '10116', (188, 191))	('restoring', 'PosReg', (75, 84))	('Cox2', 'Gene', '17709', (33, 37))	('morphine', 'Chemical', 'MESH:D009020', (160, 168))	('microglial phagocytic activity', 'CPA', (85, 115))
27548	33178687	Astrocytes may also utilize exosomes to play their role in regulating homeostasis in CNS, disruption of astrocytic balance in expressing amino acid transporters and protein kinases could relate to neurological diseases.	('neurological diseases', 'Disease', (197, 218))	('neurological diseases', 'Disease', 'MESH:D020271', (197, 218))	('expressing amino acid transporters', 'MPA', (126, 160))	('relate', 'Reg', (187, 193))	('regulating homeostasis in CNS', 'MPA', (59, 88))	('disruption', 'Var', (90, 100))	('protein', 'Enzyme', (165, 172))
27562	33178687	Cortical neuron-derived exosomes containing miR-181c-3p have been shown to inhibit neuroinflammation in an ischemic brain injury rat model by downregulating chemokine (C-X-C motif) ligand 1 (CXCL1) in Astrocytes.	('ischemic brain injury', 'Disease', (107, 128))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('inhibit', 'NegReg', (75, 82))	('rat', 'Species', '10116', (129, 132))	('downregulating', 'NegReg', (142, 156))	('ischemic brain injury', 'Disease', 'MESH:D001930', (107, 128))	('inflammation', 'Disease', (88, 100))	('miR-181c-3p', 'Var', (44, 55))
27579	33178687	Another study indicated that astrocyte-derived exosomes shuttle mutant SOD1, which was transported to the spinal neurons and attenuated neuronal cell death in ALS.	('ALS', 'Gene', '6647', (159, 162))	('ALS', 'Phenotype', 'HP:0007354', (159, 162))	('ALS', 'Gene', (159, 162))	('attenuated neuronal cell death', 'Disease', (125, 155))	('SOD1', 'Gene', (71, 75))	('attenuated neuronal cell death', 'Disease', 'MESH:C538265', (125, 155))	('SOD1', 'Gene', '6647', (71, 75))	('mutant', 'Var', (64, 70))
27585	33178687	Dysfunction in alpha-synuclein containing cells including astrocytes could be critical in the initiation or progression of PD and resolving these pathways may be a therapeutic innovation in PD.	('Dysfunction', 'Var', (0, 11))	('PD', 'Disease', 'MESH:D010300', (123, 125))	('alpha-synuclein', 'Gene', (15, 30))	('alpha-synuclein', 'Gene', '6622', (15, 30))	('initiation', 'Disease', (94, 104))	('PD', 'Disease', 'MESH:D010300', (190, 192))	('initiation', 'Disease', 'MESH:D007319', (94, 104))
27586	33178687	Previous studies suggested that uptake of exosomes containing alpha-synuclein by astrocytes can have disease-causing effects by the propagation of pathologic alpha-synuclein and changing astrocyte homeostasis.	('propagation', 'Var', (132, 143))	('alpha-synuclein', 'Gene', (62, 77))	('uptake', 'MPA', (32, 38))	('changing', 'Reg', (178, 186))	('pathologic', 'Var', (147, 157))	('alpha-synuclein', 'Gene', '6622', (62, 77))	('astrocyte homeostasis', 'MPA', (187, 208))	('alpha-synuclein', 'Gene', '6622', (158, 173))	('alpha-synuclein', 'Gene', (158, 173))
27588	33178687	Inhibition of astrocyte-neuron communication could be the cause of PD.	('PD', 'Disease', 'MESH:D010300', (67, 69))	('astrocyte-neuron communication', 'CPA', (14, 44))	('Inhibition', 'Var', (0, 10))
27589	33178687	For example, astrocyte-derived exosome miR-200a-3p prevents MPP(+)-induced apoptotic cell death through down-regulation of mitogen-activated protein kinase kinase 4 (MKK4) pathway.	('mitogen-activated protein kinase kinase 4', 'Gene', (123, 164))	('down-regulation', 'NegReg', (104, 119))	('miR-200a-3p', 'Var', (39, 50))	('mitogen-activated protein kinase kinase 4', 'Gene', '6416', (123, 164))	('prevents', 'NegReg', (51, 59))	('death', 'Disease', 'MESH:D003643', (90, 95))	('death', 'Disease', (90, 95))	('MKK4', 'Gene', '6416', (166, 170))	('MKK4', 'Gene', (166, 170))
27595	33178687	Those changes eventually result in pro-inflammatory development, tumor promotion, and progression.	('tumor', 'Disease', (65, 70))	('pro-inflammatory development', 'CPA', (35, 63))	('changes', 'Var', (6, 13))	('progression', 'CPA', (86, 97))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('result in', 'Reg', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
27597	33178687	Previous research illustrated that drug-resistant cancers are caused by gene-gene, gene-miRNA, protein-protein signaling, and cell-to-cell interaction.	('drug-resistant cancers', 'Disease', (35, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('gene-gene', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('gene-miRNA', 'Var', (83, 93))	('drug-resistant cancers', 'Disease', 'MESH:D009369', (35, 57))	('caused by', 'Reg', (62, 71))	('rat', 'Species', '10116', (24, 27))	('protein-protein signaling', 'MPA', (95, 120))
27598	33178687	The transfer of genetic materials between cells in the tumor microenvironment, especially between tumor cells, has been demonstrated to promote tumor growth, invasion, and resistance to anti-tumor drugs.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('promote', 'PosReg', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('rat', 'Species', '10116', (127, 130))	('tumor', 'Disease', (98, 103))	('iron', 'Chemical', 'MESH:D007501', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('transfer', 'Var', (4, 12))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('resistance', 'CPA', (172, 182))	('tumor', 'Disease', (55, 60))	('invasion', 'CPA', (158, 166))	('genetic materials', 'Var', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
27606	33178687	It was also reported that glioma cell-derived exosomes transfer long non-coding RNA, which was activated by transforming growth factor-beta (TGF-beta) into astrocytes and cause miR-204-3p targeting in astrocytes and further promote the invasion of glioma cells.	('glioma', 'Disease', (248, 254))	('miR-204-3p', 'Var', (177, 187))	('transforming growth factor-beta', 'Gene', (108, 139))	('transforming growth factor-beta', 'Gene', '7124', (108, 139))	('TGF-beta', 'Gene', (141, 149))	('glioma', 'Disease', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (248, 254))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('promote', 'PosReg', (224, 231))	('TGF-beta', 'Gene', '7039', (141, 149))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
27618	33178687	A research revealed that the inhibition of astrocytic miR-223 decreased the exosome mediated reduction in the expression of glutamate Receptor, Ionotropic, N-Methyl D-Aspartate 2B (Grin2b) in neurons.	('Ionotropic', 'MPA', (144, 154))	('reduction', 'NegReg', (93, 102))	('exosome', 'MPA', (76, 83))	('decreased', 'NegReg', (62, 71))	('miR-223', 'Gene', '407008', (54, 61))	('N-Methyl D-Aspartate', 'Chemical', 'MESH:D016202', (156, 176))	('Grin2b', 'Gene', '2904', (181, 187))	('expression', 'MPA', (110, 120))	('glutamate Receptor', 'MPA', (124, 142))	('miR-223', 'Gene', (54, 61))	('inhibition', 'Var', (29, 39))	('Grin2b', 'Gene', (181, 187))
27643	31925333	Growing evidence indicates that aberrant expression of IGFBP2 in cancer acts as a hub of an oncogenic network, integrating multiple cancer signaling pathways and serving as a potential therapeutic target for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('IGFBP2', 'Gene', (55, 61))	('cancer', 'Disease', (208, 214))	('hub', 'Gene', '1993', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hub', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('men', 'Species', '9606', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('rat', 'Species', '10116', (116, 119))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('aberrant expression', 'Var', (32, 51))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
27660	31925333	Most IGFBPs contain putative heparin-binding domains (HBD) :consensus sequences for glycosaminoglycan (GAG) recognition that have a determined structure as XBBXBX and XBBBXXBX, where B stands for a basic residue and X for a hydropathic residue.	('IGFBPs', 'Gene', (5, 11))	('IGFBPs', 'Gene', '3484;3485;488516;282260;16008;25662;3486;3487;3488;3489', (5, 11))	('heparin', 'Chemical', 'MESH:D006493', (29, 36))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (84, 101))	('GAG', 'Chemical', 'MESH:D006025', (103, 106))	('XBBBXXBX', 'Var', (167, 175))
27671	31925333	Mature human IGFBP2, but not IGFBP3-6, possesses an RGD motif (Arg-Gly-Asp) at position 265-267 in the C-domain.	('IGFBP3-6', 'Gene', '3486;3487;3488;3489', (29, 37))	('Arg-Gly-Asp', 'Var', (63, 74))	('human', 'Species', '9606', (7, 12))	('IGFBP2', 'Gene', (13, 19))	('IGFBP3-6', 'Gene', (29, 37))	('Arg-Gly-Asp', 'Chemical', 'MESH:C047981', (63, 74))
27675	31925333	A second HBD domain, HBD2, was identified as a pH-dependent heparin-binding site in C-BP-2, with protonation of two histidine residues (His228 and His271, also located in C-BP-2) being responsible for the acidity-dependent HBD2 binding to GAGs.	('GAG', 'Chemical', 'MESH:D006025', (239, 242))	('C-BP-2', 'Gene', '871', (171, 177))	('heparin', 'Chemical', 'MESH:D006493', (60, 67))	('histidine', 'Chemical', 'MESH:D006639', (116, 125))	('binding', 'Interaction', (228, 235))	('His228', 'Chemical', '-', (136, 142))	('His271', 'Var', (147, 153))	('C-BP-2', 'Gene', (84, 90))	('His271', 'Chemical', '-', (147, 153))	('His228', 'Var', (136, 142))	('C-BP-2', 'Gene', '871', (84, 90))	('C-BP-2', 'Gene', (171, 177))
27679	31925333	During the preimplantation period, IGF-I plays an important role as its supplementation can enhance cell proliferation, mitogenesis, and regulate apoptosis.	('IGF-I', 'Gene', (35, 40))	('peri', 'Gene', '5346', (27, 31))	('regulate', 'Reg', (137, 145))	('mitogenesis', 'CPA', (120, 131))	('IGF-I', 'Gene', '3479', (35, 40))	('rat', 'Species', '10116', (112, 115))	('peri', 'Gene', (27, 31))	('cell proliferation', 'CPA', (100, 118))	('apoptosis', 'CPA', (146, 155))	('men', 'Species', '9606', (78, 81))	('supplementation', 'Var', (72, 87))	('enhance', 'PosReg', (92, 99))	('preimplantation period', 'Phenotype', 'HP:0032479', (11, 33))
27680	31925333	Meanwhile, IGFII is known to modulate fetal growth in vivo, and a mutated IGF-II gene resulted in a growth deficiency of both the embryo and the placenta.	('IGF-II', 'Gene', '3481', (74, 80))	('mutated', 'Var', (66, 73))	('growth deficiency of both the embryo', 'Disease', 'MESH:D020964', (100, 136))	('IGFII', 'Gene', '3481', (11, 16))	('IGFII', 'Gene', (11, 16))	('growth deficiency of both the embryo', 'Disease', (100, 136))	('growth deficiency', 'Phenotype', 'HP:0001510', (100, 117))	('resulted in', 'Reg', (86, 97))	('IGF-II', 'Gene', (74, 80))
27691	31925333	Aberrant expression patterns of IGFBP2 have been detected in many types of human cancers and broadly associate with a poor prognosis.	('detected', 'Reg', (49, 57))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('IGFBP2', 'Gene', (32, 38))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('expression', 'MPA', (9, 19))	('associate with', 'Reg', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))
27696	31925333	As a candidate biomarker, aberrant expression of IGFBP2 was detected in high-grade gliomas and identified as one of nine genes in a signature associated with poor prognosis.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('IGFBP2', 'Gene', (49, 55))	('aberrant expression', 'Var', (26, 45))	('gliomas', 'Disease', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('detected', 'Reg', (60, 68))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))
27699	31925333	Similarly, the combination of K-Ras and IGFBP2 also leads to astrocytoma formation, with an incidence of 17.4%, suggesting that IGFBP2 and Akt likely lie in converging pathways that are required for gliomagenesis.	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('Akt', 'Gene', '207', (139, 142))	('K-Ras', 'Gene', '3845', (30, 35))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('IGFBP2', 'Gene', (128, 134))	('astrocytoma', 'Disease', (61, 72))	('K-Ras', 'Gene', (30, 35))	('Akt', 'Gene', (139, 142))	('astrocytoma', 'Disease', 'MESH:D001254', (61, 72))	('leads to', 'Reg', (52, 60))	('IGFBP2', 'Gene', (40, 46))	('combination', 'Var', (15, 26))	('glioma', 'Disease', (199, 205))
27702	31925333	In the PDGFB-driven RCAS model, co-delivery of IGFBP2 was found to enhance malignancy, resulting in the progression of oligodendroglioma to anaplastic oligodendroglioma in 37.9% of the co-injected mice, while also increasing overall tumor incidence from 90.9% to 96.6%.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('oligodendroglioma to anaplastic oligodendroglioma', 'Disease', (119, 168))	('tumor', 'Disease', (233, 238))	('RCAS', 'Chemical', '-', (20, 24))	('oligodendroglioma to anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (119, 168))	('IGFBP2', 'Gene', (47, 53))	('co-delivery', 'Var', (32, 43))	('enhance', 'PosReg', (67, 74))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('mice', 'Species', '10090', (197, 201))	('malignancy', 'Disease', (75, 85))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
27703	31925333	In a new in vivo glioma model with highly expressed PDGFB and expression levels of IGFBP2 controlled using doxycycline, IGFBP2 was shown to promote glioma progression in a time-dependent manner.	('IGFBP2', 'Gene', (83, 89))	('PDGFB', 'Gene', (52, 57))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('glioma', 'Disease', (148, 154))	('doxycycline', 'Chemical', 'MESH:D004318', (107, 118))	('IGFBP2', 'Var', (120, 126))	('promote', 'PosReg', (140, 147))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', (17, 23))
27724	31925333	In LAPC-4 and DU145 prostate cancer cells, delivery of IGFBP2 upregulated the expression of hTERT, the regulatory subunit of telomerase that is directly associated with telomerase expression level and is believed to play a role in cell immortality.	('IGFBP2', 'Gene', (55, 61))	('expression', 'MPA', (78, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('LAPC-4', 'CellLine', 'CVCL:4744', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('upregulated', 'PosReg', (62, 73))	('prostate cancer', 'Disease', (20, 35))	('hTERT', 'Gene', '7015', (92, 97))	('DU145', 'CellLine', 'CVCL:0105', (14, 19))	('delivery', 'Var', (43, 51))	('hTERT', 'Gene', (92, 97))
27730	31925333	Clinical findings and cell modeling in vivo have confirmed that high levels of IGFBP2 associate with higher risk of peri-pancreas lymph node metastasis, which is an independent prognostic factor in PDAC.	('peri', 'Gene', (116, 120))	('peri', 'Gene', '5346', (116, 120))	('high levels', 'Var', (64, 75))	('IGFBP2', 'Gene', (79, 85))
27737	31925333	As set forth, aberrant expression of IGFBP2 is detected in many malignancies and is tightly related to an increasingly malignant status, pointing to a potential involvement of IGFBP2 in tumor initiation.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('malignancies', 'Disease', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('related', 'Reg', (92, 99))	('tumor initiation', 'Disease', 'MESH:D009369', (186, 202))	('IGFBP2', 'Gene', (37, 43))	('aberrant', 'Var', (14, 22))	('tumor initiation', 'Disease', (186, 202))	('detected', 'Reg', (47, 55))	('men', 'Species', '9606', (168, 171))
27743	31925333	Among the integrin family, expression of integrin beta in various cell types is involved in malignant progression, and crosstalk between IGFBP2 and integrin beta1 is implicated in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('implicated', 'Reg', (166, 176))	('malignant progression', 'CPA', (92, 113))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('integrin beta1', 'Gene', '3688', (148, 162))	('tumor', 'Disease', (180, 185))	('IGFBP2', 'Gene', (137, 143))	('crosstalk', 'Var', (119, 128))	('involved', 'Reg', (80, 88))	('integrin beta1', 'Gene', (148, 162))
27746	31925333	Moreover, studies have shown that IGFBP2 promotes ERK phosphorylation and nuclear translocation in an integrin-dependent manner, and the inhibition of ERK abrogates exogenous IGFBP2-induced proliferation and cell cycle progression.	('rat', 'Species', '10116', (197, 200))	('ERK', 'Gene', '5594', (50, 53))	('ERK', 'Gene', (50, 53))	('promotes', 'PosReg', (41, 49))	('inhibition', 'Var', (137, 147))	('cell cycle progression', 'CPA', (208, 230))	('ERK', 'Gene', '5594', (151, 154))	('proliferation', 'CPA', (190, 203))	('nuclear translocation', 'MPA', (74, 95))	('IGFBP2-induced', 'Gene', (175, 189))	('IGFBP2', 'Gene', (34, 40))	('ERK', 'Gene', (151, 154))	('abrogates', 'NegReg', (155, 164))	('phosphorylation', 'MPA', (54, 69))
27748	31925333	PTEN is an important negative regulator of the cell-survival signaling pathway initiated by PI3K and is frequently disrupted in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cell-survival signaling pathway', 'Pathway', (47, 78))	('initiated', 'Reg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PTEN', 'Gene', (0, 4))	('PI3K', 'Var', (92, 96))	('cancer', 'Disease', (128, 134))
27749	31925333	IGFBP2 is considered to be a candidate biomarker for PTEN status and PI3K/Akt pathway activation, and crosstalk between IGFBP2/PTEN is involved in oncogenic processes of multiple cancer types.	('Akt', 'Gene', '207', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('crosstalk', 'Var', (102, 111))	('Akt', 'Gene', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('involved', 'Reg', (135, 143))	('activation', 'PosReg', (86, 96))	('cancer', 'Disease', (179, 185))	('IGFBP2/PTEN', 'Gene', (120, 131))
27751	31925333	Among these signature gene alterations, the most salient was an increase in IGFBP2 mRNA.	('IGFBP2', 'Gene', (76, 82))	('increase', 'PosReg', (64, 72))	('mRNA', 'MPA', (83, 87))	('rat', 'Species', '10116', (31, 34))	('alterations', 'Var', (27, 38))
27766	31925333	However, co-injecting a mutant form of IkappaBalpha (inhibiting NF-kappaB activation by retaining it in the cytoplasm) with PDGFB and IGFBP2 robustly prevents glioma progression in the RCAS/Ntv-a glial-specific transgenic mouse model, suggesting that IGFBP2 requires active or nuclear NF-kappaB to induce progression.	('mutant', 'Var', (24, 30))	('glioma', 'Disease', (159, 165))	('IkappaBalpha', 'Gene', '18035', (39, 51))	('RCAS', 'Chemical', '-', (185, 189))	('prevents', 'NegReg', (150, 158))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('IkappaBalpha', 'Gene', (39, 51))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('mouse', 'Species', '10090', (222, 227))	('inhibiting', 'NegReg', (53, 63))
27770	31925333	Phosphorylation at this site targets the IkappaBs for ubiquitin-dependent degradation, and eventually releases the RELA subunit.	('releases', 'PosReg', (102, 110))	('ubiquitin-dependent degradation', 'MPA', (54, 85))	('targets', 'Reg', (29, 36))	('Phosphorylation', 'Var', (0, 15))	('kappaB', 'Gene', '4790', (42, 48))	('kappaB', 'Gene', (42, 48))	('RELA', 'Gene', (115, 119))	('RELA', 'Gene', '5970', (115, 119))
27774	31925333	Consistently, as a transcriptional enhancer of the VEGF gene, IGFBP2 with NLS mutation failed to promote transcriptional activation of VEGF and induce angiogenesis in vivo, confirming that nuclear IGFBP2 is the key for VEGF transcriptional activation of.	('VEGF', 'Gene', (219, 223))	('IGFBP2', 'Gene', (62, 68))	('mutation', 'Var', (78, 86))	('VEGF', 'Gene', '7422', (51, 55))	('VEGF', 'Gene', (135, 139))	('VEGF', 'Gene', '7422', (219, 223))	('NLS', 'Gene', (74, 77))	('transcriptional', 'MPA', (105, 120))	('VEGF', 'Gene', (51, 55))	('angiogenesis', 'CPA', (151, 163))	('VEGF', 'Gene', '7422', (135, 139))	('induce', 'Reg', (144, 150))
27786	31925333	Nuclear p65 enrichment leads to EMT initiation.	('p65', 'Gene', '5970', (8, 11))	('men', 'Species', '9606', (18, 21))	('Nuclear', 'Var', (0, 7))	('p65', 'Gene', (8, 11))	('EMT initiation', 'CPA', (32, 46))	('leads to', 'Reg', (23, 31))
27788	31925333	Aberrant angiogenesis provides nutrients and oxygen to tumor cells, ultimately facilitating uncontrolled proliferation and malignant progression.	('facilitating', 'Reg', (79, 91))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('angiogenesis', 'CPA', (9, 21))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('oxygen', 'Chemical', 'MESH:D010100', (45, 51))	('tumor', 'Disease', (55, 60))	('rat', 'Species', '10116', (112, 115))	('uncontrolled proliferation', 'CPA', (92, 118))	('malignant progression', 'CPA', (123, 144))
27789	31925333	In human neuroblastoma, IGFBP2 overexpression activates a pattern of gene sets involved in proliferation, migration and angiogenesis, among which the mRNA of vascular endothelial growth factor (VEGF) shows a 2-fold up-regulation.	('pattern', 'MPA', (58, 65))	('neuroblastoma', 'Disease', (9, 22))	('gene sets', 'Gene', (69, 78))	('vascular endothelial growth factor', 'Gene', (158, 192))	('overexpression', 'Var', (31, 45))	('human', 'Species', '9606', (3, 8))	('activates', 'PosReg', (46, 55))	('VEGF', 'Gene', '7422', (194, 198))	('VEGF', 'Gene', (194, 198))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('up-regulation', 'PosReg', (215, 228))	('rat', 'Species', '10116', (109, 112))	('vascular endothelial growth factor', 'Gene', '7422', (158, 192))	('rat', 'Species', '10116', (98, 101))	('proliferation', 'CPA', (91, 104))	('migration', 'CPA', (106, 115))	('IGFBP2', 'Gene', (24, 30))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))
27791	31925333	Using a xenograft model of angiogenesis, studies demonstrated that nuclear IGFBP2 accounts for pathologic angiogenesis via enhancement of VEGF promoter transcriptional activity and subsequent proangiogenic activity.	('nuclear', 'Var', (67, 74))	('rat', 'Species', '10116', (56, 59))	('proangiogenic activity', 'CPA', (192, 214))	('IGFBP2', 'Gene', (75, 81))	('VEGF', 'Gene', '7422', (138, 142))	('enhancement', 'PosReg', (123, 134))	('men', 'Species', '9606', (130, 133))	('VEGF', 'Gene', (138, 142))
27797	31925333	Recent studies have shown that elevated IGFBP2 expression is detected in VM positive glioma samples, and IGFBP2 promotes VM formation in vitro and in vivo via activation of CD144 and MMP2.	('activation', 'PosReg', (159, 169))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('promotes', 'PosReg', (112, 120))	('VM formation', 'CPA', (121, 133))	('IGFBP2', 'Var', (105, 111))	('CD144', 'Gene', '1003', (173, 178))	('MMP2', 'Gene', (183, 187))	('CD144', 'Gene', (173, 178))	('elevated IGFBP2', 'Phenotype', 'HP:0030269', (31, 46))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', (85, 91))	('IGFBP2', 'Gene', (40, 46))	('elevated', 'PosReg', (31, 39))	('MMP2', 'Gene', '4313', (183, 187))	('expression', 'MPA', (47, 57))
27802	31925333	Protein array data from the Cancer Genome Atlas GBM cohort showed that IGFBP2 levels are significantly decreased in G-CIMP+ cases.	('G-CIMP+', 'Chemical', '-', (116, 123))	('G-CIMP+', 'Var', (116, 123))	('decreased', 'NegReg', (103, 112))	('IGFBP2', 'Gene', (71, 77))	('Cancer', 'Disease', 'MESH:D009369', (28, 34))	('Cancer', 'Disease', (28, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))
27804	31925333	Mechanistically, HSCs from IGFBP2-null mice have decreased expression of the antiapoptotic molecule Bcl-2, and increased levels of multiple cell cycle inhibitors, including p21, p19, p16, p57, and PTEN.	('IGFBP2-null', 'Gene', (27, 38))	('Bcl-2', 'Gene', (100, 105))	('increased', 'PosReg', (111, 120))	('p21', 'Var', (173, 176))	('p57', 'Gene', (188, 191))	('p16', 'Gene', '12578', (183, 186))	('Bcl-2', 'Gene', '12043', (100, 105))	('p57', 'Gene', '12721', (188, 191))	('decreased', 'NegReg', (49, 58))	('levels of', 'MPA', (121, 130))	('expression', 'MPA', (59, 69))	('PTEN', 'Var', (197, 201))	('p16', 'Gene', (183, 186))	('mice', 'Species', '10090', (39, 43))	('p19', 'Gene', (178, 181))	('p19', 'Gene', '12581', (178, 181))
27817	31925333	Both in vitro and in vivo, OGX-225 resulted in a decrease in IGFBP2 expression level and abolished the associated aggressive phenotype of MDA-MB-231 cells that constitutively over-express IGFBP2.	('over-express', 'PosReg', (175, 187))	('decrease', 'NegReg', (49, 57))	('IGFBP2', 'Gene', (61, 67))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (138, 148))	('expression level', 'MPA', (68, 84))	('OGX-225', 'Var', (27, 34))	('aggressive', 'MPA', (114, 124))	('abolished', 'NegReg', (89, 98))
27824	31925333	Moreover, IGFBP2 peptide-specific T cells have been shown to respond to IGFBP2 protein; IGFBP2 peptide vaccination significantly inhibits tumor growth in the neu transgenic mouse model.	('peptide', 'Var', (95, 102))	('inhibits', 'NegReg', (129, 137))	('tumor', 'Disease', (138, 143))	('neu', 'Gene', '13866', (158, 161))	('mouse', 'Species', '10090', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('neu', 'Gene', (158, 161))	('IGFBP2 peptide', 'Var', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
27830	31925333	Furthermore, decreased expression of miR-491-3p secondary to genomic deletion is a key event in the generation of elevated IGFBP2 expression via the target site on IGFBP2 3'-UTR.	('expression', 'MPA', (130, 140))	('decreased', 'NegReg', (13, 22))	('miR-491', 'Gene', '574444', (37, 44))	('rat', 'Species', '10116', (104, 107))	('miR-491', 'Gene', (37, 44))	('elevated IGFBP2', 'Phenotype', 'HP:0030269', (114, 129))	('deletion', 'Var', (69, 77))	('IGFBP2', 'Gene', (123, 129))	('elevated', 'PosReg', (114, 122))	('expression', 'MPA', (23, 33))
27851	32158359	The extracellular acidification rate (ECAR), colony formation assay and levels of Glut1 and PKM2 were measured to assess the glucose metabolic and proliferation changes in GBM cells overexpressing miR-181b.	('PKM2', 'Gene', '5315', (92, 96))	('glucose', 'Chemical', 'MESH:D005947', (125, 132))	('GBM', 'Disease', 'MESH:D005909', (172, 175))	('Glut1', 'Gene', (82, 87))	('glucose metabolic', 'CPA', (125, 142))	('GBM', 'Disease', (172, 175))	('miR-181b', 'Chemical', '-', (197, 205))	('extracellular acidification', 'MPA', (4, 31))	('Glut1', 'Gene', '6513', (82, 87))	('PKM2', 'Gene', (92, 96))	('miR-181b', 'Var', (197, 205))	('proliferation', 'CPA', (147, 160))
27852	32158359	Immunoblotting and luciferase reporter assay were performed to confirm the expression and role of SP1 as a direct target of miR-181b.	('miR-181b', 'Chemical', '-', (124, 132))	('SP1', 'Gene', (98, 101))	('miR-181b', 'Var', (124, 132))
27856	32158359	And, SP1 was confirmed as a direct target of miR-181b while upregulation of SP1 could reverse the influence of overexpression of miR-181b.	('miR-181b', 'Chemical', '-', (129, 137))	('SP1', 'Gene', (76, 79))	('upregulation', 'PosReg', (60, 72))	('miR-181b', 'Chemical', '-', (45, 53))	('miR-181b', 'Var', (45, 53))
27858	32158359	Finally, miR-181b could inhibit the tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('miR-181b', 'Var', (9, 17))	('inhibit', 'NegReg', (24, 31))	('miR-181b', 'Chemical', '-', (9, 17))	('tumor', 'Disease', (36, 41))
27873	32158359	Aberrant expression of miR-181 family has been found in many tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('miR-181', 'Chemical', '-', (23, 30))	('Aberrant', 'Var', (0, 8))	('found', 'Reg', (47, 52))	('expression', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-181 family', 'Gene', (23, 37))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
27874	32158359	Our group firstly identified that miR-181a and miR-181b were down-regulation in human glioma tissues and cells, which played a critical role in the pathogenesis of gliomas.	('glioma', 'Disease', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('miR-181b', 'Var', (47, 55))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('miR-181b', 'Chemical', '-', (47, 55))	('miR-181', 'Chemical', '-', (47, 54))	('down-regulation', 'NegReg', (61, 76))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('miR-181', 'Chemical', '-', (34, 41))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('human', 'Species', '9606', (80, 85))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('gliomas', 'Disease', (164, 171))	('miR-181a', 'Var', (34, 42))	('glioma', 'Disease', (164, 170))
27875	32158359	For example, our previous work revealed that miR-181b modulates chemo-sensitivity of GBM cells to TMZ via targeting EGFR.	('GBM', 'Disease', 'MESH:D005909', (85, 88))	('targeting', 'Reg', (106, 115))	('miR-181b', 'Chemical', '-', (45, 53))	('modulates', 'Reg', (54, 63))	('miR-181b', 'Var', (45, 53))	('GBM', 'Disease', (85, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('chemo-sensitivity', 'MPA', (64, 81))
27892	32158359	Briefly, the SP1 3'-UTR are cloned into the SacI and HindIII sites of the pmiRNA-Report vector (Genechem, Shanghai, China) and confirmed by a sequencing to form the wild-type (WT) and mutated (Mut).	('mutated', 'Var', (184, 191))	('miR', 'Gene', '22877', (75, 78))	('miR', 'Gene', (75, 78))
27895	32158359	The cells were co-transfected with a mixture of luciferase reporter vectors (pGL3-basic) containing wild type sequence or mutant sequence of specific PKM2 and Glut1 promoter fragment.	('PKM2', 'Gene', (150, 154))	('Glut1', 'Gene', (159, 164))	('PKM2', 'Gene', '5315', (150, 154))	('pGL3', 'Gene', (77, 81))	('Glut1', 'Gene', '6513', (159, 164))	('mutant sequence', 'Var', (122, 137))	('pGL3', 'Gene', '6391', (77, 81))
27912	32158359	Therefore, to extend this study, we also detected PKM2 expression levels, and PKM2 was significantly suppressed by miR-181b (Fig.	('PKM2', 'Gene', '5315', (78, 82))	('expression levels', 'MPA', (55, 72))	('PKM2', 'Gene', (50, 54))	('miR-181b', 'Chemical', '-', (115, 123))	('PKM2', 'Gene', '5315', (50, 54))	('miR-181b', 'Var', (115, 123))	('PKM2', 'Gene', (78, 82))	('suppressed', 'NegReg', (101, 111))
27914	32158359	Meanwhile, miR-181b inhibited the cell proliferation of U87 and U251 (Fig.	('cell proliferation', 'CPA', (34, 52))	('miR-181b', 'Var', (11, 19))	('inhibited', 'NegReg', (20, 29))	('miR-181b', 'Chemical', '-', (11, 19))	('U251', 'CellLine', 'CVCL:0021', (64, 68))
27922	32158359	In addition, we examined the SP1 levels in normal and glioma tissues and the results indicated a negative relationship between miR-181b and SP1 (Fig.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('miR-181b', 'Chemical', '-', (127, 135))	('miR-181b', 'Var', (127, 135))	('glioma', 'Disease', (54, 60))	('negative', 'NegReg', (97, 105))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))
27923	32158359	Together, these data suggest that miR-181b directly regulate SP1.	('SP1', 'Gene', (61, 64))	('regulate', 'Reg', (52, 60))	('miR-181b', 'Chemical', '-', (34, 42))	('miR-181b', 'Var', (34, 42))
27924	32158359	Since we have confirmed that SP1 was a direct target of miR-181b, we tend to investigate whether SP1 could affect the glucose metabolism and proliferation in GBM cells.	('affect', 'Reg', (107, 113))	('GBM', 'Disease', 'MESH:D005909', (158, 161))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('glucose metabolism', 'MPA', (118, 136))	('proliferation', 'CPA', (141, 154))	('miR-181b', 'Chemical', '-', (56, 64))	('miR-181b', 'Var', (56, 64))	('GBM', 'Disease', (158, 161))
27926	32158359	Extracellular acidification assays, Immunoblotting assay and colony formation were employed to evaluate the effects of SP1 knockdown on cell glucose metabolism and proliferation in U87 and U251 cells.	('knockdown', 'Var', (123, 132))	('glucose', 'Chemical', 'MESH:D005947', (141, 148))	('U251', 'CellLine', 'CVCL:0021', (189, 193))	('SP1', 'Gene', (119, 122))
27927	32158359	As expected, knock-down of SP1 expression inhibited the glucose metabolism and cells proliferation (Fig.	('knock-down', 'Var', (13, 23))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('inhibited', 'NegReg', (42, 51))	('SP1', 'Gene', (27, 30))	('glucose metabolism', 'CPA', (56, 74))	('cells proliferation', 'CPA', (79, 98))
27930	32158359	Therefore, we addressed whether miR-181b suppresses GBM progression by targeting SP1.	('targeting', 'Reg', (71, 80))	('SP1', 'Gene', (81, 84))	('GBM', 'Disease', (52, 55))	('GBM', 'Disease', 'MESH:D005909', (52, 55))	('suppresses', 'NegReg', (41, 51))	('miR-181b', 'Chemical', '-', (32, 40))	('miR-181b', 'Var', (32, 40))
27932	32158359	The decreased levels of SP1 due to miR-181b over-expression were partly reversed by SP1 over-expression (Fig.	('decreased', 'NegReg', (4, 13))	('SP1', 'Gene', (84, 87))	('miR-181b', 'Var', (35, 43))	('miR-181b', 'Chemical', '-', (35, 43))	('levels of SP1', 'MPA', (14, 27))	('over-expression', 'PosReg', (88, 103))	('over-expression', 'PosReg', (44, 59))
27934	32158359	To further confirm, SP1 is a vital target of miR-181b in glucose metabolism and cell proliferation.	('miR-181b', 'Chemical', '-', (45, 53))	('glucose metabolism', 'MPA', (57, 75))	('cell proliferation', 'CPA', (80, 98))	('glucose', 'Chemical', 'MESH:D005947', (57, 64))	('miR-181b', 'Var', (45, 53))
27942	32158359	3c, we found that knockdown of SP1 significantly decreased Glut1 and PKM2 on protein levels in GBM cells.	('knockdown', 'Var', (18, 27))	('Glut1', 'Gene', '6513', (59, 64))	('PKM2', 'Gene', (69, 73))	('decreased', 'NegReg', (49, 58))	('PKM2', 'Gene', '5315', (69, 73))	('GBM', 'Disease', (95, 98))	('GBM', 'Disease', 'MESH:D005909', (95, 98))	('Glut1', 'Gene', (59, 64))	('SP1', 'Gene', (31, 34))
27943	32158359	Here, we examined the mRNA level changes of Glut1 and PKM2 after SP1 knockdown.	('Glut1', 'Gene', '6513', (44, 49))	('PKM2', 'Gene', '5315', (54, 58))	('Glut1', 'Gene', (44, 49))	('PKM2', 'Gene', (54, 58))	('SP1', 'Gene', (65, 68))	('knockdown', 'Var', (69, 78))
27944	32158359	The results showed that knockdown of SP1 also significantly decreased Glut1 and PKM2 on mRNA levels in U87 and U251 cells (Fig.	('Glut1', 'Gene', (70, 75))	('decreased', 'NegReg', (60, 69))	('U251', 'CellLine', 'CVCL:0021', (111, 115))	('SP1', 'Gene', (37, 40))	('mRNA levels', 'MPA', (88, 99))	('Glut1', 'Gene', '6513', (70, 75))	('PKM2', 'Gene', (80, 84))	('PKM2', 'Gene', '5315', (80, 84))	('knockdown', 'Var', (24, 33))
27947	32158359	Next, to further examine whether SP1 could regulate Glut1 and PKM2 transcription activity via binding in the promoter of Glut1 and PKM2, we constructed wild type and mutant luciferase reporter (Fig.	('Glut1', 'Gene', (52, 57))	('transcription activity', 'MPA', (67, 89))	('regulate', 'Reg', (43, 51))	('Glut1', 'Gene', (121, 126))	('binding', 'Interaction', (94, 101))	('PKM2', 'Gene', (62, 66))	('Glut1', 'Gene', '6513', (52, 57))	('mutant', 'Var', (166, 172))	('Glut1', 'Gene', '6513', (121, 126))	('PKM2', 'Gene', (131, 135))	('PKM2', 'Gene', '5315', (62, 66))	('PKM2', 'Gene', '5315', (131, 135))
27950	32158359	Next, we tend to investigate whether miR-181b targeting SP1 could affect the tumorogenesis and progression in vivo.	('miR-181b', 'Var', (37, 45))	('progression', 'CPA', (95, 106))	('miR-181b', 'Chemical', '-', (37, 45))	('affect', 'Reg', (66, 72))	('SP1', 'Gene', (56, 59))	('tumorogenesis', 'Disease', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumorogenesis', 'Disease', 'MESH:D002471', (77, 90))
27955	32158359	6a, b, miR-181b overexpression displayed a significant reduction of tumor growth.	('tumor', 'Disease', (68, 73))	('overexpression', 'PosReg', (16, 30))	('reduction', 'NegReg', (55, 64))	('miR-181b', 'Chemical', '-', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('miR-181b', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
27956	32158359	Compared with miR-181b overexpression group, miR-181b plus SP1 overexpression could significantly promote the growth of tumors.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('promote', 'PosReg', (98, 105))	('miR-181b', 'Chemical', '-', (14, 22))	('miR-181b', 'Chemical', '-', (45, 53))	('miR-181b', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
27957	32158359	Histologic analysis indicated that tumors derived from U87/miR-181b cells had a significantly decreased SP1, Glut1 and PKM2 expression while miR-181b plus SP1 overexpression tumors expressed higher SP1, Glut1 and PKM2 levels than miR-181b overexpression tumors (Fig.	('higher', 'PosReg', (191, 197))	('PKM2', 'Gene', (119, 123))	('tumors', 'Disease', (254, 260))	('PKM2', 'Gene', '5315', (119, 123))	('miR-181b', 'Chemical', '-', (230, 238))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('SP1', 'MPA', (104, 107))	('Glut1', 'Gene', (109, 114))	('U87/miR-181b', 'Var', (55, 67))	('Glut1', 'Gene', (203, 208))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumors', 'Disease', (174, 180))	('PKM2', 'Gene', (213, 217))	('PKM2', 'Gene', '5315', (213, 217))	('miR-181b', 'Chemical', '-', (141, 149))	('SP1', 'MPA', (198, 201))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('miR-181b', 'Chemical', '-', (59, 67))	('decreased', 'NegReg', (94, 103))	('miR-181b', 'Var', (141, 149))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('Glut1', 'Gene', '6513', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Glut1', 'Gene', '6513', (203, 208))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
27958	32158359	Together, these results suggest that miR-181b could inhibit glioma growth via targeting SP1 in vivo.	('miR-181b', 'Var', (37, 45))	('inhibit', 'NegReg', (52, 59))	('miR-181b', 'Chemical', '-', (37, 45))	('targeting', 'Reg', (78, 87))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('SP1', 'Protein', (88, 91))	('glioma', 'Disease', (60, 66))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
27960	32158359	As SP1 was directly regulated by miR-181b, we then analyzed SP1 levels in GBM cells and tissues.	('miR-181b', 'Chemical', '-', (33, 41))	('miR-181b', 'Var', (33, 41))	('regulated', 'Reg', (20, 29))	('GBM', 'Disease', (74, 77))	('GBM', 'Disease', 'MESH:D005909', (74, 77))
27965	32158359	Since our results have identified the significance of miR-181b in GBM cells, we then tend to apply these information for GBM treatment.	('miR-181b', 'Var', (54, 62))	('GBM', 'Disease', (66, 69))	('GBM', 'Disease', (121, 124))	('GBM', 'Disease', 'MESH:D005909', (66, 69))	('GBM', 'Disease', 'MESH:D005909', (121, 124))	('miR-181b', 'Chemical', '-', (54, 62))
27978	32158359	found that miR-181b could inhibits glycolysis in gastric cancer cells by targeting hexokinase 2.	('inhibits', 'NegReg', (26, 34))	('hexokinase 2', 'Gene', '3099', (83, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('miR-181b', 'Var', (11, 19))	('targeting', 'Reg', (73, 82))	('miR-181b', 'Chemical', '-', (11, 19))	('hexokinase 2', 'Gene', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', (49, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('glycolysis', 'MPA', (35, 45))
27989	32158359	Together, we proposed that dysregulation of SP1 by miR-181b could transcriptionally induce PKM2 and Glut1, and regulate glucose metabolism in glioma.	('PKM2', 'Gene', (91, 95))	('glucose', 'Chemical', 'MESH:D005947', (120, 127))	('PKM2', 'Gene', '5315', (91, 95))	('Glut1', 'Gene', (100, 105))	('glioma', 'Disease', (142, 148))	('miR-181b', 'Chemical', '-', (51, 59))	('Glut1', 'Gene', '6513', (100, 105))	('dysregulation', 'Var', (27, 40))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('induce', 'PosReg', (84, 90))	('glucose metabolism', 'MPA', (120, 138))	('miR-181b', 'Gene', (51, 59))	('regulate', 'Reg', (111, 119))
27990	32158359	In summary, our study certificated that miR-181b functioned as a tumor suppressor by directly targeting SP1 to prevent glucose metabolism and cell proliferation.	('SP1', 'Gene', (104, 107))	('miR-181b', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('cell proliferation', 'CPA', (142, 160))	('prevent', 'NegReg', (111, 118))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('targeting', 'Reg', (94, 103))	('miR-181b', 'Chemical', '-', (40, 48))	('glucose metabolism', 'MPA', (119, 137))
27991	32158359	We also demonstrated that miR-181b targeting SP1 could induce PKM2 and Glut1.	('miR-181b', 'Var', (26, 34))	('PKM2', 'Gene', (62, 66))	('miR-181b', 'Chemical', '-', (26, 34))	('Glut1', 'Gene', (71, 76))	('induce', 'PosReg', (55, 61))	('PKM2', 'Gene', '5315', (62, 66))	('Glut1', 'Gene', '6513', (71, 76))	('SP1', 'Gene', (45, 48))
27997	31183364	The genetic alterations of CTRP1 occurred at a low rate in GBM (2 of 591 sequenced cases/patients, 0.33%).	('genetic alterations', 'Var', (4, 23))	('GBM', 'Disease', (59, 62))	('patient', 'Species', '9606', (89, 96))	('patients', 'Species', '9606', (89, 97))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('CTRP1', 'Gene', (27, 32))
27999	31183364	CTRP1 knockdown significantly inhibited the proliferation and migration in human GBM cells, suggesting the inhibition of CTRP1 on human GMB progression.	('GBM', 'Phenotype', 'HP:0012174', (81, 84))	('CTRP1', 'Gene', (121, 126))	('human', 'Species', '9606', (75, 80))	('inhibited', 'NegReg', (30, 39))	('knockdown', 'Var', (6, 15))	('CTRP1', 'Gene', (0, 5))	('inhibition', 'NegReg', (107, 117))	('GMB', 'Chemical', 'MESH:C032138', (136, 139))	('human', 'Species', '9606', (130, 135))
28003	31183364	The effect of CTRP1 on GBM cells was also investigated through the knockdown of CTRP1 in U87 and U251 cells.	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('CTRP1', 'Gene', (80, 85))	('knockdown', 'Var', (67, 76))	('U251', 'CellLine', 'CVCL:0021', (97, 101))	('U87', 'Gene', (89, 92))	('U87', 'Gene', '641648', (89, 92))
28018	31183364	CTRP1 treatment can facilitate the production of the chemokine (C-C motif) ligand 2 (CCL2, also known as MCP-1) belonging to the CC chemokines family in monocyte and primary human macrophages.	('MCP-1', 'Gene', (105, 110))	('chemokine (C-C motif) ligand 2', 'Gene', '6347', (53, 83))	('MCP-1', 'Gene', '6347', (105, 110))	('treatment', 'Var', (6, 15))	('production', 'MPA', (35, 45))	('CTRP1', 'Gene', (0, 5))	('facilitate', 'PosReg', (20, 30))
28077	30456343	Similarly, neither the mean nor the median calculated diffusivities were significantly different between tumor models, except the average bulk diffusivity between G62 and G528 in which G528 was significantly higher [supplementary material Figs.	('higher', 'PosReg', (208, 214))	('tumor', 'Disease', (105, 110))	('bulk diffusivity', 'MPA', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('G62', 'Var', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('G528', 'Var', (171, 175))	('G528', 'Var', (185, 189))
28126	30456343	Briefly, Glioblastoma stem cells (GSCs) were cultured and maintained as previously described, and then steriotactically injected into 8-10 week old male Nonobese diabetic severe combined immunodeficiency (NOD SCID) mice with 15 000 GSCs [G2 (n = 3), G34 (n = 5), G62 (n = 4)] or 400 000 GSCs [G528 (n = 4)].	('diabetic', 'Disease', (162, 170))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (171, 203))	('G34', 'Var', (250, 253))	('mice', 'Species', '10090', (215, 219))	('SCID', 'Disease', (209, 213))	('immunodeficiency', 'Phenotype', 'HP:0002721', (187, 203))	('immunodeficiency', 'Disease', (187, 203))	('immunodeficiency', 'Disease', 'MESH:D007153', (187, 203))	('SCID', 'Disease', 'MESH:D053632', (209, 213))	('diabetic', 'Disease', 'MESH:D003920', (162, 170))	('Glioblastoma', 'Phenotype', 'HP:0012174', (9, 21))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (178, 203))	('Glioblastoma', 'Disease', (9, 21))	('Glioblastoma', 'Disease', 'MESH:D005909', (9, 21))	('G62', 'Var', (263, 266))
28155	29377763	We observed that expression of EGFRvIII elevates the activation of macroautophagy/autophagy during starvation and hypoxia and explored the underlying mechanism and consequence.	('macroautophagy/autophagy', 'CPA', (67, 91))	('EGFR', 'Gene', '1956', (31, 35))	('activation', 'PosReg', (53, 63))	('EGFR', 'Gene', (31, 35))	('expression', 'Var', (17, 27))	('elevates', 'PosReg', (40, 48))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))
28167	29377763	In cancer, EGFR is often mutated, leading to enhanced or sustained receptor signaling.	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('enhanced', 'PosReg', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('receptor signaling', 'MPA', (67, 85))	('cancer', 'Disease', (3, 9))	('mutated', 'Var', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
28171	29377763	In GBM patients with amplification of the EGFR gene, the overall prevalence of EGFRvIII is 50-60% and has been reported to contribute to tumor stem cell maintenance.	('EGFR', 'Gene', '1956', (42, 46))	('tumor', 'Disease', (137, 142))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (42, 46))	('contribute', 'Reg', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('amplification', 'Var', (21, 34))	('patients', 'Species', '9606', (7, 15))
28182	29377763	Based on our observations that EGFRvIII expression results in increased autophagy activation in metabolically challenged cells, we hypothesized that the increased survival and growth of EGFRvIII-expressing cells and tumors during stressful conditions is supported by autophagy.	('increased', 'PosReg', (62, 71))	('EGFR', 'Gene', '1956', (31, 35))	('autophagy', 'CPA', (72, 81))	('growth', 'CPA', (176, 182))	('expression', 'Var', (40, 50))	('tumors', 'Disease', (216, 222))	('EGFR', 'Gene', (31, 35))	('increased', 'PosReg', (153, 162))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('activation', 'PosReg', (82, 92))	('EGFR', 'Gene', (186, 190))	('EGFR', 'Gene', '1956', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
28184	29377763	EGFR is often overexpressed or mutated in diverse cancer types and especially in glioblastoma.	('glioblastoma', 'Disease', (81, 93))	('EGFR', 'Gene', (0, 4))	('cancer', 'Disease', (50, 56))	('overexpressed', 'PosReg', (14, 27))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('EGFR', 'Gene', '1956', (0, 4))	('mutated', 'Var', (31, 38))
28185	29377763	One of the most commonly found mutations in EGFR is the constitutive active deletion variant EGFRvIII, which contributes to increased intrinsic radioresistance but also increases tolerance to microenvironmental factors that contribute to therapy resistance (e.g., hypoxia).	('mutations', 'Var', (31, 40))	('EGFR', 'Gene', '1956', (93, 97))	('deletion variant', 'Var', (76, 92))	('increased', 'PosReg', (124, 133))	('intrinsic radioresistance', 'CPA', (134, 159))	('EGFR', 'Gene', (93, 97))	('increases', 'PosReg', (169, 178))	('hypoxia', 'Disease', 'MESH:D000860', (264, 271))	('tolerance', 'MPA', (179, 188))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('hypoxia', 'Disease', (264, 271))
28205	29377763	In agreement with an autophagy dependence, targeting LC3B sensitized cells to serum deprivation.	('LC3B', 'Gene', (53, 57))	('LC3B', 'Gene', '81631', (53, 57))	('targeting', 'Var', (43, 52))
28272	29377763	Comparable to CQ, inhibition of autophagy through targeting LC3B, increased glucose consumption in EGFRvIII-expressing cells (Fig.	('increased glucose', 'Phenotype', 'HP:0003074', (66, 83))	('glucose consumption', 'CPA', (76, 95))	('EGFR', 'Gene', (99, 103))	('increased', 'PosReg', (66, 75))	('CQ', 'Chemical', 'MESH:D002738', (14, 16))	('LC3B', 'Gene', '81631', (60, 64))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('autophagy', 'CPA', (32, 41))	('EGFR', 'Gene', '1956', (99, 103))	('targeting', 'Var', (50, 59))	('LC3B', 'Gene', (60, 64))
28310	29377763	Our data indicates that EGFRvIII expression changes the tumor cell dependence on autophagy to tolerate low oxygen levels.	('EGFR', 'Gene', '1956', (24, 28))	('changes', 'Reg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expression', 'Var', (33, 43))	('EGFR', 'Gene', (24, 28))	('tumor', 'Disease', (56, 61))	('oxygen', 'Chemical', 'MESH:D010100', (107, 113))	('rat', 'Species', '10116', (98, 101))	('low oxygen levels', 'Phenotype', 'HP:0012418', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
28318	29377763	Similar to our observations, oncogenic RRAS promotes glucose uptake and utilization in glycolysis (reviewed in).	('promotes', 'PosReg', (44, 52))	('glucose uptake', 'MPA', (53, 67))	('RRAS', 'Gene', '6237', (39, 43))	('RRAS', 'Gene', (39, 43))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('utilization in glycolysis', 'MPA', (72, 97))	('oncogenic', 'Var', (29, 38))
28321	29377763	In addition to being converted to ATP, pyruvate is able to prevent toxic effects of oxygen radicals and peroxides and indirectly prevents the depletion of glutathione during hypoxia, and may therefore decrease the toxic effects after reoxygenation.	('prevents', 'NegReg', (129, 137))	('pyruvate', 'Var', (39, 47))	('oxygen radicals', 'MPA', (84, 99))	('oxygen', 'Chemical', 'MESH:D010100', (236, 242))	('hypoxia', 'Disease', (174, 181))	('glutathione', 'Chemical', 'MESH:D005978', (155, 166))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('depletion of glutathione', 'MPA', (142, 166))	('peroxides', 'Chemical', 'MESH:D010545', (104, 113))	('toxic effects', 'MPA', (67, 80))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('toxic effects after reoxygenation', 'MPA', (214, 247))	('decrease', 'NegReg', (201, 209))	('oxygen', 'Chemical', 'MESH:D010100', (84, 90))	('pyruvate', 'Chemical', 'MESH:D019289', (39, 47))
28332	29377763	Interestingly, other mutation types in the RAS-RAF-MAPK/ERK pathway have also been associated with increased dependence on autophagy for survival.	('ERK', 'Gene', '2048', (56, 59))	('ERK', 'Gene', (56, 59))	('mutation', 'Var', (21, 29))	('RAF', 'Gene', '22882', (47, 50))	('RAF', 'Gene', (47, 50))
28333	29377763	Also the BRAFV600E mutation, which occurs in over 50% of childhood central nervous system tumors, results in elevated autophagy and increased sensitivity to pharmacological or genetic autophagy inhibition in terms of cell viability.	('elevated', 'PosReg', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('BRAFV600E', 'Var', (9, 18))	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))	('sensitivity to pharmacological', 'MPA', (142, 172))	('increased', 'PosReg', (132, 141))	('autophagy', 'CPA', (118, 127))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('childhood central nervous system tumors', 'Disease', 'MESH:D016543', (57, 96))	('nervous system tumors', 'Phenotype', 'HP:0004375', (75, 96))	('childhood central nervous system tumors', 'Disease', (57, 96))
28353	29377763	Glutamax-I (35050038) and pyruvate (11360039) were obtained from Life Technologies, DMEM (BE12-604F) and fetal bovine serum (FBS) were from GE-Healthcare.	('11360039', 'Var', (36, 44))	('pyruvate', 'Chemical', 'MESH:D019289', (26, 34))	('Glutamax-I', 'Chemical', '-', (0, 10))	('bovine', 'Species', '9913', (111, 117))	('DMEM', 'Chemical', '-', (84, 88))	('35050038', 'Var', (12, 20))
28355	29377763	Cell lines were obtained from and maintained as described by ATCC (HTB-14 (U87) and HTB-17 (U373)), negative for mycoplasma contamination (Lonza Mycoalerts, LT07-318).	('mycoplasma', 'Disease', 'MESH:D009175', (113, 123))	('U87', 'Gene', (75, 78))	('HTB-14', 'Disease', 'OMIM:615513', (67, 73))	('HTB-14', 'Disease', (67, 73))	('U87', 'Gene', '641648', (75, 78))	('U373', 'Var', (92, 96))	('mycoplasma', 'Disease', (113, 123))
28357	29377763	For doxycycline (Sigma, D9891) inducible knockdown of LC3B, shRNA [TTTCTCACTCTCATACACCTCT] (Sigma Aldrich, TRCN0000152696) was expressed from Tet-pLKO-puro (addgene, 21915; depositor Dmitri Wiederschain) as described previously.	('LC3B', 'Gene', '81631', (54, 58))	('knockdown', 'Var', (41, 50))	('doxycycline', 'Chemical', 'MESH:D004318', (4, 15))	('LC3B', 'Gene', (54, 58))
28358	29377763	ATG7 knockdown was induced using pTRIPZ lentiviral delivery of shATG7 [ATACAGTGTTCCAATAGCTGGG] (Dharmacon).	('ATG7', 'Gene', (65, 69))	('knockdown', 'Var', (5, 14))	('ATG7', 'Gene', '10533', (0, 4))	('ATG7', 'Gene', '10533', (65, 69))	('ATG7', 'Gene', (0, 4))
28393	27959794	When microglia are plated in the bottom chamber, TGF-beta acts as a chemotactic attractant for glioma cells in the upper chamber, and silencing of the Type II receptor on glioma cells with shRNAs abolishes their migration.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('TGF-beta', 'Gene', (49, 57))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('Type II receptor', 'Protein', (151, 167))	('rat', 'Species', '10116', (215, 218))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', (171, 177))	('silencing', 'Var', (134, 143))	('abolishes', 'NegReg', (196, 205))	('migration', 'CPA', (212, 221))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
28421	27959794	Activated microglia and macrophages are the major source of EGF in gliomas, and thus the governing equation for EGF is  where a6 and B1a6 are secretion rates of EGF by M1 type and M2 type of microglia, respectively, and dE is the decay rate of EGF.	('EGF', 'Gene', (60, 63))	('EGF', 'Gene', '1950', (244, 247))	('EGF', 'Gene', '1950', (161, 164))	('EGF', 'Gene', (112, 115))	('rat', 'Species', '10116', (152, 155))	('rat', 'Species', '10116', (236, 239))	('gliomas', 'Disease', 'MESH:D005910', (67, 74))	('EGF', 'Gene', (161, 164))	('gliomas', 'Disease', (67, 74))	('gliomas', 'Phenotype', 'HP:0009733', (67, 74))	('EGF', 'Gene', '1950', (60, 63))	('B1a6', 'Var', (133, 137))	('EGF', 'Gene', '1950', (112, 115))	('EGF', 'Gene', (244, 247))	('secretion', 'MPA', (142, 151))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
28424	27959794	Here a7 and B2a7 are secretion rates of TGF-beta by M1 and M2 types of microglia, respectively, B2 is a scaling parameter, and dG is the decay rate.	('secretion', 'MPA', (21, 30))	('rat', 'Species', '10116', (143, 146))	('TGF-beta', 'Gene', (40, 48))	('B2a7', 'Var', (12, 16))	('rat', 'Species', '10116', (31, 34))
28435	27959794	In the simulations, the number of invading glioma cells increased ~2-fold in the presence of M1/M2 microglia in the lower chamber (+MG in Figure 4B) relative to the control (absence of microglia; -MG in Figure 4B).	('M1/M2', 'Var', (93, 98))	('increased', 'PosReg', (56, 65))	('glioma', 'Disease', (43, 49))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
28438	27959794	found that the neutralizing antibody (Ab) abrogated the invasion-promoting effect of microglia in the lower chamber, i.e., the number of migrating cells was reduced in the presence of the antibody (+MG+Ab) when compared to the MG case in the absence of the antibody (+MG-Ab).	('abrogated', 'NegReg', (42, 51))	('+MG+Ab', 'Var', (198, 204))	('MG-Ab', 'Chemical', '-', (268, 273))	('MG+', 'Chemical', 'MESH:D008274', (199, 202))	('rat', 'Species', '10116', (140, 143))	('invasion-promoting effect', 'CPA', (56, 81))	('number of migrating cells', 'CPA', (127, 152))	('reduced', 'NegReg', (157, 164))
28439	27959794	showed that a knockdown of TGF-beta type II receptor (TbetaIIR) by plasmid-transcribed shRNA can effectively inhibit TGF-beta signaling and transcriptional responses, thus blocking invasiveness of human glioblastoma cells.	('TGF-beta signaling', 'MPA', (117, 135))	('TGF-beta type II receptor', 'Gene', '7048', (27, 52))	('blocking', 'NegReg', (172, 180))	('TGF-beta type II receptor', 'Gene', (27, 52))	('TbetaIIR', 'Gene', '7048', (54, 62))	('inhibit', 'NegReg', (109, 116))	('glioblastoma', 'Disease', (203, 215))	('transcriptional responses', 'MPA', (140, 165))	('knockdown', 'Var', (14, 23))	('glioblastoma', 'Disease', 'MESH:D005909', (203, 215))	('human', 'Species', '9606', (197, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (203, 215))	('TbetaIIR', 'Gene', (54, 62))
28441	27959794	The mathematical model also predicts that the invasiveness of tumor cells is inhibited in the presence of antibody against TGF-beta (+MG+Ab) relative to control cases: -MG-Ab (no M1/M2 in the lower chamber; no antiboy), +MG-Ab (M1/M2 in the lower chamber; no antibody).	('MG+', 'Chemical', 'MESH:D008274', (134, 137))	('MG-Ab', 'Chemical', '-', (221, 226))	('MG-Ab', 'Chemical', '-', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibited', 'NegReg', (77, 86))	('tumor', 'Disease', (62, 67))	('antibody', 'Var', (106, 114))	('TGF-beta', 'Gene', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
28478	27959794	As shown in experiments, TIMP cannot block the invasion of tumor cells completely, but they do suggest that blocking MMP activity in the brain will also slow down the invasion of glioma cells into the brain stroma.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('MMP activity', 'Protein', (117, 129))	('tumor', 'Disease', (59, 64))	('brain stroma', 'Disease', (201, 213))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('TIMP', 'Gene', '7076', (25, 29))	('blocking', 'Var', (108, 116))	('slow down', 'NegReg', (153, 162))	('brain stroma', 'Disease', 'MESH:D001927', (201, 213))	('TIMP', 'Gene', (25, 29))	('glioma', 'Disease', (179, 185))
28479	27959794	Another potentially-effective therapeutic approach to slowing invasion is to apply an antibody against TGF-beta signaling (also see Figure 5), given its pivotal roles in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('antibody', 'Var', (86, 94))	('TGF-beta signaling', 'Gene', (103, 121))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))
28482	27959794	Cell-cell signaling is an integral process in tumor growth, since many mutations and chromosomal changes affect signaling pathways involving growth factors or cytokines.	('signaling pathways', 'Pathway', (112, 130))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('affect', 'Reg', (105, 111))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
28527	27027349	Furthermore, structural modifications of nimbolide to various amide derivatives have conferred improved cytotoxicity.	('amide', 'Chemical', 'MESH:D000577', (62, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (104, 116))	('structural modifications', 'Var', (13, 37))	('nimbolide', 'Gene', (41, 50))	('nimbolide', 'Chemical', 'MESH:C042198', (41, 50))	('improved', 'PosReg', (95, 103))	('cytotoxicity', 'Disease', (104, 116))
28566	27027349	For instance, chemopreventive agents hinder tumour initiation by preventing interaction between carcinogens or reactive free radicals and DNA, hence lowering the chance of DNA damage and mutations.	('tumour initiation', 'Disease', (44, 61))	('preventing', 'NegReg', (65, 75))	('free radical', 'Chemical', 'MESH:D005609', (120, 132))	('DNA damage', 'MPA', (172, 182))	('interaction', 'Interaction', (76, 87))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('mutations', 'Var', (187, 196))	('hinder', 'NegReg', (37, 43))	('tumour initiation', 'Disease', 'MESH:D009369', (44, 61))	('lowering', 'NegReg', (149, 157))
28578	27027349	Apart from G1/S phasearrest, nimbolidealso caused cell cycle arrest at both the G0/G1 and G2/M phases.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('nimbolidealso', 'Chemical', '-', (29, 42))	('G2/M phases', 'CPA', (90, 101))	('nimbolidealso', 'Var', (29, 42))	('cell cycle arrest', 'CPA', (50, 67))
28596	27027349	Furthermore, nimbolide resulted in generation of reactive oxygen species (ROS), which are required for ERK activation, which in turn up-regulated DRs and triggered apoptosis via the extrinsic pathway.	('triggered', 'Reg', (154, 163))	('ERK', 'Gene', (103, 106))	('nimbolide', 'Chemical', 'MESH:C042198', (13, 22))	('ERK', 'Gene', '5594', (103, 106))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('apoptosis', 'CPA', (164, 173))	('DRs', 'CPA', (146, 149))	('rat', 'Species', '10116', (39, 42))	('up-regulated', 'PosReg', (133, 145))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (49, 72))	('nimbolide', 'Var', (13, 22))
28597	27027349	ROS also induced lipid peroxidation of cellular membranes, generating toxic metabolites such as malondialdehyde (MDA) that can react with DNA to form adducts to induce apoptosis.	('ROS', 'Var', (0, 3))	('malondialdehyde', 'MPA', (96, 111))	('induce', 'Reg', (161, 167))	('induced', 'Reg', (9, 16))	('malondialdehyde', 'Chemical', 'MESH:D008315', (96, 111))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('lipid peroxidation', 'MPA', (17, 35))	('MDA', 'Chemical', 'MESH:D008315', (113, 116))	('rat', 'Species', '10116', (63, 66))
28620	27027349	Hence, mutations in the Wnt pathway correlate to human birth defects and cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('birth defects', 'Disease', 'MESH:D000014', (55, 68))	('Wnt pathway', 'Pathway', (24, 35))	('birth defects', 'Disease', (55, 68))	('mutations', 'Var', (7, 16))
28623	27027349	This effect was found to be mediated via an increased production of reactive oxygen species due to GSH/GSSG imbalance.	('imbalance', 'Var', (108, 117))	('imbalance', 'Phenotype', 'HP:0002172', (108, 117))	('production of reactive oxygen species', 'MPA', (54, 91))	('GSSG', 'Chemical', 'MESH:D019803', (103, 107))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (68, 91))	('GSH', 'Chemical', '-', (99, 102))	('increased', 'PosReg', (44, 53))	('increased production of reactive oxygen', 'Phenotype', 'HP:0025464', (44, 83))
28643	27027349	In another in vivo study withnimbolide in the DMBA-painted buccal pouch of hamster, nimbolidetreatment increased the levels of various antioxidant enzymes (glutathione peroxidase, gamma-glutamyltranspeptidase, superoxide dismutase, and catalase) compared to control group.	('nimbolide', 'Chemical', 'MESH:C042198', (84, 93))	('increased', 'PosReg', (103, 112))	('hamster', 'Species', '10034', (75, 82))	('nimbolidetreatment', 'Var', (84, 102))	('gamma-glutamyltranspeptidase', 'MPA', (180, 208))	('superoxide dismutase', 'MPA', (210, 230))	('catalase', 'Gene', (236, 244))	('levels of', 'MPA', (117, 126))	('glutathione', 'Chemical', 'MESH:D005978', (156, 167))	('DMBA', 'Chemical', 'MESH:D015127', (46, 50))	('antioxidant enzymes', 'MPA', (135, 154))	('nimbolide', 'Chemical', 'MESH:C042198', (29, 38))	('catalase', 'Gene', '24248', (236, 244))
28704	27285755	U87 MG cell viability was decreased by CRLX101 and CPT.	('CRLX101', 'Chemical', 'MESH:C542292', (39, 46))	('U87 MG', 'CellLine', 'CVCL:0022', (0, 6))	('decreased', 'NegReg', (26, 35))	('CPT', 'Chemical', 'MESH:D002166', (51, 54))	('CRLX101', 'Var', (39, 46))
28705	27285755	Moreover, CRLX101 induced less cytotoxicity to human astrocytes compared to CPT.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('CRLX101', 'Var', (10, 17))	('CPT', 'Chemical', 'MESH:D002166', (76, 79))	('less', 'NegReg', (26, 30))	('cytotoxicity', 'Disease', (31, 43))	('CRLX101', 'Chemical', 'MESH:C542292', (10, 17))	('human', 'Species', '9606', (47, 52))
28709	27285755	Taken together, this preclinical study showed that CRLX101 possesses antitumor abilities by inducing cell cycle arrest and apoptosis in glioma cells and inhibiting tumor angiogenesis, thereby prolonging the lifespan of mice bearing intracranial gliomas.	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('glioma cells', 'Disease', (136, 148))	('inducing', 'NegReg', (92, 100))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('intracranial gliomas', 'Disease', 'MESH:D005910', (232, 252))	('mice', 'Species', '10090', (219, 223))	('gliomas', 'Phenotype', 'HP:0009733', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('inhibiting', 'NegReg', (153, 163))	('lifespan', 'CPA', (207, 215))	('glioma cells', 'Disease', 'MESH:D005910', (136, 148))	('CRLX101', 'Var', (51, 58))	('apoptosis', 'CPA', (123, 132))	('tumor', 'Disease', (73, 78))	('arrest', 'Disease', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('prolonging', 'PosReg', (192, 202))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('intracranial gliomas', 'Disease', (232, 252))	('CRLX101', 'Chemical', 'MESH:C542292', (51, 58))
28727	27285755	CRLX101 exhibited anticancer activity in various cancer xenografts, such as colorectal, breast, and pancreatic cancers and is currently in phase 2 clinical trials for metastatic renal cell carcinoma (NCT02187302) and recurrent ovarian cancer (NCT01652079) in combination with bevacizumab, and in phase 1b/2a in combination with chemoradiation in neoadjuvant rectal cancer (NCT02010567).	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('bevacizumab', 'Chemical', 'MESH:D000068258', (276, 287))	('NCT02187302', 'Var', (200, 211))	('colorectal', 'Disease', 'MESH:D015179', (76, 86))	('renal cell carcinoma', 'Disease', (178, 198))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (178, 198))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', (49, 55))	('ovarian cancer', 'Disease', (227, 241))	('cancer', 'Disease', (365, 371))	('NCT01652079', 'Var', (243, 254))	('rectal cancer', 'Phenotype', 'HP:0100743', (358, 371))	('ovarian cancer', 'Phenotype', 'HP:0100615', (227, 241))	('CRLX101', 'Chemical', 'MESH:C542292', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancers', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancer', 'Disease', (22, 28))	('breast', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('neoadjuvant rectal cancer', 'Disease', 'MESH:D012004', (346, 371))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (178, 198))	('colorectal', 'Disease', (76, 86))	('pancreatic cancers', 'Disease', 'MESH:D010190', (100, 118))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (217, 241))	('cancer', 'Disease', (235, 241))	('ovarian cancer', 'Disease', 'MESH:D010051', (227, 241))	('CRLX101', 'Gene', (0, 7))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))	('neoadjuvant rectal cancer', 'Disease', (346, 371))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
28736	27285755	CRLX101 has also been shown to inhibit HIF-1alpha preclinically.	('HIF-1alpha', 'Gene', '3091', (39, 49))	('CRLX101', 'Var', (0, 7))	('CRLX101', 'Chemical', 'MESH:C542292', (0, 7))	('HIF-1alpha', 'Gene', (39, 49))	('inhibit', 'NegReg', (31, 38))
28745	27285755	Although both fluorescent drugs were located inside the cell cytoplasm, stronger fluorescence was found in CRLX101-treated cells compared to CPT-treated cells (Figure 1E).	('CPT', 'Chemical', 'MESH:D002166', (141, 144))	('fluorescence', 'MPA', (81, 93))	('stronger', 'PosReg', (72, 80))	('CRLX101', 'Chemical', 'MESH:C542292', (107, 114))	('CRLX101-treated', 'Var', (107, 122))
28747	27285755	Treatment of U87 MG cells with 25~400 nM CRLX101 or CPT for 72 hours decreased cell numbers and caused cell shrinkage (Figure 2A, top and third rows).	('CPT', 'Gene', (52, 55))	('cell numbers', 'CPA', (79, 91))	('cell shrinkage', 'CPA', (103, 117))	('CPT', 'Chemical', 'MESH:D002166', (52, 55))	('CRLX101', 'Var', (41, 48))	('decreased', 'NegReg', (69, 78))	('U87 MG', 'CellLine', 'CVCL:0022', (13, 19))	('CRLX101', 'Chemical', 'MESH:C542292', (41, 48))
28748	27285755	CRLX101 only slightly inhibited the growth of normal HA-h astrocytes (Figure 2A, second row).	('CRLX101', 'Chemical', 'MESH:C542292', (0, 7))	('growth', 'CPA', (36, 42))	('inhibited', 'NegReg', (22, 31))	('CRLX101', 'Var', (0, 7))
28758	27285755	The percentage of total apoptosis significantly increased after U87 MG cells were treated with 50~400 nM CRLX101 and CPT for 72 hours (Figure 3C).	('increased', 'PosReg', (48, 57))	('CPT', 'Chemical', 'MESH:D002166', (117, 120))	('CRLX101', 'Chemical', 'MESH:C542292', (105, 112))	('50~400 nM CRLX101', 'Var', (95, 112))	('U87 MG', 'CellLine', 'CVCL:0022', (64, 70))	('CRLX101', 'Var', (105, 112))
28760	27285755	Exposure of U87 MG cells to 200 nM CRLX101 and CPT induced apoptosis from 36 to 72 hours (Figure 3D) without necrosis (data not shown).	('U87 MG', 'CellLine', 'CVCL:0022', (12, 18))	('CRLX101', 'Var', (35, 42))	('CPT', 'Gene', (47, 50))	('apoptosis', 'CPA', (59, 68))	('necrosis', 'Disease', (109, 117))	('CRLX101', 'Chemical', 'MESH:C542292', (35, 42))	('CPT', 'Chemical', 'MESH:D002166', (47, 50))	('necrosis', 'Disease', 'MESH:D009336', (109, 117))
28768	27285755	CRLX101 prolonged the survival rate of mice as assessed by a Kaplan-Meier survival curve and analyzed using a log-rank test (Figure 4C).	('CRLX101', 'Var', (0, 7))	('CRLX101', 'Chemical', 'MESH:C542292', (0, 7))	('prolonged', 'PosReg', (8, 17))	('survival rate', 'CPA', (22, 35))	('mice', 'Species', '10090', (39, 43))	('rat', 'Species', '10116', (31, 34))
28769	27285755	In addition, administration of CRLX101 or CPT decreased Topo-I expression in tumor sections (Figure 4D).	('CPT', 'Chemical', 'MESH:D002166', (42, 45))	('Topo-I', 'Protein', (56, 62))	('CRLX101', 'Var', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CRLX101', 'Chemical', 'MESH:C542292', (31, 38))	('rat', 'Species', '10116', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('decreased', 'NegReg', (46, 55))	('tumor', 'Disease', (77, 82))	('CPT', 'Gene', (42, 45))
28773	27285755	Exposure of U87 MG cells to 200 nM CRLX101 or CPT suppressed protein levels of VEGF in time-dependent manners (Figure 5D-5F).	('suppressed', 'NegReg', (50, 60))	('CPT', 'Gene', (46, 49))	('U87 MG', 'CellLine', 'CVCL:0022', (12, 18))	('CRLX101', 'Var', (35, 42))	('VEGF', 'Gene', '7422', (79, 83))	('protein levels', 'MPA', (61, 75))	('CPT', 'Chemical', 'MESH:D002166', (46, 49))	('CRLX101', 'Chemical', 'MESH:C542292', (35, 42))	('VEGF', 'Gene', (79, 83))
28775	27285755	Subsequently, VEGF expression in tumor region was suppressed by CRLX101 and CPT (Figure 6B).	('suppressed', 'NegReg', (50, 60))	('expression', 'MPA', (19, 29))	('CPT', 'Gene', (76, 79))	('CRLX101', 'Chemical', 'MESH:C542292', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('VEGF', 'Gene', '7422', (14, 18))	('CPT', 'Chemical', 'MESH:D002166', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('VEGF', 'Gene', (14, 18))	('CRLX101', 'Var', (64, 71))
28777	27285755	In addition, CRLX101 markedly reduced the protein level of VEGF compared to the vehicle and CPT groups (Figure 6D and 6E).	('CRLX101', 'Var', (13, 20))	('CRLX101', 'Chemical', 'MESH:C542292', (13, 20))	('VEGF', 'Gene', '7422', (59, 63))	('reduced', 'NegReg', (30, 37))	('CPT', 'Chemical', 'MESH:D002166', (92, 95))	('VEGF', 'Gene', (59, 63))
28778	27285755	A preclinical study showed better efficacy with CRLX101 than CPT-11 in inhibiting DNA Topo-I catalytic activities and prolonging the survival of lymphoma xenograft-bearing mice.	('inhibiting', 'NegReg', (71, 81))	('survival', 'CPA', (133, 141))	('DNA Topo-I catalytic activities', 'MPA', (82, 113))	('CPT-11', 'Chemical', 'MESH:D000077146', (61, 67))	('mice', 'Species', '10090', (172, 176))	('prolonging', 'PosReg', (118, 128))	('lymphoma', 'Disease', (145, 153))	('CRLX101', 'Var', (48, 55))	('CRLX101', 'Chemical', 'MESH:C542292', (48, 55))	('lymphoma', 'Disease', 'MESH:D008223', (145, 153))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))
28783	27285755	A study showed that, after administration of CRLX101, concentrations of released CPT in tumor tissues harvested from LS174T colorectal cancer xenograft mice were higher than in the other tissues, such as the liver, spleen, lungs, and heart.	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('rectal cancer', 'Phenotype', 'HP:0100743', (128, 141))	('CRLX101', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CPT', 'MPA', (81, 84))	('tumor', 'Disease', (88, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('LS174', 'CellLine', 'CVCL:1384', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('colorectal cancer', 'Disease', (124, 141))	('concentrations', 'MPA', (54, 68))	('CRLX101', 'Chemical', 'MESH:C542292', (45, 52))	('CPT', 'Chemical', 'MESH:D002166', (81, 84))	('rat', 'Species', '10116', (61, 64))	('mice', 'Species', '10090', (152, 156))	('rat', 'Species', '10116', (35, 38))	('higher', 'PosReg', (162, 168))	('LS174T', 'Var', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
28786	27285755	reported a longer mean elimination half-life for polymer-conjugated CPT than for CPT injection in multiple cancer models.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CPT', 'Chemical', 'MESH:D002166', (81, 84))	('longer', 'PosReg', (11, 17))	('CPT', 'Gene', (68, 71))	('polymer', 'Chemical', 'MESH:D011108', (49, 56))	('elimination half-life', 'MPA', (23, 44))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('polymer-conjugated', 'Var', (49, 67))	('CPT', 'Chemical', 'MESH:D002166', (68, 71))	('cancer', 'Disease', (107, 113))
28791	27285755	Therefore, CRLX101 should be explored further as a potential agent for brain cancer therapy.	('brain cancer', 'Disease', 'MESH:D001932', (71, 83))	('brain cancer', 'Phenotype', 'HP:0030692', (71, 83))	('CRLX101', 'Var', (11, 18))	('CRLX101', 'Chemical', 'MESH:C542292', (11, 18))	('brain cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
28794	27285755	Our results are consistent with previous studies, reporting lower in vitro potency of CRLX101 due to slow CPT release from CRLX101.	('CRLX101', 'Var', (123, 130))	('CRLX101', 'Chemical', 'MESH:C542292', (123, 130))	('slow CPT release', 'MPA', (101, 117))	('CRLX101', 'Chemical', 'MESH:C542292', (86, 93))	('CRLX101', 'Gene', (86, 93))	('CPT', 'Chemical', 'MESH:D002166', (106, 109))	('lower', 'NegReg', (60, 65))
28795	27285755	Importantly, CRLX101 had higher cytotoxicity in U87 MG cells than in normal HA-h astrocytes.	('U87', 'Var', (48, 51))	('CRLX101', 'Var', (13, 20))	('CRLX101', 'Chemical', 'MESH:C542292', (13, 20))	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('higher', 'PosReg', (25, 31))	('U87 MG', 'CellLine', 'CVCL:0022', (48, 54))	('cytotoxicity', 'Disease', (32, 44))
28800	27285755	CRLX101 suppressed the expression of Topo-I and increased apoptosis in tumor tissues compared to the vehicle or CPT groups.	('increased', 'PosReg', (48, 57))	('CRLX101', 'Var', (0, 7))	('CRLX101', 'Chemical', 'MESH:C542292', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Topo-I', 'Protein', (37, 43))	('apoptosis', 'CPA', (58, 67))	('CPT', 'Chemical', 'MESH:D002166', (112, 115))	('tumor', 'Disease', (71, 76))	('suppressed', 'NegReg', (8, 18))	('expression', 'MPA', (23, 33))
28811	27285755	Moreover, our in vivo results indicate that CRLX101 was more effective than CPT in inducing apoptosis and suppressing angiogenesis due to CRLX101's improved drug delivery profile and enhanced permeability and retention effect.	('CRLX101', 'Chemical', 'MESH:C542292', (44, 51))	('apoptosis', 'CPA', (92, 101))	('drug delivery profile', 'MPA', (157, 178))	('permeability', 'MPA', (192, 204))	('suppressing', 'NegReg', (106, 117))	('inducing', 'Reg', (83, 91))	('CPT', 'Chemical', 'MESH:D002166', (76, 79))	('improved', 'PosReg', (148, 156))	('CRLX101', 'Var', (138, 145))	('enhanced', 'PosReg', (183, 191))	('CRLX101', 'Chemical', 'MESH:C542292', (138, 145))	('retention', 'MPA', (209, 218))	('angiogenesis', 'CPA', (118, 130))
28813	27285755	Further improvement in efficacy may be possible by combining CRLX101 with antiangiogenic therapy.	('efficacy', 'MPA', (23, 31))	('CRLX101', 'Chemical', 'MESH:C542292', (61, 68))	('CRLX101', 'Var', (61, 68))
28816	27285755	In our in vivo brain tumor model, CRLX101 prolonged the survival rate of nude mice with intracranial gliomas by inducing apoptosis.	('brain tumor', 'Disease', (15, 26))	('brain tumor', 'Disease', 'MESH:D001932', (15, 26))	('intracranial gliomas', 'Disease', (88, 108))	('prolonged', 'PosReg', (42, 51))	('CRLX101', 'Var', (34, 41))	('brain tumor', 'Phenotype', 'HP:0030692', (15, 26))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('survival rate', 'CPA', (56, 69))	('CRLX101', 'Chemical', 'MESH:C542292', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('inducing', 'PosReg', (112, 120))	('intracranial gliomas', 'Disease', 'MESH:D005910', (88, 108))	('apoptosis', 'CPA', (121, 130))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('nude mice', 'Species', '10090', (73, 82))	('rat', 'Species', '10116', (65, 68))
28846	27285755	The cytogram of the four quadrants in the figure was used to distinguish normal (annexin V-/PI-), early apoptotic (annexin V+/PI-), late apoptotic (annexin V+/PI+), and necrotic cells (annexin V-/PI+).	('annexin', 'Var', (81, 88))	('necrotic', 'Disease', (169, 177))	('annexin V+/PI-', 'Var', (115, 129))	('annexin V+/PI+', 'Var', (148, 162))	('necrotic', 'Disease', 'MESH:D009336', (169, 177))
28922	26351148	Together these studies confirm aberrant HLA-G expression by low- and high-grade gliomas, but do not clarify whether HLA-G expression contributes to tumor growth by immune suppression or remodeling of the tumor micro-environment.	('HLA-G', 'Gene', '3135', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('aberrant', 'Var', (31, 39))	('tumor', 'Disease', (148, 153))	('HLA-G', 'Gene', (40, 45))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('expression', 'MPA', (46, 56))	('HLA-G', 'Gene', '3135', (40, 45))	('HLA-G', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
28930	26351148	In vitro experiments have demonstrated that tumor cells expressing CD1d may be especially susceptible to direct NKT cell lysis.	('direct NKT cell lysis', 'CPA', (105, 126))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('CD1d', 'Var', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('susceptible', 'Reg', (90, 101))	('tumor', 'Disease', (44, 49))
28944	26351148	CD4+ type II NKT cells were shown to produce higher levels of IL-13 and IL-4 compared to type I NKT cells, and NKT cell-dependent IL-13 was found to be necessary for tumor recurrence in a growth-regression-recurrence-pattern 15-12RM fibrosarcoma tumor model.	('IL-13', 'Gene', '3596', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('fibrosarcoma tumor', 'Disease', (233, 251))	('IL-4', 'Gene', '3565', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('IL-13', 'Gene', (130, 135))	('fibrosarcoma tumor', 'Disease', 'MESH:D005354', (233, 251))	('IL-13', 'Gene', (62, 67))	('CD4+', 'Var', (0, 4))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (166, 171))	('IL-13', 'Gene', '3596', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('higher', 'PosReg', (45, 51))	('IL-4', 'Gene', (72, 76))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (233, 245))	('levels', 'MPA', (52, 58))
28976	26351148	Antibody binding to Ag on the surface of live tumor cells can trigger a multitude of responses including neutralization of the target protein function, tumor clearance by phagocytosis and/or adaptive immunity, complement-dependent cytotoxicity, chemoattraction of other leukocytes, or antibody-dependent cell-mediated cytotoxicity.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cytotoxicity', 'Disease', (318, 330))	('cytotoxicity', 'Disease', 'MESH:D064420', (231, 243))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (152, 157))	('trigger', 'Reg', (62, 69))	('binding', 'Interaction', (9, 16))	('protein', 'Protein', (134, 141))	('adaptive immunity', 'CPA', (191, 208))	('Antibody', 'Var', (0, 8))	('chemoattraction', 'CPA', (245, 260))	('neutralization', 'MPA', (105, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (318, 330))	('cytotoxicity', 'Disease', (231, 243))
29024	26351148	For ACT therapies to be maximally effective, they should spare healthy tissues by targeting truly tumor-specific Ags that arise by mutations, ideally by mutations that drive the malignant phenotype.	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
29026	26351148	used whole exomic sequencing to show that TILs isolated from a patient with meta-static cholangiocarcinoma contained CD4+ Th1 cells specific for a mutated peptide derived from ERBB2IP (ERBB2IPE850G), an ERBB2IP-interacting protein mutated in that patient's cancer.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (88, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('patient', 'Species', '9606', (247, 254))	('ERBB2IP', 'Gene', (185, 192))	('cholangiocarcinoma', 'Disease', (88, 106))	('ERBB2IP', 'Gene', '55914', (185, 192))	('ERBB2IP', 'Gene', (203, 210))	('ERBB2IP', 'Gene', '55914', (203, 210))	('ERBB2IP', 'Gene', '55914', (176, 183))	('ERBB2IPE850G', 'Gene', (185, 197))	('ERBB2IPE850G', 'Gene', '55914;1956', (185, 197))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Disease', (257, 263))	('mutated', 'Var', (147, 154))	('ERBB2IP', 'Gene', (176, 183))	('cancer', 'Disease', 'MESH:D009369', (257, 263))
29033	26351148	reported that poorly immunogenic B16/F10 melanoma cells colonized the lungs of IL-17-deficient mice in significantly higher numbers than the lungs of wild-type controls, and that Th17 ACT triggered a strong tumor-specific CTL response in wild-type mice.	('F10 melanoma', 'Disease', (37, 49))	('IL-17', 'Gene', (79, 84))	('F10 melanoma', 'Disease', 'MESH:D005171', (37, 49))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('IL-17', 'Gene', '16171', (79, 84))	('mice', 'Species', '10090', (248, 252))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('higher', 'PosReg', (117, 123))	('Th17', 'Var', (179, 183))	('tumor', 'Disease', (207, 212))
29039	26351148	CD4+ ThCTLs comprise TILs in solid tumors such as melanoma and hepatocellular carcinoma (HCC).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (63, 87))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('CD4+', 'Var', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('HCC', 'Phenotype', 'HP:0001402', (89, 92))	('melanoma and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (50, 87))	('ThCTLs', 'Chemical', '-', (5, 11))	('solid tumors', 'Disease', (29, 41))
29060	26351148	Polyfunctionality is a point on a continuum between one Th subset and another.	('Polyfunctionality', 'Var', (0, 17))	('Th', 'Chemical', 'MESH:D013910', (56, 58))	('bet', 'Gene', '92737', (44, 47))	('bet', 'Gene', (44, 47))
29064	26351148	showed ThPOK gene silencing begins with upregulation of Runx3, a transcription factor that orchestrates expression of specific genes by CD8+ CTLs.	('silencing', 'NegReg', (18, 27))	('gene', 'Var', (13, 17))	('Runx3', 'Gene', (56, 61))	('CD8', 'Gene', (136, 139))	('Runx3', 'Gene', '864', (56, 61))	('upregulation', 'PosReg', (40, 52))	('ThPOK', 'Gene', (7, 12))	('CD8', 'Gene', '925', (136, 139))	('ThPOK', 'Gene', '51043', (7, 12))
29067	26351148	Further insights into the signals and transcription factors that drive differentiation of CD4+ Th into anti-tumor effector cells will no doubt lead to more effective in vitro culture conditions to drive functionally heterogeneous TILs into effector subsets, or will permit differentiation of PBMCs into long-lived T cells for CAR-based therapies.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CAR', 'Gene', (326, 329))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Th', 'Chemical', 'MESH:D013910', (95, 97))	('tumor', 'Disease', (108, 113))	('CAR', 'Gene', '653108', (326, 329))	('CD4+', 'Var', (90, 94))
29120	33953301	Incident primary intracranial glioma cases (ICD9 and 10 topography codes: 191 and C71, respectively) were comprised of WHO grade IV glioblastomas (GBM) (ICD-O-3 histology code: 9440-9441), and lower grade gliomas ('nonGBM')(ICD-O-3 histology codes: 9380, 9382, 9400-01, 9410-11, 9420, 9424-25, 9450-9451).	('intracranial glioma', 'Disease', (17, 36))	('C71', 'Var', (82, 85))	('glioblastomas', 'Disease', (132, 145))	('gliomas', 'Disease', (205, 212))	('gliomas', 'Phenotype', 'HP:0009733', (205, 212))	('gliomas', 'Disease', 'MESH:D005910', (205, 212))	('9400-01', 'Var', (261, 268))	('intracranial glioma', 'Disease', 'MESH:D005910', (17, 36))	('glioblastomas', 'Phenotype', 'HP:0012174', (132, 145))	('9424-25', 'Var', (285, 292))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('glioblastomas', 'Disease', 'MESH:D005909', (132, 145))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
29131	33953301	Polyomaviruses lead to strong and reproducible antibody responses to the major capsid protein VP1, a sensitive cumulative marker of past or present infection.	('past', 'Gene', '10938', (132, 136))	('past', 'Gene', (132, 136))	('Polyomaviruses', 'Var', (0, 14))	('infection', 'Disease', (148, 157))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('antibody responses', 'MPA', (47, 65))	('Polyomaviruses', 'Species', '36362', (0, 14))
29142	33953301	In Janus, associations of glioma with viral markers were considered overall, and according to glioma grade including WHO grade IV GBM (n = 196) and all lower glioma grades, combined (n = 127) including 56 astrocytomas (ICD-O-3: 9400-01, 9410-11, 9420, 9424-25), 27 oligodendrogliomas (9450 and 9451), 24 astrocytic tumors (9380) and 20 mixed gliomas (9382).	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('gliomas', 'Disease', 'MESH:D005910', (276, 283))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('gliomas', 'Phenotype', 'HP:0009733', (342, 349))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('astrocytomas', 'Disease', (205, 217))	('oligodendrogliomas', 'Disease', (265, 283))	('9424-25', 'Var', (252, 259))	('gliomas', 'Phenotype', 'HP:0009733', (276, 283))	('glioma', 'Disease', (342, 348))	('glioma', 'Disease', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Disease', 'MESH:D005910', (342, 348))	('9410-11', 'Var', (237, 244))	('glioma', 'Disease', (158, 164))	('gliomas', 'Disease', (342, 349))	('astrocytomas', 'Disease', 'MESH:D001254', (205, 217))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('9450', 'Var', (285, 289))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', (276, 282))	('gliomas', 'Disease', (276, 283))	('astrocytic tumors', 'Disease', (304, 321))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('astrocytic tumors', 'Disease', 'MESH:D001254', (304, 321))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (265, 283))	('gliomas', 'Disease', 'MESH:D005910', (342, 349))	('glioma', 'Disease', 'MESH:D005910', (276, 282))
29145	33953301	For JCV, tertile boundaries were 253-598, 601-1352, and 1365-14,967 for tertiles 1, 2, and 3, respectively; these figures were 251-1095, 1111-3695, and 3703-18,864, respectively, for BKV; 255-3052, 3069-5769, and 5774-18,637, respectively, for HPyV6; and 251-2837, 2846-6327, and 6346-17,802, respectively, for MCPyV.	('HPyV6', 'Species', '746830', (244, 249))	('MCPyV', 'Species', '493803', (311, 316))	('255-3052', 'Var', (188, 196))	('253-598', 'Var', (33, 40))	('BKV', 'Species', '1891762', (183, 186))	('251-2837', 'Var', (255, 263))	('251-1095', 'Var', (127, 135))
29172	33953301	For example, a positive association for MCPyV seroprevalence was demonstrated for the period from 1972 to 1981 (OR: 1.74; 95% CI 0.99, 3.05; p = 0.055) and for the period from 1982 to 1991 (OR: 1.46; 95% CI 0.95, 2.24; p = 0.086), though neither result was statistically significant in stratified analyses.	('seroprevalence', 'Var', (46, 60))	('MCPyV', 'Gene', (40, 45))	('MCPyV', 'Species', '493803', (40, 45))
29189	33953301	Whereas studies to date have not demonstrated MCPyV viral protein expression in human glial tumors, MCPyV may contribute to glioma via a range of mechanisms such as neuroinflammation, insertional mutagenesis, or effects on gene expression that would not leave traces of viral integration in the tumor genome.	('glioma', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('glial tumors', 'Disease', 'MESH:D005910', (86, 98))	('insertional mutagenesis', 'Var', (184, 207))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('human', 'Species', '9606', (80, 85))	('MCPyV', 'Species', '493803', (100, 105))	('glial tumors', 'Disease', (86, 98))	('tumor', 'Disease', (295, 300))	('neuroinflammation', 'Disease', (165, 182))	('effects', 'Reg', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('MCPyV', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (92, 97))	('MCPyV', 'Species', '493803', (46, 51))	('contribute', 'Reg', (110, 120))
29210	33953301	Finally, we did not consider antibodies to the viral T-antigens in MCPyV which are the key oncogenic drivers for MCC; demonstation of a more prominent association of the T-antigen in MCPyV with glioma risk, as has been demonstrated in MCC, would strengthen the case for a causal association.	('MCPyV', 'Species', '493803', (183, 188))	('MCPyV', 'Species', '493803', (67, 72))	('glioma', 'Disease', (194, 200))	('association', 'Interaction', (151, 162))	('T-antigen', 'Var', (170, 179))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('MCPyV', 'Gene', (183, 188))
29220	32168910	While TP53 deletion is rare in glioblastomas, these tumors often carry TP53 mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', '7157', (6, 10))	('mutations', 'Var', (76, 85))	('TP53', 'Gene', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('carry', 'Reg', (65, 70))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('glioblastomas', 'Phenotype', 'HP:0012174', (31, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('glioblastomas', 'Disease', 'MESH:D005909', (31, 44))	('deletion', 'Var', (11, 19))	('TP53', 'Gene', (71, 75))	('glioblastomas', 'Disease', (31, 44))
29221	32168910	Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53wt stabilization and senescence.	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('senescence', 'CPA', (118, 128))	('inhibition', 'Var', (23, 33))	('attenuated glioblastoma', 'Disease', (43, 66))	('MK2', 'Gene', '9261', (19, 22))	('MK2', 'Gene', (19, 22))	('attenuated glioblastoma', 'Disease', 'MESH:C538265', (43, 66))
29223	32168910	However, MK2 inhibition also increased the stability of p53 mutants and enhanced the proliferation of p53-mutant stem cells.	('p53', 'Gene', (56, 59))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', '7157', (56, 59))	('increased', 'PosReg', (29, 38))	('enhanced', 'PosReg', (72, 80))	('mutants', 'Var', (60, 67))	('inhibition', 'NegReg', (13, 23))	('MK2', 'Gene', (9, 12))	('p53', 'Gene', (102, 105))	('MK2', 'Gene', '9261', (9, 12))	('stability', 'MPA', (43, 52))	('proliferation', 'CPA', (85, 98))
29224	32168910	These observations reveal that in response to DNA damaging chemotherapy, targeting MK2 in p53-mutated cells produces a phenotype that is distinct from the p53-deficient phenotype.	('p53', 'Gene', (90, 93))	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('p53', 'Gene', '7157', (90, 93))	('MK2', 'Gene', '9261', (83, 86))	('MK2', 'Gene', (83, 86))	('targeting', 'Var', (73, 82))
29226	32168910	However, targeting MK2 in tumors with TP53 mutations may accelerate disease progression.	('TP53', 'Gene', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (43, 52))	('disease progression', 'CPA', (68, 87))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MK2', 'Gene', '9261', (19, 22))	('MK2', 'Gene', (19, 22))	('accelerate', 'PosReg', (57, 67))	('tumors', 'Disease', (26, 32))	('TP53', 'Gene', '7157', (38, 42))
29227	32168910	These findings are highly relevant since TP53 mutations occur in over 50% of all cancers.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('occur', 'Reg', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
29229	32168910	Pro-tumorigenic MK2 functions include the deregulation of apoptosis in skin tumors, enhanced metastasis of breast tumors and polarization of macrophages into their M2 state that promotes angiogenesis in colorectal cancer.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('skin tumors', 'Disease', 'MESH:D012878', (71, 82))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('skin tumors', 'Phenotype', 'HP:0008069', (71, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('promotes', 'PosReg', (178, 186))	('tumor', 'Disease', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('MK2', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('metastasis', 'CPA', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('apoptosis', 'CPA', (58, 67))	('enhanced', 'PosReg', (84, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('breast tumors', 'Disease', 'MESH:D001943', (107, 120))	('angiogenesis', 'CPA', (187, 199))	('breast tumors', 'Disease', (107, 120))	('deregulation', 'Var', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('skin tumors', 'Disease', (71, 82))	('colorectal cancer', 'Disease', (203, 220))	('MK2', 'Gene', '9261', (16, 19))	('breast tumors', 'Phenotype', 'HP:0100013', (107, 120))
29235	32168910	We have shown that active MK2 is expressed in clinical glioblastoma specimens and that p38 -MK2 regulates inflammation in the presence of the EGFRvIII and HRasG12V mutants.	('HRasG12V mutants', 'Var', (155, 171))	('p38', 'Gene', (87, 90))	('MK2', 'Gene', '9261', (26, 29))	('clinical', 'Species', '191496', (46, 54))	('glioblastoma', 'Disease', (55, 67))	('MK2', 'Gene', (92, 95))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('p38', 'Gene', '1432', (87, 90))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('regulates', 'Reg', (96, 105))	('MK2', 'Gene', (26, 29))	('MK2', 'Gene', '9261', (92, 95))	('inflammation', 'Disease', (106, 118))	('mutants', 'Var', (164, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))
29236	32168910	In glioma xenografts, anti-tumour activity of p38 MAPK inhibitor LY2228820 was linked to the reduction of inflammatory tumour microenvironment.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('reduction', 'NegReg', (93, 102))	('inflammatory tumour', 'Disease', 'MESH:D009369', (106, 125))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('LY2228820', 'Chemical', 'MESH:C580958', (65, 74))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('p38', 'Gene', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('LY2228820', 'Var', (65, 74))	('tumour', 'Disease', (27, 33))	('tumour', 'Disease', (119, 125))	('glioma', 'Disease', (3, 9))	('MAPK', 'Gene', (50, 54))	('MAPK', 'Gene', '1432', (50, 54))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('inflammatory tumour', 'Disease', (106, 125))	('p38', 'Gene', '1432', (46, 49))
29243	32168910	These studies also suggested that MK2 inhibition could be synthetically lethal to tumors with mutated p53; however, this remains unsubstantiated.	('mutated', 'Var', (94, 101))	('MK2', 'Gene', (34, 37))	('MK2', 'Gene', '9261', (34, 37))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('p53', 'Gene', '7157', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'NegReg', (38, 48))	('p53', 'Gene', (102, 105))
29244	32168910	While TP53 deletion is rare in gliomas (<1%), p53 mutations occur in 48-91% of lower-grade gliomas and ~30% of glioblastomas.	('glioblastomas', 'Disease', (111, 124))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('mutations', 'Var', (50, 59))	('gliomas', 'Disease', (91, 98))	('p53', 'Gene', (46, 49))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('p53', 'Gene', '7157', (46, 49))	('glioblastomas', 'Phenotype', 'HP:0012174', (111, 124))	('glioblastomas', 'Disease', 'MESH:D005909', (111, 124))	('occur', 'Reg', (60, 65))	('gliomas', 'Disease', 'MESH:D005910', (31, 38))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))	('gliomas', 'Disease', (31, 38))
29245	32168910	To investigate whether MK2 inhibition is synthetically lethal to p53 mutations, we sought to delineate the MK2 signaling in p53wt and p53-mutated glioblastoma cells.	('mutations', 'Var', (69, 78))	('p53', 'Gene', (65, 68))	('p53', 'Gene', (124, 127))	('p53', 'Gene', '7157', (134, 137))	('p53', 'Gene', '7157', (65, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('MK2', 'Gene', '9261', (107, 110))	('MK2', 'Gene', (107, 110))	('p53', 'Gene', '7157', (124, 127))	('MK2', 'Gene', (23, 26))	('glioblastoma', 'Disease', (146, 158))	('p53', 'Gene', (134, 137))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('MK2', 'Gene', '9261', (23, 26))
29250	32168910	Furthermore, patients with high MK2 mRNA expression (top 25%) exhibited shorter disease-free (Figure 1B,C) and overall (Figure 1D,E) survival.	('shorter', 'NegReg', (72, 79))	('patients', 'Species', '9606', (13, 21))	('mRNA expression', 'Var', (36, 51))	('high', 'Var', (27, 31))	('MK2', 'Gene', '9261', (32, 35))	('MK2', 'Gene', (32, 35))	('overall', 'CPA', (111, 118))
29261	32168910	Although patients with high MK2 mRNA levels had shorter survival times (Figure 1B-E), the MK2 protein did not correlate with the patient survival (p = 0.081, log-rank test).	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (23, 27))	('MK2', 'Gene', '9261', (28, 31))	('MK2', 'Gene', (28, 31))	('survival times', 'CPA', (56, 70))	('MK2', 'Gene', (90, 93))	('MK2', 'Gene', '9261', (90, 93))	('shorter', 'NegReg', (48, 55))	('patient', 'Species', '9606', (9, 16))	('patient', 'Species', '9606', (129, 136))
29262	32168910	However, patients with high expression of p-MK2 had the worst survival (p = 0.027, log-rank test, Figure 1H).	('patients', 'Species', '9606', (9, 17))	('high expression', 'Var', (23, 38))	('worst', 'NegReg', (56, 61))	('MK2', 'Gene', '9261', (44, 47))	('MK2', 'Gene', (44, 47))
29264	32168910	To investigate the role of MK2 in glioblastoma cell proliferation and in response to temozolomide, we first confirmed that temozolomide activates MK2 (p-MK2, Figure 2A) and MK2 down-stream target Hsp27 (p-Hsp27, Figure 2B).	('MK2', 'Gene', (27, 30))	('Hsp27', 'Gene', '3315', (196, 201))	('MK2', 'Gene', '9261', (173, 176))	('MK2', 'Gene', (146, 149))	('Hsp27', 'Gene', (205, 210))	('temozolomide', 'Var', (123, 135))	('Hsp27', 'Gene', (196, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('MK2', 'Gene', (153, 156))	('MK2', 'Gene', '9261', (27, 30))	('MK2', 'Gene', (173, 176))	('glioblastoma', 'Disease', (34, 46))	('MK2', 'Gene', '9261', (146, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('temozolomide', 'Chemical', 'MESH:D000077204', (123, 135))	('down-stream', 'NegReg', (177, 188))	('temozolomide', 'Chemical', 'MESH:D000077204', (85, 97))	('activates', 'PosReg', (136, 145))	('MK2', 'Gene', '9261', (153, 156))	('Hsp27', 'Gene', '3315', (205, 210))
29267	32168910	We found that MK2 knockdown in p53wt A172 cells significantly reduced clonogenic survival in the absence or presence of temozolomide (Figure 2D).	('knockdown', 'Var', (18, 27))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('temozolomide', 'Chemical', 'MESH:D000077204', (120, 132))	('MK2', 'Gene', '9261', (14, 17))	('MK2', 'Gene', (14, 17))	('clonogenic survival', 'CPA', (70, 89))	('reduced', 'NegReg', (62, 69))
29268	32168910	In contrast, MK2 knockdown in the p53R273H U251 cells did not affect the clonogenic survival and did not improve efficacy of temozolomide (Figure 2E).	('MK2', 'Gene', (13, 16))	('p53R273H', 'Mutation', 'p.R53,273H', (34, 42))	('efficacy', 'MPA', (113, 121))	('clonogenic survival', 'CPA', (73, 92))	('p53R273H', 'Var', (34, 42))	('temozolomide', 'Chemical', 'MESH:D000077204', (125, 137))	('knockdown', 'Var', (17, 26))	('U251', 'CellLine', 'CVCL:0021', (43, 47))	('MK2', 'Gene', '9261', (13, 16))
29270	32168910	To recapitulate the effectiveness of MK2 inhibition in A172 cells, we employed an ATP-competitive MK2 inhibitor PF-3644022 and an allosteric MK2 inhibitor IV (MK2i).	('MK2', 'Gene', '9261', (159, 162))	('MK2', 'Gene', (159, 162))	('ATP', 'Chemical', 'MESH:D000255', (82, 85))	('MK2', 'Gene', '9261', (141, 144))	('MK2', 'Gene', (141, 144))	('MK2i', 'Chemical', '-', (159, 163))	('PF-3644022', 'Chemical', 'MESH:C549914', (112, 122))	('MK2', 'Gene', '9261', (37, 40))	('MK2', 'Gene', (37, 40))	('PF-3644022', 'Var', (112, 122))	('MK2', 'Gene', '9261', (98, 101))	('MK2', 'Gene', (98, 101))
29272	32168910	As single agents, only MK2i significantly decreased the clonogenic survival of p53wt A172 cells (Figure 2G).	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('decreased', 'NegReg', (42, 51))	('clonogenic survival', 'CPA', (56, 75))	('MK2i', 'Var', (23, 27))	('MK2i', 'Chemical', '-', (23, 27))
29274	32168910	Conversely, both MK2 inhibitors failed to exhibit any effect on the clonogenic survival and temozolomide efficacy in p53R273H U251 cells (Figure 2H).	('temozolomide', 'Chemical', 'MESH:D000077204', (92, 104))	('clonogenic survival', 'CPA', (68, 87))	('MK2', 'Gene', '9261', (17, 20))	('MK2', 'Gene', (17, 20))	('U251', 'CellLine', 'CVCL:0021', (126, 130))	('temozolomide efficacy', 'MPA', (92, 113))	('p53R273H', 'Mutation', 'p.R53,273H', (117, 125))	('p53R273H', 'Var', (117, 125))
29275	32168910	To further validate that MK2 inhibition attenuates the proliferation of p53wt cells, we employed CRISPR/Cas9 gene editing technology to knock out MK2 in cells (Supplementary Figure S2A).	('inhibition attenuates', 'NegReg', (29, 50))	('MK2', 'Gene', '9261', (25, 28))	('MK2', 'Gene', (25, 28))	('proliferation', 'CPA', (55, 68))	('p53', 'Gene', (72, 75))	('knock', 'Var', (136, 141))	('p53', 'Gene', '7157', (72, 75))	('MK2', 'Gene', '9261', (146, 149))	('MK2', 'Gene', (146, 149))
29276	32168910	Two p53R273H U251 clones (A and B) were completely lacking MK2 (MK2null) and showed a reduction of Hsp27 phosphorylation (Figure 2I).	('reduction', 'NegReg', (86, 95))	('phosphorylation', 'MPA', (105, 120))	('p53R273H', 'Mutation', 'p.R53,273H', (4, 12))	('MK2', 'Gene', '9261', (59, 62))	('p53R273H', 'Var', (4, 12))	('MK2', 'Gene', (59, 62))	('lacking', 'NegReg', (51, 58))	('Hsp27', 'Gene', (99, 104))	('Hsp27', 'Gene', '3315', (99, 104))	('U251', 'Gene', (13, 17))	('MK2', 'Gene', '9261', (64, 67))	('MK2', 'Gene', (64, 67))	('U251', 'CellLine', 'CVCL:0021', (13, 17))
29280	32168910	As expected, the loss of MK2 failed to affect the growth of the p53R273H U251 spheroids (Figure 2M).	('p53R273H', 'Var', (64, 72))	('MK2', 'Gene', (25, 28))	('MK2', 'Gene', '9261', (25, 28))	('U251', 'CellLine', 'CVCL:0021', (73, 77))	('U251', 'Gene', (73, 77))	('loss', 'Var', (17, 21))	('p53R273H', 'Mutation', 'p.R53,273H', (64, 72))
29284	32168910	Surprisingly, temozolomide-treated p53wt A172 cells showed robust gamma-H2AX foci confirming DNA damage; however, this was decreased by silencing MK2 (Supplementary Figure S3A,B).	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('decreased', 'NegReg', (123, 132))	('temozolomide', 'Chemical', 'MESH:D000077204', (14, 26))	('MK2', 'Gene', '9261', (146, 149))	('MK2', 'Gene', (146, 149))	('silencing', 'Var', (136, 145))
29285	32168910	Similarly, MK2 depletion failed to promote mitotic arrest (Supplementary Figure S3C), another feature associated with the accumulation of DNA damage.	('depletion', 'Var', (15, 24))	('MK2', 'Gene', '9261', (11, 14))	('MK2', 'Gene', (11, 14))	('mitotic arrest', 'Disease', (43, 57))	('mitotic arrest', 'Disease', 'MESH:D006323', (43, 57))
29288	32168910	Cell cycle analysis revealed that MK2 knockdown or inhibition significantly increased the percentage of p53wt A172 cells in the G0/G1 phases (Figure 3A,B).	('inhibition', 'NegReg', (51, 61))	('p53', 'Gene', (104, 107))	('MK2', 'Gene', (34, 37))	('MK2', 'Gene', '9261', (34, 37))	('increased', 'PosReg', (76, 85))	('p53', 'Gene', '7157', (104, 107))	('G0/G1 phases', 'CPA', (128, 140))	('knockdown', 'Var', (38, 47))
29290	32168910	However, MK2-depleted p53R273H U251 cells exhibited cell cycles that were identical to the scramble-transfected cells (Figure 3C).	('p53R273H U251', 'Var', (22, 35))	('exhibited', 'Reg', (42, 51))	('U251', 'CellLine', 'CVCL:0021', (31, 35))	('MK2', 'Gene', '9261', (9, 12))	('MK2', 'Gene', (9, 12))	('cell cycles', 'CPA', (52, 63))	('p53R273H', 'Mutation', 'p.R53,273H', (22, 30))
29291	32168910	While MK2 inhibition alone did not result in apoptosis in p53wt A172 cells; MK2 inhibition increased temozolomide-induced apoptosis (Figure 3D,E).	('MK2', 'Gene', '9261', (6, 9))	('MK2', 'Gene', (6, 9))	('MK2', 'Gene', '9261', (76, 79))	('MK2', 'Gene', (76, 79))	('temozolomide-induced apoptosis', 'MPA', (101, 131))	('temozolomide', 'Chemical', 'MESH:D000077204', (101, 113))	('increased', 'PosReg', (91, 100))	('p53', 'Gene', (58, 61))	('inhibition', 'Var', (80, 90))	('p53', 'Gene', '7157', (58, 61))
29295	32168910	However, we could not detect senescent cells in p53R273H MK2null U251 clones (Supplementary Figure S3D).	('U251', 'CellLine', 'CVCL:0021', (65, 69))	('p53R273H', 'Mutation', 'p.R53,273H', (48, 56))	('p53R273H', 'Var', (48, 56))	('U251', 'Gene', (65, 69))	('MK2', 'Gene', '9261', (57, 60))	('MK2', 'Gene', (57, 60))
29296	32168910	Given the synthetic lethality between MK2 and p53 deletion in non-small-cell lung cancer models, we queried whether the lack of response of p53R273H glioblastoma cells is due to the different histological cancer type (lung vs. brain) or different p53 status (mutation vs. deletion).	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('p53R273H', 'Mutation', 'p.R53,273H', (140, 148))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (62, 88))	('cancer', 'Disease', (82, 88))	('lung cancer', 'Disease', (77, 88))	('p53', 'Gene', (247, 250))	('glioblastoma', 'Disease', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MK2', 'Gene', '9261', (38, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', (46, 49))	('cancer', 'Disease', (205, 211))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('p53', 'Gene', '7157', (140, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('deletion', 'Var', (50, 58))	('MK2', 'Gene', (38, 41))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (247, 250))
29298	32168910	In line with its tumor-suppressive role, p53 deletion increased the clonogenicity of parental U87 cells but weakly improved the efficacy of temozolomide (Figure 3J, brown bars).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('p53', 'Gene', '7157', (41, 44))	('tumor', 'Disease', (17, 22))	('U87', 'Gene', '641648', (94, 97))	('temozolomide', 'Chemical', 'MESH:D000077204', (140, 152))	('clonogenicity', 'CPA', (68, 81))	('increased', 'PosReg', (54, 63))	('improved', 'PosReg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('efficacy', 'MPA', (128, 136))	('deletion', 'Var', (45, 53))	('U87', 'Gene', (94, 97))	('p53', 'Gene', (41, 44))
29301	32168910	Importantly, knockdown of p53wt in MK2null clones rendered U87 glioblastoma cells significantly more sensitive to temozolomide (Figure 3K, brown bars).	('U87', 'Gene', '641648', (59, 62))	('MK2', 'Gene', (35, 38))	('MK2', 'Gene', '9261', (35, 38))	('glioblastoma', 'Disease', (63, 75))	('more', 'PosReg', (96, 100))	('p53', 'Gene', (26, 29))	('temozolomide', 'Chemical', 'MESH:D000077204', (114, 126))	('p53', 'Gene', '7157', (26, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('U87', 'Gene', (59, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('sensitive to temozolomide', 'MPA', (101, 126))	('knockdown', 'Var', (13, 22))
29302	32168910	To probe the mechanism of differential chemosensitivity, i.e., MK2 deficiency induces senescence (Figure 3G-I), MK2 + p53 co-deficiency is reported to induce apoptosis , we monitored the extent of apoptosis by measuring cleaved PARP (c-PARP).	('PARP', 'Gene', (236, 240))	('PARP', 'Gene', (228, 232))	('PARP', 'Gene', '1302', (236, 240))	('induces', 'Reg', (78, 85))	('MK2', 'Gene', (63, 66))	('MK2', 'Gene', '9261', (63, 66))	('p53', 'Gene', (118, 121))	('co-deficiency', 'Disease', (122, 135))	('senescence', 'MPA', (86, 96))	('p53', 'Gene', '7157', (118, 121))	('PARP', 'Gene', '1302', (228, 232))	('deficiency', 'Var', (67, 77))	('co-deficiency', 'Disease', 'MESH:D060085', (122, 135))	('MK2', 'Gene', '9261', (112, 115))	('MK2', 'Gene', (112, 115))
29304	32168910	These glioblastoma data confirm synthetic lethality (i.e., apoptosis) between MK2 and p53 deletion, but also implicate that p53 mutation and p53 deletion evoke different cellular responses to MK2 inhibition.	('deletion', 'Var', (90, 98))	('glioblastoma', 'Disease', (6, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (6, 18))	('MK2', 'Gene', '9261', (78, 81))	('MK2', 'Gene', (192, 195))	('p53', 'Gene', '7157', (141, 144))	('p53', 'Gene', '7157', (86, 89))	('evoke', 'Reg', (154, 159))	('apoptosis', 'CPA', (59, 68))	('mutation', 'Var', (128, 136))	('p53', 'Gene', (86, 89))	('p53', 'Gene', (141, 144))	('cellular', 'CPA', (170, 178))	('p53', 'Gene', '7157', (124, 127))	('MK2', 'Gene', (78, 81))	('MK2', 'Gene', '9261', (192, 195))	('p53', 'Gene', (124, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (6, 18))	('deletion', 'Var', (145, 153))
29306	32168910	Inhibition of MK2 reduced HDM2 phosphorylation, which was accompanied with increased expression of both wild-type and mutated p53 (Figure 4A-D).	('HDM2', 'Gene', (26, 30))	('expression', 'MPA', (85, 95))	('p53', 'Gene', '7157', (126, 129))	('HDM2', 'Gene', '4193', (26, 30))	('MK2', 'Gene', '9261', (14, 17))	('MK2', 'Gene', (14, 17))	('mutated', 'Var', (118, 125))	('reduced', 'NegReg', (18, 25))	('increased', 'PosReg', (75, 84))	('p53', 'Gene', (126, 129))
29307	32168910	Furthermore, loss of MK2 increased the stability of both p53wt and p53R273H when compared to parental cells expressing MK2 (Figure 4E).	('MK2', 'Gene', (119, 122))	('MK2', 'Gene', '9261', (21, 24))	('MK2', 'Gene', (21, 24))	('increased', 'PosReg', (25, 34))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('p53', 'Gene', (57, 60))	('stability', 'MPA', (39, 48))	('MK2', 'Gene', '9261', (119, 122))	('loss', 'Var', (13, 17))	('p53', 'Gene', '7157', (57, 60))	('p53R273H', 'Mutation', 'p.R53,273H', (67, 75))
29315	32168910	Except for BAX, loss of MK2 increased transcription of p53 target genes with or without temozolomide treatment (Figure 5A-D).	('increased', 'PosReg', (28, 37))	('p53', 'Gene', (55, 58))	('MK2', 'Gene', (24, 27))	('p53', 'Gene', '7157', (55, 58))	('BAX', 'Gene', (11, 14))	('transcription', 'MPA', (38, 51))	('BAX', 'Gene', '581', (11, 14))	('MK2', 'Gene', '9261', (24, 27))	('loss', 'Var', (16, 20))	('temozolomide', 'Chemical', 'MESH:D000077204', (88, 100))
29316	32168910	In line with increased mRNA expression, MK2 knockout in p53wt cells resulted in increased levels of p21 (coded by CDKN1A), PUMA (coded by BBC3) and NOXA (coded by PMAIP1), while BAX levels remained unchanged (Figure 5E).	('p21', 'Gene', '1026', (100, 103))	('knockout', 'Var', (44, 52))	('NOXA', 'Gene', (148, 152))	('BBC3', 'Gene', '27113', (138, 142))	('CDKN1A', 'Gene', (114, 120))	('CDKN1A', 'Gene', '1026', (114, 120))	('p53', 'Gene', '7157', (56, 59))	('MK2', 'Gene', (40, 43))	('PUMA', 'Gene', '27113', (123, 127))	('p21', 'Gene', (100, 103))	('BBC3', 'Gene', (138, 142))	('p53', 'Gene', (56, 59))	('PMAIP1', 'Gene', (163, 169))	('levels', 'MPA', (90, 96))	('BAX', 'Gene', '581', (178, 181))	('BAX', 'Gene', (178, 181))	('increased', 'PosReg', (80, 89))	('mRNA expression', 'MPA', (23, 38))	('PMAIP1', 'Gene', '5366', (163, 169))	('PUMA', 'Gene', (123, 127))	('NOXA', 'Gene', '5366', (148, 152))	('MK2', 'Gene', '9261', (40, 43))
29318	32168910	To ascertain that MK2 inhibition attenuates cell proliferation via p53wt signaling, we depleted p53wt in parental and MK2null U87 cells.	('inhibition', 'Var', (22, 32))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('cell proliferation', 'CPA', (44, 62))	('MK2', 'Gene', '9261', (18, 21))	('MK2', 'Gene', (18, 21))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('attenuates', 'NegReg', (33, 43))	('MK2', 'Gene', (118, 121))	('MK2', 'Gene', '9261', (118, 121))	('U87', 'Gene', (126, 129))	('U87', 'Gene', '641648', (126, 129))
29320	32168910	Furthermore, the decreased proliferation in MK2null U87 clones was also lost upon the deletion of p53wt (Figure 5G), in line with increased clonogenic survival of p53-depleted MK2null cells (Figure 3K).	('U87', 'Gene', (52, 55))	('decreased', 'NegReg', (17, 26))	('p53', 'Gene', (163, 166))	('proliferation', 'CPA', (27, 40))	('p53', 'Gene', '7157', (163, 166))	('U87', 'Gene', '641648', (52, 55))	('MK2', 'Gene', '9261', (176, 179))	('MK2', 'Gene', (176, 179))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (98, 101))	('lost', 'NegReg', (72, 76))	('MK2', 'Gene', '9261', (44, 47))	('MK2', 'Gene', (44, 47))	('deletion', 'Var', (86, 94))
29322	32168910	This is supported by the analysis of p53R273H MK2null U251 clones, which revealed that the increased p53R273H expression in the nucleus (Figure 5H) was not accompanied by increased p21 levels (Figure 5I) or senescence (Supplementary Figure S3D).	('p53R273H', 'Mutation', 'p.R53,273H', (37, 45))	('p21', 'Gene', (181, 184))	('MK2', 'Gene', '9261', (46, 49))	('MK2', 'Gene', (46, 49))	('U251', 'CellLine', 'CVCL:0021', (54, 58))	('p53R273H', 'Mutation', 'p.R53,273H', (101, 109))	('p21', 'Gene', '1026', (181, 184))	('p53R273H', 'Var', (101, 109))
29323	32168910	The data derived from A172, U87 and U251 cells demonstrate that MK2 inhibition stabilizes both wild-type and mutated p53 (Figure 4).	('U87', 'Gene', '641648', (28, 31))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('stabilizes', 'PosReg', (79, 89))	('mutated', 'Var', (109, 116))	('U251', 'CellLine', 'CVCL:0021', (36, 40))	('inhibition', 'NegReg', (68, 78))	('MK2', 'Gene', '9261', (64, 67))	('MK2', 'Gene', (64, 67))	('U87', 'Gene', (28, 31))
29325	32168910	However, the stabilization of p53 mutants (Figure 4E) is necessary for their oncogenic activities.	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (30, 33))	('mutants', 'Var', (34, 41))
29328	32168910	RN1, HW1 and RKI1 cells harbor an intact TP53 gene; however, they carry a homozygous CDKN2A deletion, thereby not expressing the p14/ARF protein, which promotes HDM2 degradation and p53 stability.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('p14', 'Gene', '1029', (129, 132))	('HDM2', 'Gene', '4193', (161, 165))	('HDM2', 'Gene', (161, 165))	('degradation', 'MPA', (166, 177))	('deletion', 'Var', (92, 100))	('p53', 'Gene', '7157', (182, 185))	('CDKN2A', 'Gene', (85, 91))	('ARF', 'Disease', 'MESH:D058186', (133, 136))	('stability', 'MPA', (186, 195))	('CDKN2A', 'Gene', '1029', (85, 91))	('ARF', 'Disease', (133, 136))	('HW1', 'CellLine', 'CVCL:F560', (5, 8))	('promotes', 'PosReg', (152, 160))	('p53', 'Gene', (182, 185))	('p14', 'Gene', (129, 132))
29330	32168910	Inhibition of MK2 in p53wt RN1 and HW1 cells induced a minor increase in the p53 expression in the absence of temozolomide, but increased p53wt expression in temozolomide-treated cells (Figure 6A-C).	('p53', 'Gene', (138, 141))	('MK2', 'Gene', '9261', (14, 17))	('MK2', 'Gene', (14, 17))	('HW1', 'CellLine', 'CVCL:F560', (35, 38))	('temozolomide', 'Chemical', 'MESH:D000077204', (158, 170))	('increased', 'PosReg', (128, 137))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', '7157', (138, 141))	('temozolomide', 'Chemical', 'MESH:D000077204', (110, 122))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('Inhibition', 'Var', (0, 10))	('increase', 'PosReg', (61, 69))	('p53', 'Gene', (21, 24))
29331	32168910	In functional assays, MK2 inhibitors reduced clonogenic survival and induced senescence in p53wt cells, with the most prominent effect observed in temozolomide co-treated cells (Figure 6D-G).	('temozolomide', 'Chemical', 'MESH:D000077204', (147, 159))	('senescence', 'MPA', (77, 87))	('inhibitors', 'Var', (26, 36))	('clonogenic survival', 'CPA', (45, 64))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('MK2', 'Gene', '9261', (22, 25))	('MK2', 'Gene', (22, 25))	('reduced', 'NegReg', (37, 44))	('induced', 'Reg', (69, 76))
29334	32168910	Taken together, MK2 inhibitors reduced the clonogenic growth of glioblastoma cells harboring the intact TP53 gene.	('glioblastoma', 'Disease', (64, 76))	('reduced', 'NegReg', (31, 38))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('inhibitors', 'Var', (20, 30))	('MK2', 'Gene', '9261', (16, 19))	('MK2', 'Gene', (16, 19))	('gene', 'Var', (109, 113))
29343	32168910	Importantly, we provide evidence suggesting that the MK2-dependent degradation of p53 appears to be a general regulatory mechanism for both wild-type and mutated p53.	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (162, 165))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('mutated', 'Var', (154, 161))	('MK2', 'Gene', '9261', (53, 56))	('MK2', 'Gene', (53, 56))
29344	32168910	While wild-type p53 is a potent tumor suppressor, mutated p53 proteins exhibit gain-of-function oncogenic properties.	('oncogenic properties', 'CPA', (96, 116))	('proteins', 'Protein', (62, 70))	('p53', 'Gene', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutated', 'Var', (50, 57))	('p53', 'Gene', '7157', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('gain-of-function', 'PosReg', (79, 95))	('p53', 'Gene', (58, 61))	('tumor', 'Disease', (32, 37))	('p53', 'Gene', '7157', (58, 61))
29350	32168910	Compared to the wild-type counterpart, p53 mutants are intrinsically more stable due to the lack of autoregulatory loops with negative regulators, and the stabilization of p53 mutants is a prerequisite for their gain-of-function properties.	('mutants', 'Var', (176, 183))	('p53', 'Gene', '7157', (172, 175))	('gain-of-function', 'PosReg', (212, 228))	('autoregulatory loops with', 'MPA', (100, 125))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('mutants', 'Var', (43, 50))	('p53', 'Gene', (172, 175))
29351	32168910	We determined that the stability of p53 mutants is further amplified upon MK2 inhibition.	('amplified', 'PosReg', (59, 68))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('mutants', 'Var', (40, 47))	('inhibition', 'NegReg', (78, 88))	('MK2', 'Gene', '9261', (74, 77))	('MK2', 'Gene', (74, 77))	('stability', 'MPA', (23, 32))
29353	32168910	Thus, the administration of MK2 inhibitors to patients with mutated p53 could have dire consequences.	('patients', 'Species', '9606', (46, 54))	('MK2', 'Gene', '9261', (28, 31))	('MK2', 'Gene', (28, 31))	('mutated', 'Var', (60, 67))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))
29355	32168910	MK2 inhibition has been shown as synthetically lethal to p53 deficiency.	('MK2', 'Gene', '9261', (0, 3))	('MK2', 'Gene', (0, 3))	('p53', 'Gene', (57, 60))	('inhibition', 'NegReg', (4, 14))	('p53', 'Gene', '7157', (57, 60))	('deficiency', 'Var', (61, 71))
29356	32168910	While some of these reports suggested that MK2 inhibition could be lethal to p53 mutations, none have directly manipulated MK2 in p53-mutated cells.	('inhibition', 'NegReg', (47, 57))	('p53', 'Gene', '7157', (130, 133))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('mutations', 'Var', (81, 90))	('p53', 'Gene', (130, 133))	('MK2', 'Gene', (43, 46))	('MK2', 'Gene', '9261', (123, 126))	('MK2', 'Gene', (123, 126))	('MK2', 'Gene', '9261', (43, 46))
29357	32168910	Herein, we show that targeting MK2 in p53-mutated cells produces a phenotype that is distinct from the p53-deficient phenotype.	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('MK2', 'Gene', '9261', (31, 34))	('MK2', 'Gene', (31, 34))	('targeting', 'Var', (21, 30))
29364	32168910	In support of biased MK2 signaling, MK2 inhibition blocks TNF production in macrophages stimulated with lipopolysaccharide; however, when the same cells were treated with Smac mimetics, MK2 inhibition increased TNF production.	('inhibition', 'Var', (40, 50))	('MK2', 'Gene', '9261', (21, 24))	('MK2', 'Gene', (21, 24))	('inhibition', 'NegReg', (190, 200))	('increased', 'PosReg', (201, 210))	('Smac', 'Gene', '56616', (171, 175))	('TNF', 'Gene', '7124', (58, 61))	('TNF', 'Gene', (211, 214))	('MK2', 'Gene', '9261', (186, 189))	('MK2', 'Gene', (186, 189))	('Smac', 'Gene', (171, 175))	('MK2', 'Gene', (36, 39))	('blocks', 'NegReg', (51, 57))	('MK2', 'Gene', '9261', (36, 39))	('TNF', 'Gene', '7124', (211, 214))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (104, 122))	('TNF', 'Gene', (58, 61))
29373	32168910	However, there is less potential for the translation of MK2 inhibitors into the therapeutic regimens of lower-grade gliomas, in which TP53 mutations are found with a 48%-91% frequency.	('TP53', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('MK2', 'Gene', '9261', (56, 59))	('MK2', 'Gene', (56, 59))	('gliomas', 'Disease', (116, 123))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))	('TP53', 'Gene', '7157', (134, 138))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
29376	32168910	p53R273H mutation in U251 was confirmed by DNA sequencing (Supplementary Figure S9).	('p53R273H', 'Mutation', 'p.R53,273H', (0, 8))	('U251', 'CellLine', 'CVCL:0021', (21, 25))	('p53R273H', 'Var', (0, 8))	('U251', 'Gene', (21, 25))
29387	32168910	Antibodies (all from Cell Signaling, Danvers, MA, USA, unless otherwise stated) against MK2 (#3042), p53 (#2524), p-p53 (#9286), p-MDM2 (#3521), lamin A/C (#2032), Hsp27 (#95357), p-Hsp27 (#2401), beta-tubulin (#T8328), GAPDH (#97166), p21 (#2947), PUMA (#12450), PARP (#9532), Noxa (#14766), BAX (#5023) and anti-rabbit (#7074) and anti-mouse (#7076) HRP-linked secondary antibodies were used for immunoblotting.	('lamin A/C', 'Gene', (145, 154))	('PUMA', 'Gene', (249, 253))	('GAPDH', 'Gene', (220, 225))	('Hsp27', 'Gene', '3315', (164, 169))	('Hsp27', 'Gene', (182, 187))	('#T8328', 'Var', (211, 217))	('#5023', 'Var', (298, 303))	('#14766', 'Var', (284, 290))	('Noxa', 'Gene', (278, 282))	('#9532', 'Var', (270, 275))	('MDM2', 'Gene', (131, 135))	('PARP', 'Gene', '1302', (264, 268))	('Hsp27', 'Gene', (164, 169))	('lamin A/C', 'Gene', '4000', (145, 154))	('#2401', 'Var', (189, 194))	('BAX', 'Gene', '581', (293, 296))	('p21', 'Gene', (236, 239))	('BAX', 'Gene', (293, 296))	('MK2', 'Gene', (88, 91))	('MDM2', 'Gene', '4193', (131, 135))	('p53', 'Gene', '7157', (101, 104))	('PARP', 'Gene', (264, 268))	('#97166', 'Var', (227, 233))	('PUMA', 'Gene', '27113', (249, 253))	('p53', 'Gene', '7157', (116, 119))	('#2947', 'Var', (241, 246))	('GAPDH', 'Gene', '2597', (220, 225))	('#12450', 'Var', (255, 261))	('beta-tubulin', 'Protein', (197, 209))	('p21', 'Gene', '1026', (236, 239))	('p53', 'Gene', (101, 104))	('Hsp27', 'Gene', '3315', (182, 187))	('Noxa', 'Gene', '5366', (278, 282))	('MK2', 'Gene', '9261', (88, 91))	('p53', 'Gene', (116, 119))
29389	32168910	For immunohistochemistry, antibodies against MK2 (Abcam #ab194452, Cambridge, UK) and p-MK2 (#3007) were used.	('MK2', 'Gene', '9261', (45, 48))	('MK2', 'Gene', (45, 48))	('MK2', 'Gene', '9261', (88, 91))	('#3007', 'Var', (93, 98))	('MK2', 'Gene', (88, 91))
29400	32168910	A172 (2.0 x 103), U251 (0.5 x 103), U87 (2.0 x 103), RN1 (4.0 x 103), HW1 (6.0 x 103) and RKI1 (6.0 x 103) cells were treated with MK2 inhibitor IV, PF-3644022 +- temozolomide.	('U251', 'CellLine', 'CVCL:0021', (18, 22))	('U87', 'Gene', (36, 39))	('HW1', 'CellLine', 'CVCL:F560', (70, 73))	('U87', 'Gene', '641648', (36, 39))	('PF-3644022', 'Chemical', 'MESH:C549914', (149, 159))	('temozolomide', 'Chemical', 'MESH:D000077204', (163, 175))	('MK2', 'Gene', '9261', (131, 134))	('MK2', 'Gene', (131, 134))	('PF-3644022 +- temozolomide', 'Var', (149, 175))
29407	32168910	qRT-PCR was performed using CDKN1A (QT00062090), PML (QT00090447), YPEL3 (QT00078589), BBC3 (QT00082859), BAX (QT00031192) and PMAIP1(QT0006138) primers (all Qiagen) with KAPA SYBR FAST Universal 2X qPCR Master Mix (Kapa Biosystems, Cat# KK4602, Wilmington, MA, USA).	('BBC3', 'Gene', (87, 91))	('YPEL3', 'Gene', (67, 72))	('Cat', 'Gene', (233, 236))	('BAX', 'Gene', (106, 109))	('QT00090447', 'Var', (54, 64))	('BAX', 'Gene', '581', (106, 109))	('QT00082859', 'Var', (93, 103))	('PML', 'Gene', '5371', (49, 52))	('YPEL3', 'Gene', '83719', (67, 72))	('CDKN1A', 'Gene', (28, 34))	('QT00078589', 'Var', (74, 84))	('PMAIP1', 'Gene', (127, 133))	('Cat', 'Gene', '847', (233, 236))	('CDKN1A', 'Gene', '1026', (28, 34))	('PML', 'Gene', (49, 52))	('QT00062090', 'Var', (36, 46))	('BBC3', 'Gene', '27113', (87, 91))	('PMAIP1', 'Gene', '5366', (127, 133))
29412	32168910	Secondary antibodies were Alexa488-conjugated anti-mouse IgG against p53, gamma-H2AX Ser139 and Ki-67 (Life Technologies).	('p53', 'Gene', '7157', (69, 72))	('p53', 'Gene', (69, 72))	('Ki-67', 'Var', (96, 101))	('Ser139', 'Chemical', '-', (85, 91))	('Alexa488', 'Chemical', '-', (26, 34))
29425	32168910	For the first time, our findings in p53-mutated cells reveal that the administration of the MK2 inhibitor may trigger the undesirable stabilization of p53 mutants, thereby causing the acceleration of the malignant processes.	('mutants', 'Var', (155, 162))	('p53', 'Gene', '7157', (151, 154))	('stabilization', 'MPA', (134, 147))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('malignant processes', 'CPA', (204, 223))	('acceleration', 'PosReg', (184, 196))	('MK2', 'Gene', '9261', (92, 95))	('p53', 'Gene', (151, 154))	('MK2', 'Gene', (92, 95))
29426	32168910	These findings are highly relevant since p53 mutations occur in over 50% of all cancers.	('p53', 'Gene', '7157', (41, 44))	('mutations', 'Var', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('occur', 'Reg', (55, 60))	('p53', 'Gene', (41, 44))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
29430	32168910	DNA sequencing data to confirm p53 R273H mutation in U251 cells.	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('R273H', 'Mutation', 'rs28934576', (35, 40))	('R273H', 'Var', (35, 40))	('U251', 'CellLine', 'CVCL:0021', (53, 57))
29455	31395879	compared gene expression, copy number alterations, mutations, and protein expression between cell lines and primary tumor samples.	('al', 'Chemical', 'MESH:D000535', (38, 40))	('mutations', 'Var', (51, 60))	('primary tumor', 'Disease', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('primary tumor', 'Disease', 'MESH:D009369', (108, 121))	('copy number alterations', 'Var', (26, 49))
29456	31395879	They created another cell line suitability score by summing the correlations across all four molecular profiles, although it is notable that only gene expression and copy number alterations had a substantial effect on their score as mutations and protein expression had extremely low correlations across all cell lines (R < 0.1).	('low', 'NegReg', (280, 283))	('correlations', 'Interaction', (284, 296))	('al', 'Chemical', 'MESH:D000535', (205, 207))	('al', 'Chemical', 'MESH:D000535', (84, 86))	('copy number alterations', 'Var', (166, 189))	('al', 'Chemical', 'MESH:D000535', (304, 306))	('al', 'Chemical', 'MESH:D000535', (113, 115))	('al', 'Chemical', 'MESH:D000535', (178, 180))
29493	31395879	which evaluated high-grade ovarian cancer cell lines based on copy number alterations and selected mutations (Supplementary Data 5).	('ovarian cancer', 'Disease', (27, 41))	('copy number alterations', 'Var', (62, 85))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('al', 'Chemical', 'MESH:D000535', (74, 76))
29638	30376874	Chromatin immunoprecipitation (ChIP) assay and quantitative Sequenom MassARRAY methylation analysis were performed to explore whether HOTAIRM1 could regulate histone and DNA modification status of the HOXA1 gene transcription start sites (TSS) and activate its transcription.	('regulate', 'Reg', (149, 157))	('activate', 'PosReg', (248, 256))	('HOXA1', 'Gene', (201, 206))	('transcription', 'MPA', (261, 274))	('HOTAIRM1', 'Var', (134, 142))	('HOXA1', 'Gene', '3198', (201, 206))
29641	30376874	HOTAIRM1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration and invasion, and inducing cell apoptosis.	('silencing', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('inhibiting', 'NegReg', (56, 66))	('inducing', 'Reg', (115, 123))	('HOTAIRM1', 'Gene', (0, 8))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cell proliferation', 'CPA', (67, 85))	('cell apoptosis', 'CPA', (124, 138))
29642	30376874	In vivo experiments showed knockdown of HOTAIRM1 lessened the tumor growth.	('knockdown', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('HOTAIRM1', 'Gene', (40, 48))	('tumor', 'Disease', (62, 67))	('lessened', 'NegReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
29646	30376874	We investigated the potential role of HOTAIRM1 to promote GBM cell proliferation, migration, invasion and inhibit cell apoptosis by epigenetic regulation of HOXA1 gene that can be targeted simultaneously to effectively treat GBM, thus putting forward a promising strategy for GBM treatment.	('HOXA1', 'Gene', '3198', (157, 162))	('promote', 'PosReg', (50, 57))	('GBM cell proliferation', 'CPA', (58, 80))	('migration', 'CPA', (82, 91))	('inhibit', 'NegReg', (106, 113))	('epigenetic regulation', 'Var', (132, 153))	('HOXA1', 'Gene', (157, 162))	('invasion', 'CPA', (93, 101))	('cell apoptosis', 'CPA', (114, 128))
29659	30376874	After HOTAIRM1 silencing cell proliferation, apoptosis, migration, invasion and tumor growth in vivo were assessed, which implied HOTAIRM1 might exert oncogenic properties in GBM.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('oncogenic properties', 'CPA', (151, 171))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('silencing', 'Var', (15, 24))	('HOTAIRM1', 'Var', (130, 138))	('HOTAIRM1', 'Gene', (6, 14))	('GBM', 'Disease', (175, 178))
29660	30376874	More importantly, HOTAIRM1 could interact with EZH2, G9a and DNA methyltransferases (Dnmts) and sequester them away from the transcription start sites (TSS) of HOXA1 gene, thereby activating the HOXA1 oncogene expression.	('oncogene', 'Gene', (201, 209))	('EZH2', 'Gene', (47, 51))	('HOXA1', 'Gene', '3198', (195, 200))	('HOXA1', 'Gene', '3198', (160, 165))	('expression', 'MPA', (210, 220))	('activating', 'PosReg', (180, 190))	('G9a', 'Gene', (53, 56))	('G9a', 'Gene', '10919', (53, 56))	('HOXA1', 'Gene', (160, 165))	('interact', 'Interaction', (33, 41))	('HOXA1', 'Gene', (195, 200))	('EZH2', 'Gene', '2146', (47, 51))	('HOTAIRM1', 'Var', (18, 26))
29662	30376874	Primary patient-derived GBM cells (G0410, G0515, and G0923) were cultured in Minimum Essential Medium (MEM Alpha) (GIBICO) supplemented with 20% FBS.	('G0515', 'Var', (42, 47))	('G0923', 'Var', (53, 58))	('patient', 'Species', '9606', (8, 15))	('Minimum Essential Medium', 'Chemical', '-', (77, 101))	('G0410', 'Var', (35, 40))
29670	30376874	Primary GBM samples (designated G0410, G0515, and G0923) were obtained from patients undergoing resection in accordance with a protocol approved by the Jilin University Medical Center Institutional Review Board.	('G0410', 'Var', (32, 37))	('G0923', 'Var', (50, 55))	('patients', 'Species', '9606', (76, 84))	('G0515', 'Var', (39, 44))
29691	30376874	Briefly, lentiviral particles expressing HOTAIRM1-specific shRNAs or pMagic7.1 vector were co-transfected into 293 T cells with the mixed set of packaging plasmids (SPAX2 and MD2G) using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA).	('HOTAIRM1-specific', 'Var', (41, 58))	('Lipofectamine', 'Chemical', 'MESH:C086724', (187, 200))	('SPAX2', 'Gene', '10749', (165, 170))	('pMagic7.1', 'Gene', (69, 78))	('SPAX2', 'Gene', (165, 170))	('293 T', 'CellLine', 'CVCL:0063', (111, 116))
29700	30376874	ChIP grade antibodies were as follows: anti- H3K27me3, anti- H3K9me2, anti-EZH2, normal rabbit IgG, and normal mouse IgG (Milliore); anti-G9a, anti-DnmT1, anti-DnmT3a, and anti-DnmT3b (Abcam).	('anti- H3K9me2', 'Var', (55, 68))	('G9a', 'Gene', '10919', (138, 141))	('DnmT3a', 'Gene', (160, 166))	('EZH2', 'Gene', (75, 79))	('DnmT1', 'Gene', '1786', (148, 153))	('DnmT3b', 'Gene', (177, 183))	('anti- H3K27me3', 'Var', (39, 53))	('rabbit', 'Species', '9986', (88, 94))	('mouse', 'Species', '10090', (111, 116))	('DnmT3b', 'Gene', '1789', (177, 183))	('DnmT3a', 'Gene', '1788', (160, 166))	('DnmT1', 'Gene', (148, 153))	('EZH2', 'Gene', '2146', (75, 79))	('G9a', 'Gene', (138, 141))
29714	30376874	Next, we screened a cohort of established GBM cell lines and primary patient-derived GBM cells for their HOTAIRM1 expression and showed that the majority of the GBM cell have elevated expression of HOTAIRM1 compared with human astrocytes (HA) (Fig.	('HOTAIRM1', 'Var', (198, 206))	('human', 'Species', '9606', (221, 226))	('elevated', 'PosReg', (175, 183))	('patient', 'Species', '9606', (69, 76))	('expression', 'MPA', (184, 194))
29715	30376874	Finally, RNA FISH showed HOTAIRM1 localized both in the cytoplasm and nucleus of U87 and A172 cells, and this experimental result preliminarily suggests us that HOTAIRM1 is possible to regulate gene expression at transcriptional or post-transcriptional levels.	('gene expression', 'MPA', (194, 209))	('regulate', 'Reg', (185, 193))	('U87', 'CellLine', 'CVCL:0022', (81, 84))	('HOTAIRM1', 'Var', (161, 169))
29716	30376874	We measured HORAIRM1 levels in A172 and U87 cells after treated with siHOTAIRM1-1 or siHOTAIRM1-2.	('U87', 'CellLine', 'CVCL:0022', (40, 43))	('HORAIRM1', 'MPA', (12, 20))	('siHOTAIRM1-2', 'Var', (85, 97))
29717	30376874	The CCK8 and BrdU cell proliferation assays indicated that cell growth and proliferation were reduced by the knockdown of HOTAIRM1 in GBM cells (Fig.	('reduced', 'NegReg', (94, 101))	('knockdown', 'Var', (109, 118))	('HOTAIRM1', 'Gene', (122, 130))	('BrdU', 'Chemical', 'MESH:D001973', (13, 17))
29722	30376874	2g and h, the tumor growth of mice injected cells transfected with shHOTAIRM1 were significantly decreased compared with those injected cells transfected with shControl.	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', (14, 19))	('decreased', 'NegReg', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('shHOTAIRM1', 'Var', (67, 77))
29725	30376874	To check whether the HOTAIRM1 plays a regulatory role in gene expression at the HOXA1 gene, we analyzed the changes in HOXA1 mRNAs levels, after silencing of HOTAIRM1.	('HOXA1', 'Gene', '3198', (119, 124))	('HOXA1', 'Gene', (80, 85))	('silencing', 'Var', (145, 154))	('HOXA1', 'Gene', '3198', (80, 85))	('HOTAIRM1', 'Gene', (158, 166))	('HOXA1', 'Gene', (119, 124))
29727	30376874	We also investigate the changes in mRNA levels for other genes in HOXA gene cluster after silencing of HOTAIRM1 by qRT-PCR method.	('HOTAIRM1', 'Gene', (103, 111))	('HOXA', 'Gene', '3197', (66, 70))	('mRNA levels', 'MPA', (35, 46))	('silencing', 'Var', (90, 99))	('HOXA', 'Gene', (66, 70))	('changes', 'Reg', (24, 31))
29728	30376874	The result indicates knockdown of HOTAIRM1 had no effect on other HOXA genes expression at the transcriptional level (Additional file 11: Figure S5C).	('HOXA', 'Gene', '3197', (66, 70))	('expression', 'MPA', (77, 87))	('HOXA', 'Gene', (66, 70))	('HOTAIRM1', 'Gene', (34, 42))	('knockdown', 'Var', (21, 30))
29734	30376874	Our results showed that HOXA1 mRNA levels were up-regulated in GBM cells compared with that in HA cells (Fig.	('GBM', 'Var', (63, 66))	('up-regulated', 'PosReg', (47, 59))	('HOXA1', 'Gene', '3198', (24, 29))	('HOXA1', 'Gene', (24, 29))
29735	30376874	Furthermore, we observed HOXA1 expression in the large cohorts of GBM patients available from The Cancer Genome Atlas (TCGA) database, data showed that HOXA1 were significantly increased in GBM (from 523 patients) compared with that in 10 normal brain tissues (Fig.	('HOXA1', 'Gene', (25, 30))	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (204, 212))	('HOXA1', 'Gene', (152, 157))	('Cancer Genome Atlas', 'Disease', (98, 117))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HOXA1', 'Gene', '3198', (25, 30))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (98, 117))	('HOXA1', 'Gene', '3198', (152, 157))	('increased', 'PosReg', (177, 186))	('GBM', 'Var', (190, 193))
29738	30376874	In our first ChIP assays, using antibodies against H3K9me2, and H3K27me3, we found H3K9me2 and H3K27me3 modifies in the HOXA1 TSS in GBM cell lines and primary GBM cells were significantly decreased compared with that in HA cells (Fig.	('decreased', 'NegReg', (189, 198))	('H3K27me3', 'Var', (95, 103))	('H3K9me2', 'Var', (83, 90))	('HOXA1', 'Gene', (120, 125))	('HOXA1', 'Gene', '3198', (120, 125))
29739	30376874	We next confirmed the enrichment of histone H3K9me2 methyltransferase G9a and H3K27me3 methyltransferase EZH2 in the TSS regions of HOXA1 in HA cells were higher than that in GBM cells (Fig.	('G9a', 'Gene', (70, 73))	('G9a', 'Gene', '10919', (70, 73))	('HOXA1', 'Gene', (132, 137))	('H3K27me3', 'Var', (78, 86))	('HOXA1', 'Gene', '3198', (132, 137))	('higher', 'PosReg', (155, 161))	('EZH2', 'Gene', '2146', (105, 109))	('EZH2', 'Gene', (105, 109))
29741	30376874	G9a is responsible for monomethylation and dimethylation of H3K9, and H3K9me2 and H3K27me3 are important modifications for gene silencing.	('H3K9', 'Protein', (60, 64))	('monomethylation', 'MPA', (23, 38))	('H3K27me3', 'Var', (82, 90))	('H3K9me2', 'Var', (70, 77))	('G9a', 'Gene', (0, 3))	('dimethylation', 'MPA', (43, 56))	('G9a', 'Gene', '10919', (0, 3))
29742	30376874	We performed identical ChIP assays after knockdown of HOTAIRM1, H3K9me2 and H3k27me3 modifications were increased in the HOXA1 TSS regions in A172, U87, and G0401 cells (Fig.	('H3K9me2', 'Protein', (64, 71))	('G0401', 'CellLine', 'CVCL:8Z77', (157, 162))	('HOXA1', 'Gene', (121, 126))	('increased', 'PosReg', (104, 113))	('HOTAIRM1', 'Gene', (54, 62))	('HOXA1', 'Gene', '3198', (121, 126))	('U87', 'CellLine', 'CVCL:0022', (148, 151))	('H3k27me3 modifications', 'Var', (76, 98))
29743	30376874	Moreover, our ChIP assay results confirmed that G9a and EZH2 were also enriched in the TSS region of the HOXA1 gene in HOTAIRM1-inhibiting GBM cell (Fig.	('GBM cell', 'CPA', (139, 147))	('HOTAIRM1-inhibiting', 'Var', (119, 138))	('HOXA1', 'Gene', (105, 110))	('EZH2', 'Gene', '2146', (56, 60))	('EZH2', 'Gene', (56, 60))	('HOXA1', 'Gene', '3198', (105, 110))	('G9a', 'Gene', (48, 51))	('G9a', 'Gene', '10919', (48, 51))
29746	30376874	The H3K9me2/H3K27me3 and G9a/EZH2 enrichment increased in 3 regions (HOXA1-1, A1-2, A1-3) near to HOXA1 TSS, especially in predicted promoter region (HOXA1-2), whereas the change of enrichment was not detected in other 2 regions (HOXA1-4, 1-5) and in HOXA2, HOXA11 gene TSS regions (Additional file 12: Figure S6 F-I).	('HOXA1-2', 'Gene', '3198;3199', (150, 157))	('HOXA1-4', 'Gene', '3198;3199;3200;3201', (230, 237))	('HOXA1-2', 'Gene', (150, 157))	('HOXA1', 'Gene', '3198', (69, 74))	('G9a', 'Gene', '10919', (25, 28))	('HOXA1', 'Gene', (230, 235))	('increased', 'PosReg', (45, 54))	('HOXA1', 'Gene', '3198', (258, 263))	('HOXA2', 'Gene', '3199', (251, 256))	('HOXA1', 'Gene', (150, 155))	('HOXA1', 'Gene', '3198', (98, 103))	('HOXA11', 'Gene', (258, 264))	('HOXA1-1', 'Gene', (69, 76))	('HOXA1', 'Gene', (69, 74))	('H3K9me2/H3K27me3', 'Var', (4, 20))	('G9a', 'Gene', (25, 28))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))	('HOXA11', 'Gene', '3207', (258, 264))	('HOXA1-4', 'Gene', (230, 237))	('HOXA1', 'Gene', (258, 263))	('HOXA1', 'Gene', '3198', (230, 235))	('HOXA2', 'Gene', (251, 256))	('HOXA1', 'Gene', (98, 103))	('HOXA1-1', 'Gene', '3207;3198', (69, 76))	('HOXA1', 'Gene', '3198', (150, 155))
29748	30376874	These results indicated that silencing of HOTAIRM1 reduced gene-suppressive histone modification H3K9me2 and H3K27me3 in the TSS region of the HOXA1 gene, thereby decreasing HOXA1 mRNA expression level.	('HOXA1', 'Gene', '3198', (174, 179))	('reduced', 'NegReg', (51, 58))	('HOXA1', 'Gene', '3198', (143, 148))	('H3K27me3', 'Var', (109, 117))	('silencing', 'Var', (29, 38))	('H3K9me2', 'Protein', (97, 104))	('HOXA1', 'Gene', (174, 179))	('HOTAIRM1', 'Gene', (42, 50))	('HOXA1', 'Gene', (143, 148))	('decreasing', 'NegReg', (163, 173))
29750	30376874	The CpG sites of the HOXA1 gene promoter were methylated in HA cell, correlating with the promoter's transcriptionally repressed status, whereas the HOXA1 promoters were un-methylated in GBM cell lines and primary GBM cells, with HOXA1 transcriptionally active (Fig.	('HOXA1', 'Gene', '3198', (230, 235))	('HOXA1', 'Gene', '3198', (21, 26))	('HOXA1', 'Gene', (149, 154))	('methylated', 'Var', (46, 56))	('HOXA1', 'Gene', '3198', (149, 154))	('HOXA1', 'Gene', (230, 235))	('HOXA1', 'Gene', (21, 26))
29753	30376874	The results indicated that enrichments of DnmT1, DnmT3a, and DnmT3b in the promoter region of HOXA1 gene were increased by shHOTAIRM1 in A172 (Fig.	('shHOTAIRM1', 'Var', (123, 133))	('HOXA1', 'Gene', (94, 99))	('DnmT3a', 'Gene', '1788', (49, 55))	('increased', 'PosReg', (110, 119))	('DnmT1', 'Gene', (42, 47))	('DnmT3b', 'Gene', (61, 67))	('HOXA1', 'Gene', '3198', (94, 99))	('DnmT3b', 'Gene', '1789', (61, 67))	('DnmT3a', 'Gene', (49, 55))	('DnmT1', 'Gene', '1786', (42, 47))
29756	30376874	We found the loss of HOTAIRM1 had no effect on DnmT1, DnmT3a, and DnmT3b bonding to the HOXA2 and HOXA11 gene, suggesting that HOTAIRM1 specifically regulates the HOXA1 DNA methylation levels (Additional file 13: Figure S7F).	('DnmT1', 'Gene', (47, 52))	('DnmT3b', 'Gene', '1789', (66, 72))	('DnmT3b', 'Gene', (66, 72))	('HOXA2', 'Gene', '3199', (88, 93))	('DnmT3a', 'Gene', (54, 60))	('HOXA1', 'Gene', (163, 168))	('DnmT1', 'Gene', '1786', (47, 52))	('HOXA1', 'Gene', (98, 103))	('HOTAIRM1', 'Gene', (21, 29))	('HOXA1', 'Gene', '3198', (98, 103))	('HOTAIRM1', 'Var', (127, 135))	('HOXA1', 'Gene', '3198', (163, 168))	('DnmT3a', 'Gene', '1788', (54, 60))	('HOXA2', 'Gene', (88, 93))	('HOXA11', 'Gene', '3207', (98, 104))	('loss', 'Var', (13, 17))	('HOXA11', 'Gene', (98, 104))	('regulates', 'Reg', (149, 158))
29757	30376874	Given that hypomethylated DNA is associated with active genes, whereas hypermethylated genes are silent, we conclude that the transcriptional activation of the HOXA1 gene is regulated in part by HOTAIRM1-directed DNA demethylation.	('activation', 'PosReg', (142, 152))	('HOXA1', 'Gene', (160, 165))	('HOXA1', 'Gene', '3198', (160, 165))	('HOTAIRM1-directed', 'Var', (195, 212))	('transcriptional', 'MPA', (126, 141))
29758	30376874	Our ChIP assay results confirmed that HOTAIRM1 mediated HOXA1 gene activation through reducing repressive chromatin modifications of H3K9me2, H3K27me3 and DNA methylation in GBM cells.	('HOXA1', 'Gene', (56, 61))	('repressive chromatin modifications', 'MPA', (95, 129))	('activation', 'PosReg', (67, 77))	('HOXA1', 'Gene', '3198', (56, 61))	('H3K27me3', 'Protein', (142, 150))	('DNA methylation', 'MPA', (155, 170))	('reducing', 'NegReg', (86, 94))	('HOTAIRM1', 'Var', (38, 46))	('H3K9me2', 'Protein', (133, 140))
29761	30376874	7a and b), suggesting that HOTAIRM1 formed a complex with G9a, EZH2, and Dnmts and prevented them from binding the TSS of the HOXA1 gene loci.	('HOXA1', 'Gene', '3198', (126, 131))	('EZH2', 'Gene', '2146', (63, 67))	('prevented', 'NegReg', (83, 92))	('binding', 'Interaction', (103, 110))	('EZH2', 'Gene', (63, 67))	('complex', 'Interaction', (45, 52))	('HOTAIRM1', 'Var', (27, 35))	('G9a', 'Gene', (58, 61))	('G9a', 'Gene', '10919', (58, 61))	('HOXA1', 'Gene', (126, 131))
29762	30376874	This finding is consistent with the histone modifications of H3K9me2, H3K27me3 and DNA methylation levels in the HOXA1 gene domains.	('HOXA1', 'Gene', '3198', (113, 118))	('H3K9me2', 'Var', (61, 68))	('DNA methylation levels', 'MPA', (83, 105))	('HOXA1', 'Gene', (113, 118))	('H3K27me3', 'Var', (70, 78))
29770	30376874	Moreover, our in vivo experiments further showed tumor growth was effectively suppressed by HOTAIRM1 silencing.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('suppressed', 'NegReg', (78, 88))	('silencing', 'Var', (101, 110))	('HOTAIRM1', 'Gene', (92, 100))	('tumor', 'Disease', (49, 54))
29772	30376874	Currently, it has been demonstrated that HOTAIRM1 interact with Polycomb Repressive Complex 2 (PRC2) and histone demethylase UTX/MLL to regulate chromatin conformation and then affects HOXA gene cluster transcriptional activity.	('affects', 'Reg', (177, 184))	('MLL', 'Gene', (129, 132))	('UTX', 'Gene', (125, 128))	('chromatin conformation', 'MPA', (145, 167))	('regulate', 'Reg', (136, 144))	('HOXA', 'Gene', (185, 189))	('HOTAIRM1', 'Var', (41, 49))	('UTX', 'Gene', '7403', (125, 128))	('HOXA', 'Gene', '3197', (185, 189))	('MLL', 'Gene', '4297', (129, 132))
29773	30376874	Our research found that HOTAIRM1 activated transcription of the HOXA1 gene through the decrease of histone H3K9me2, H3K27me3 and DNA methylation, which are epigenetic markers associated with gene silencing.	('activated', 'PosReg', (33, 42))	('DNA methylation', 'MPA', (129, 144))	('HOXA1', 'Gene', '3198', (64, 69))	('H3K27me3', 'Var', (116, 124))	('decrease', 'NegReg', (87, 95))	('transcription', 'MPA', (43, 56))	('HOXA1', 'Gene', (64, 69))	('histone H3K9me2', 'Protein', (99, 114))
29820	29872622	Furthermore, PEG-rHDL led to more pronounced suppression of bone marrow myeloid progenitor cell proliferation and monocytosis, reduced atherosclerosis and a stable plaque phenotype.	('PEG-rHDL', 'Var', (13, 21))	('suppression', 'NegReg', (45, 56))	('PEG-rHDL', 'Chemical', '-', (13, 21))	('reduced', 'NegReg', (127, 134))	('bone marrow myeloid', 'Disease', 'MESH:D001855', (60, 79))	('atherosclerosis', 'Disease', (135, 150))	('monocytosis', 'CPA', (114, 125))	('monocytosis', 'Phenotype', 'HP:0012311', (114, 125))	('bone marrow myeloid', 'Disease', (60, 79))	('atherosclerosis', 'Disease', 'MESH:D050197', (135, 150))	('atherosclerosis', 'Phenotype', 'HP:0002621', (135, 150))
29822	29872622	Despite pegylation, altering lipid composition of rHDL could also change the circulation time and stability of rHDL in vivo.	('altering', 'Reg', (20, 28))	('change', 'Reg', (66, 72))	('circulation time', 'MPA', (77, 93))	('lipid', 'Chemical', 'MESH:D008055', (29, 34))	('lipid', 'MPA', (29, 34))	('stability', 'MPA', (98, 107))	('pegylation', 'Var', (8, 18))
29825	29872622	For example, SM enrichment has been shown to induce an ordered and rigid liquid-lipid bilayer environment in HDL particles and increase the circulation time and stability of liposome.	('ordered', 'MPA', (55, 62))	('induce', 'PosReg', (45, 51))	('lipid bilayer', 'Chemical', 'MESH:D008051', (80, 93))	('stability of liposome', 'CPA', (161, 182))	('increase', 'PosReg', (127, 135))	('circulation', 'MPA', (140, 151))	('SM', 'Chemical', 'MESH:D013109', (13, 15))	('SM enrichment', 'Var', (13, 26))
29828	29872622	The remodeling effect of LCAT is the major mechanism that mediates the instability of d-HDLs in their metabolic process and results in the leakage of encapsulated drugs before they reach the targeted cells.	('leakage of encapsulated drugs', 'MPA', (139, 168))	('d-HDLs', 'Var', (86, 92))	('LCAT', 'Gene', (25, 29))	('LCAT', 'Gene', '3931', (25, 29))	('metabolic', 'MPA', (102, 111))	('results in', 'Reg', (124, 134))
29832	29872622	found that inserting a gadolinium-binding chitosan fastener on the liposome surface followed by covalent cross-linking of the lipid bilayer provided a useful method to anchor the functional units to the liposome surface and stabilized liposomes under physiological conditions.	('gadolinium', 'Chemical', 'MESH:D005682', (23, 33))	('chitosan', 'Chemical', 'MESH:D048271', (42, 50))	('anchor', 'PosReg', (168, 174))	('inserting', 'Var', (11, 20))	('lipid bilayer', 'Chemical', 'MESH:D008051', (126, 139))
29871	29872622	R6H4 (RRRRRRHHHH), a pH-sensitive CPP with the ability of pH-responsive cellular uptake owing to histidine and cell penetration owing to arginine, has been used to improve direct cytosolic delivery of agents loaded by liposome.	('histidine', 'Chemical', 'MESH:D006639', (97, 106))	('direct cytosolic delivery', 'MPA', (172, 197))	('arginine', 'Chemical', 'MESH:D001120', (137, 145))	('R6H4', 'Chemical', '-', (0, 4))	('improve', 'PosReg', (164, 171))	('R6H4', 'Var', (0, 4))
29892	29872622	utilized a fusogenic peptide to modify rHDL for efficient accumulation in lung and delivery of encapsulated siRNA to the cytoplasm via endosomal membrane fusion.	('peptide', 'Chemical', 'MESH:D010455', (21, 28))	('rHDL', 'Gene', (39, 43))	('accumulation', 'MPA', (58, 70))	('modify', 'Var', (32, 38))
29952	29872622	GM1-rHDL presented excellent brain distribution following intranasal administration.	('GM1-rHDL', 'Chemical', '-', (0, 8))	('brain distribution', 'MPA', (29, 47))	('GM1-rHDL', 'Var', (0, 8))
29954	29872622	In addition to apoE-rHDL, apoA-I-rHDL has also been shown to lower Abeta levels following intravenous administration in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis.	('amyloidosis', 'Disease', 'MESH:D000686', (188, 199))	('lower', 'NegReg', (61, 66))	('apoE', 'Gene', '348', (15, 19))	('mice', 'Species', '10090', (140, 144))	('Abeta levels', 'MPA', (67, 79))	('PS1', 'Gene', '19164', (136, 139))	('apoA-I-rHDL', 'Var', (26, 37))	('amyloidosis', 'Disease', (188, 199))	('amyloidosis', 'Phenotype', 'HP:0011034', (188, 199))	('apoE', 'Gene', (15, 19))	('PS1', 'Gene', (136, 139))
29956	29872622	reported that D-4F, an apoA-I mimetic peptide, had the ability to bind Abeta and inhibit Abeta deposition after oral administration.	('bind', 'Interaction', (66, 70))	('inhibit', 'NegReg', (81, 88))	('D-4F', 'Var', (14, 18))	('Abeta deposition', 'Disease', (89, 105))	('Abeta', 'Protein', (71, 76))	('peptide', 'Chemical', 'MESH:D010455', (38, 45))	('Abeta deposition', 'Disease', 'MESH:D000079822', (89, 105))
29960	29284440	This study characterizes the tumorigenesis of CD133+ cells and their sensitivity to pharmacological inhibition.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CD133+', 'Var', (46, 52))
29964	29284440	CD133+ cells expressed stem cell markers and exhibited self-renewal and enhanced tumor formation.	('CD133+ cells', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('enhanced', 'PosReg', (72, 80))	('self-renewal', 'CPA', (55, 67))	('stem cell markers', 'CPA', (23, 40))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
29965	29284440	Minocycline (Mino) was more effective in reducing the survival rate of CD133+ cells, whereas CD133- cells were more sensitive to inhibition by the signal transducer and activator of transcription 3 (STAT3) inhibitor.	('signal transducer and activator of transcription 3', 'Gene', '20848', (147, 197))	('Minocycline', 'Chemical', 'MESH:D008911', (0, 11))	('Mino', 'Chemical', 'MESH:D008911', (0, 4))	('reducing', 'NegReg', (41, 49))	('Minocycline', 'Var', (0, 11))	('STAT3', 'Gene', '20848', (199, 204))	('survival rate', 'CPA', (54, 67))	('Mino', 'Chemical', 'MESH:D008911', (13, 17))	('rat', 'Species', '10116', (63, 66))	('STAT3', 'Gene', (199, 204))
29978	29284440	Previous studies showed that purified CD133+ cells generated neurospheres in culture and promoted brain tumors in in vivo models.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CD133+ cells', 'Var', (38, 50))	('brain tumors', 'Disease', 'MESH:D001932', (98, 110))	('brain tumors', 'Phenotype', 'HP:0030692', (98, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('brain tumors', 'Disease', (98, 110))	('neurospheres', 'CPA', (61, 73))	('promoted', 'PosReg', (89, 97))	('brain tumor', 'Phenotype', 'HP:0030692', (98, 109))	('rat', 'Species', '10116', (55, 58))
29981	29284440	Thus, concurrent targeting of CD133+ and CD133- cells may be an effective therapeutic strategy for patients with malignant glioma.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('CD133+', 'Var', (30, 36))	('malignant glioma', 'Disease', (113, 129))	('rat', 'Species', '10116', (88, 91))	('malignant glioma', 'Disease', 'MESH:D005910', (113, 129))	('patients', 'Species', '9606', (99, 107))	('CD133- cells', 'Var', (41, 53))
30040	29284440	We determined whether CD133+ cells promoted tumor formation in an intracranial tumor model.	('intracranial tumor', 'Disease', (66, 84))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('intracranial tumor', 'Disease', 'MESH:D001932', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('promoted', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CD133+ cells', 'Var', (22, 34))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
30042	29284440	Consistently, tumors were observed in 4 out of 4 mice injected intracranially with CD133+ cells.	('mice', 'Species', '10090', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('CD133+', 'Var', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
30045	29284440	CD133+ cells were treated with EGFR inhibitors (PD153035 and PD168393), PI3K inhibitor (LY294002), Akt inhibitor (Akt inhibitor VIII), mTOR inhibitors (rapamycin, Pl103), JNK inhibitor (SP600125), MEK inhibitor (PD98059), cSrc inhibitor (PP2), p38 MEK inhibitor (SB203580), JAK inhibitor (AG490), STAT3 inhibitor (WP1006), TGFbeta inhibitor (SB431542), or beta-catenin inhibitor (FH535) for 24 h and the number of neurospheres was measured.	('PD98059', 'Var', (212, 219))	('PD168393', 'Var', (61, 69))	('PD153035', 'Var', (48, 56))	('mTOR', 'Gene', '56717', (135, 139))	('MEK', 'Gene', (197, 200))	('TGFbeta', 'Gene', '21803', (323, 330))	('STAT3', 'Gene', '20848', (297, 302))	('beta-catenin', 'Gene', '12387', (356, 368))	('Akt', 'Gene', (99, 102))	('TGFbeta', 'Gene', (323, 330))	('beta-catenin', 'Gene', (356, 368))	('PP2', 'Gene', '18169', (238, 241))	('MEK', 'Gene', '17242', (248, 251))	('Akt', 'Gene', (114, 117))	('Akt', 'Gene', '11651', (99, 102))	('mTOR', 'Gene', (135, 139))	('PP2', 'Gene', (238, 241))	('STAT3', 'Gene', (297, 302))	('JNK', 'Gene', (171, 174))	('Akt', 'Gene', '11651', (114, 117))	('JNK', 'Gene', '26419', (171, 174))	('EGFR', 'Gene', (31, 35))	('EGFR', 'Gene', '13649', (31, 35))	('MEK', 'Gene', (248, 251))	('MEK', 'Gene', '17242', (197, 200))
30049	29284440	Previously, we showed that Mino induced cell death in C6 glioma cells.	('Mino', 'Chemical', 'MESH:D008911', (27, 31))	('C6 glioma', 'Disease', 'MESH:C567307', (54, 63))	('death', 'Disease', 'MESH:D003643', (45, 50))	('death', 'Disease', (45, 50))	('Mino', 'Var', (27, 31))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('C6 glioma', 'Disease', (54, 63))
30054	29284440	Conversely, STAT3 inhibitor WP1066 at a concentration of 5 muM reduced the number of CD133+ cells by 92% but only reduced the number of CD133- cells by 27.5% (t(18) = 11.29, p < 0.001) (Fig.	('WP1066', 'Var', (28, 34))	('reduced', 'NegReg', (63, 70))	('STAT3', 'Gene', '20848', (12, 17))	('muM', 'Gene', '56925', (59, 62))	('STAT3', 'Gene', (12, 17))	('rat', 'Species', '10116', (47, 50))	('muM', 'Gene', (59, 62))
30055	29284440	We also compared the activated states of STAT3 among CD133+, CD133-, and their parental cells from C6 glioma cells and found that CD133+ exhibited the highest phosphorylated state (Fig.	('C6 glioma', 'Disease', 'MESH:C567307', (99, 108))	('STAT3', 'Gene', (41, 46))	('C6 glioma', 'Disease', (99, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('phosphorylated state', 'MPA', (159, 179))	('STAT3', 'Gene', '20848', (41, 46))	('CD133+', 'Var', (130, 136))
30056	29284440	CD133+ C6 glioma cells were treated with STAT3 inhibitors WP1066 (5 muM) or S3 l-201 (50 muM) for 24 h and p-STAT3, STAT3, CD133, Nestin, SSES-1, and NANOG were measured using Western blotting analysis.	('STAT3', 'Gene', (41, 46))	('muM', 'Gene', (68, 71))	('C6 glioma', 'Disease', 'MESH:C567307', (7, 16))	('STAT3', 'Gene', '20848', (116, 121))	('STAT3', 'Gene', '20848', (109, 114))	('muM', 'Gene', '56925', (89, 92))	('NANOG', 'Gene', '71950', (150, 155))	('WP1066', 'Var', (58, 64))	('muM', 'Gene', (89, 92))	('S3 l-201', 'Var', (76, 84))	('Nestin', 'Gene', '18008', (130, 136))	('Nestin', 'Gene', (130, 136))	('STAT3', 'Gene', (116, 121))	('STAT3', 'Gene', (109, 114))	('STAT3', 'Gene', '20848', (41, 46))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('C6 glioma', 'Disease', (7, 16))	('NANOG', 'Gene', (150, 155))	('muM', 'Gene', '56925', (68, 71))
30057	29284440	As expected, the phosphorylated states of STAT3 were markedly inhibited by WP1066 and S3 l-201 (Fig.	('STAT3', 'Gene', (42, 47))	('S3 l-201', 'Var', (86, 94))	('phosphorylated states', 'MPA', (17, 38))	('inhibited', 'NegReg', (62, 71))	('STAT3', 'Gene', '20848', (42, 47))	('WP1066', 'Var', (75, 81))
30061	29284440	Mino alone reduced survival rate by 2.6% whereas WP1006 reduced survival rate by 23.3%.	('Mino', 'Chemical', 'MESH:D008911', (0, 4))	('reduced', 'NegReg', (11, 18))	('reduced', 'NegReg', (56, 63))	('WP1006', 'Var', (49, 55))	('survival rate', 'CPA', (19, 32))	('rat', 'Species', '10116', (28, 31))	('rat', 'Species', '10116', (73, 76))
30062	29284440	Mino plus WP1006 inhibited cell growth by 64% (Fig.	('WP1006', 'Var', (10, 16))	('inhibited', 'NegReg', (17, 26))	('cell growth', 'CPA', (27, 38))	('Mino', 'Chemical', 'MESH:D008911', (0, 4))
30063	29284440	The combination drug index (CDI) for WP1006 (25 muM) and Mino (5 muM) was 0.481.	('WP1006', 'Var', (37, 43))	('CDI', 'Chemical', '-', (28, 31))	('muM', 'Gene', '56925', (48, 51))	('muM', 'Gene', '56925', (65, 68))	('muM', 'Gene', (48, 51))	('muM', 'Gene', (65, 68))	('Mino', 'Chemical', 'MESH:D008911', (57, 61))
30069	29284440	Figure 6c shows that the expression of the cleaved fragment of caspase 3 was higher after a combined application of Mino (50 muM) and WP1006 (5 muM) than those after the application of Mino or WP1006 alone.	('muM', 'Gene', '56925', (144, 147))	('Mino', 'Chemical', 'MESH:D008911', (185, 189))	('higher', 'PosReg', (77, 83))	('caspase 3', 'Protein', (63, 72))	('WP1006', 'Var', (134, 140))	('muM', 'Gene', (144, 147))	('expression of the cleaved fragment', 'MPA', (25, 59))	('muM', 'Gene', '56925', (125, 128))	('muM', 'Gene', (125, 128))	('Mino', 'Chemical', 'MESH:D008911', (116, 120))
30070	29284440	We used the intracranial tumor model to determine whether Mino plus WP1006 could synergistically inhibit tumor growth.	('Mino', 'Var', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('inhibit', 'NegReg', (97, 104))	('Mino', 'Chemical', 'MESH:D008911', (58, 62))	('tumor', 'Disease', (25, 30))	('intracranial tumor', 'Disease', (12, 30))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('WP1006', 'Var', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('intracranial tumor', 'Disease', 'MESH:D001932', (12, 30))
30073	29284440	At day 35, Mino inhibited tumor growth by 63.3% and WP1006 inhibited tumor growth by 13%.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibited', 'NegReg', (16, 25))	('Mino', 'Chemical', 'MESH:D008911', (11, 15))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('inhibited', 'NegReg', (59, 68))	('WP1006', 'Var', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
30078	29284440	These results suggest that a combination of Mino and WP1006 synergistically inhibits the intracranial growth of U87 glioma cells.	('WP1006', 'Var', (53, 59))	('glioma', 'Disease', (116, 122))	('inhibits', 'NegReg', (76, 84))	('Mino', 'Chemical', 'MESH:D008911', (44, 48))	('Mino', 'Gene', (44, 48))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
30084	29284440	Second, neurospheres derived from CD133+ cells were positive for nestin, NANOG, and SSEA-1, markers for neural stem cells, embryonic stem cells, and pluripotent stem cells, respectively.	('SSEA-1', 'Gene', '14345', (84, 90))	('nestin', 'Gene', (65, 71))	('CD133+ cells', 'Var', (34, 46))	('nestin', 'Gene', '18008', (65, 71))	('positive', 'Reg', (52, 60))	('NANOG', 'Gene', '71950', (73, 78))	('SSEA-1', 'Gene', (84, 90))	('NANOG', 'Gene', (73, 78))
30085	29284440	Third, when CD133+ cells were inoculated into the nude mice, they were able to form tumors in vivo.	('nude mice', 'Species', '10090', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CD133+ cells', 'Var', (12, 24))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))
30089	29284440	We showed that the phosphorylated and activated level of STAT3 was higher in CD133+ cells than in CD133- cells.	('STAT3', 'Gene', '20848', (57, 62))	('CD133+ cells', 'Var', (77, 89))	('higher', 'PosReg', (67, 73))	('STAT3', 'Gene', (57, 62))
30090	29284440	STAT3 inhibitor WP1066 exhibited a potent effect on decreasing the number of neurospheres derived from CD133+ cells.	('decreasing', 'NegReg', (52, 62))	('WP1066', 'Var', (16, 22))	('STAT3', 'Gene', (0, 5))	('STAT3', 'Gene', '20848', (0, 5))
30091	29284440	In addition, the survival rate of glioma cells and the expression of cancer stem cell markers Nestin, SSES-1, and NANOG were attenuated by WP1066.	('Nestin', 'Gene', '18008', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('glioma', 'Disease', 'MESH:D005910', (34, 40))	('survival rate', 'CPA', (17, 30))	('attenuated', 'NegReg', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Nestin', 'Gene', (94, 100))	('SSES-1', 'Gene', (102, 108))	('WP1066', 'Var', (139, 145))	('expression', 'MPA', (55, 65))	('rat', 'Species', '10116', (26, 29))	('NANOG', 'Gene', '71950', (114, 119))	('glioma', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('NANOG', 'Gene', (114, 119))	('cancer', 'Disease', (69, 75))
30093	29284440	We next examined the effect of WP1066 in combination with Mino, which was more effective in reducing the survival of CD133- cells than CD133+ cells.	('WP1066', 'Var', (31, 37))	('survival', 'CPA', (105, 113))	('reducing', 'NegReg', (92, 100))	('Mino', 'Chemical', 'MESH:D008911', (58, 62))
30094	29284440	Mino plus WP1006 synergistically inhibited the survival of glioma cells in vitro as well as the intracranial growth of U87 glioma cells in vivo.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('Mino', 'Chemical', 'MESH:D008911', (0, 4))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('glioma', 'Disease', (123, 129))	('WP1006', 'Var', (10, 16))	('inhibited', 'NegReg', (33, 42))
30095	29284440	Furthermore, the expression of the cleaved fragment of caspase 3 was increased, suggesting that the combination of Mino and WP1066 induced cell death through caspase-dependent apoptosis.	('increased', 'PosReg', (69, 78))	('caspase-dependent', 'CPA', (158, 175))	('WP1066', 'Var', (124, 130))	('death', 'Disease', 'MESH:D003643', (144, 149))	('death', 'Disease', (144, 149))	('Mino', 'Chemical', 'MESH:D008911', (115, 119))	('expression of the cleaved fragment', 'MPA', (17, 51))	('caspase', 'Protein', (55, 62))
30115	28868256	We defined three patient groups that predicted the probability of tumor progression: SUVmax/NB index >1.5 and ADC <=1,400 x 10-6 mm2/s defined high-risk patients (n = 7), SUVmax/NB index <=1.5 and ADC >1,400 x 10-6 mm2/s defined low-risk patients (n = 11), and intermediate-risk (n = 12) defined the remainder of the patients.	('SUVmax/NB index <=1.5', 'Var', (171, 192))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', (66, 71))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (238, 245))	('>1.5', 'Var', (101, 105))	('patient', 'Species', '9606', (317, 324))	('patient', 'Species', '9606', (153, 160))	('patients', 'Species', '9606', (317, 325))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (238, 246))
30164	28868256	O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 10 patients, non-methylated in 11 patients, and unknown in 9 patients.	('O6-methylguanine-DNA methyltransferase', 'Gene', (0, 38))	('methylated', 'Var', (50, 60))	('patients', 'Species', '9606', (67, 75))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 38))	('MGMT', 'Gene', '4255', (40, 44))	('patients', 'Species', '9606', (98, 106))	('MGMT', 'Gene', (40, 44))	('patients', 'Species', '9606', (125, 133))
30165	28868256	Isocitrate dehydrogenase 1 (IDH1) R132 mutation was present in 2 patients, wild type in 21 patients, and unknown in 7 patients.	('patients', 'Species', '9606', (91, 99))	('IDH1', 'Gene', '3417', (28, 32))	('Isocitrate dehydrogenase 1', 'Gene', '3417', (0, 26))	('Isocitrate dehydrogenase 1', 'Gene', (0, 26))	('patients', 'Species', '9606', (65, 73))	('R132', 'Var', (34, 38))	('patients', 'Species', '9606', (118, 126))	('IDH1', 'Gene', (28, 32))
30207	28868256	However, in our study, the incorporation of low ADC into the stratification scheme with high FDG-PET uptake resulted in an even more limited median OS of 3.8 months in high-risk groups.	('FDG-PET', 'Gene', (93, 100))	('FDG', 'Chemical', 'MESH:D019788', (93, 96))	('low', 'Var', (44, 47))
30238	27765902	Angiopep-2 transport and accumulation in brain endothelial cells can be blocked by alpha2-macroglobulin, a specific ligand for LRP-1, indicating that Angiopep-2 facilitates brain-targeted drug delivery through LRP-1-mediated transcytosis.	('brain-targeted drug delivery', 'MPA', (173, 201))	('facilitates', 'PosReg', (161, 172))	('alpha2-macroglobulin', 'Gene', (83, 103))	('Angiopep-2', 'Var', (150, 160))	('alpha2-macroglobulin', 'Gene', '232345', (83, 103))
30304	27765902	Therefore, conjugation of Angiopep-2 with cell penetrating peptides could serve as an efficient glioma drug delivery system.	('Angiopep-2', 'Gene', (26, 36))	('glioma drug delivery system', 'Disease', 'MESH:D005910', (96, 123))	('conjugation', 'Var', (11, 22))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma drug delivery system', 'Disease', (96, 123))
30308	28139732	Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route.	('tumor', 'Disease', (119, 124))	('rat', 'Species', '10116', (8, 11))	('higher', 'PosReg', (54, 60))	('higher', 'PosReg', (102, 108))	('levels', 'MPA', (61, 67))	('levels', 'MPA', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('HET0016', 'Var', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
30314	28139732	Furthermore, HPssCD-HET0016 significantly prolonged survival in PDX GBM811 model.	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('HPssCD-HET0016', 'Var', (13, 27))	('prolonged', 'PosReg', (42, 51))	('HPssCD', 'Chemical', '-', (13, 19))	('survival', 'CPA', (52, 60))
30320	28139732	HET0016 was able to inhibit angiogenic responses to several growth factors as well as angiogenesis in gliosarcoma and in the cornea induced by implanted human U251 GBM cells.	('gliosarcoma', 'Disease', 'MESH:D018316', (102, 113))	('cornea', 'Disease', (125, 131))	('inhibit', 'NegReg', (20, 27))	('GBM', 'Phenotype', 'HP:0012174', (164, 167))	('gliosarcoma', 'Disease', (102, 113))	('U251', 'CellLine', 'CVCL:0021', (159, 163))	('human', 'Species', '9606', (153, 158))	('angiogenic', 'CPA', (28, 38))	('cornea', 'Disease', 'MESH:D065306', (125, 131))	('angiogenesis', 'CPA', (86, 98))	('HET0016', 'Var', (0, 7))
30321	28139732	Our previous study in breast cancer also showed decreased tumor growth after treatment with HET0016.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('decreased', 'NegReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('HET0016', 'Var', (92, 99))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
30342	28139732	IV administration of HET0016 significantly reduced the tumor growth (in delayed [day 8-21] treatment) compared to that of vehicle treated animals (p < 0.001) (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('HET0016', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('rat', 'Species', '10116', (11, 14))	('reduced', 'NegReg', (43, 50))
30347	28139732	We also evaluated the blood chemistry to determine the toxicity following 0-21 days of treatment with either vehicle, IV formulated or IP HET0016 in GBM xenografts.	('toxicity', 'Disease', (55, 63))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('IP HET0016', 'Var', (135, 145))	('toxicity', 'Disease', 'MESH:D064420', (55, 63))
30361	28139732	We observed reduced levels of COX-1, CYP4A11, p-ERK, p-AKT, p-STAT1, HIF1alpha, EGFR, VEGF, MMP-2 and p-NFKB proteins in tumors obtained from both IV treatment groups as compared to vehicle (Supplementary Figure 3b), which confirms the influence of HPbetaCD-HET0016 on cell proliferation, migration, and inflammation pathways.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CYP4A11', 'Var', (37, 44))	('reduced', 'NegReg', (12, 19))	('tumors', 'Disease', (121, 127))	('p-STAT1', 'Var', (60, 67))	('HPbetaCD', 'Chemical', 'MESH:D000073738', (249, 257))	('inflammation', 'Disease', 'MESH:D007249', (304, 316))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('inflammation', 'Disease', (304, 316))	('p-NFKB', 'Var', (102, 108))	('rat', 'Species', '10116', (281, 284))	(', EGFR,', 'Gene', '24329', (78, 85))	('COX', 'Gene', (30, 33))	('rat', 'Species', '10116', (292, 295))	('COX', 'Gene', '304024', (30, 33))
30363	28139732	First, we tested the effect of treatment in vitro 3D culture model (HF2303) and found that the treatment with HET0016 or TMZ alone or combination showed the inhibition of the growth of neurospheres Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (121, 124))	('HET0016', 'Var', (110, 117))	('HF2303', 'CellLine', 'CVCL:M656', (68, 74))	('growth of neurospheres Fig', 'CPA', (175, 201))	('inhibition', 'NegReg', (157, 167))
30365	28139732	The overall survival in GBM811 model was prolonged to 26 weeks after the treatment with HET0016 plus TMZ and radiation, while control animals (supercontrol and irradiated only control) survived only for 10 weeks similar to the clinical setting (Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (101, 104))	('GBM811', 'Var', (24, 30))	('prolonged', 'PosReg', (41, 50))	('GBM', 'Phenotype', 'HP:0012174', (24, 27))	('HET0016 plus', 'Var', (88, 100))
30367	28139732	Therefore, the current study provides evidence that combination therapy (HET0016 + TMZ) with irradiation can improve survival in GBM.	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('improve', 'PosReg', (109, 116))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('HET0016 + TMZ', 'Var', (73, 86))	('GBM', 'Disease', (129, 132))	('survival', 'CPA', (117, 125))
30369	28139732	The cumulative survival was 25% for both HET0016 plus TMZ combination group and HET0016 alone group at 26 weeks as compared to 0% in radiation only group (p < 0.18).	('cumulative survival', 'CPA', (4, 23))	('HET0016', 'Var', (41, 48))	('TMZ', 'Chemical', 'MESH:D000077204', (54, 57))
30370	28139732	Thus, data indicates combination treatment with HET0016 plus TMZ and irradiation resulted in better survival benefit as compared to radiation alone.	('survival benefit', 'CPA', (100, 116))	('TMZ', 'Chemical', 'MESH:D000077204', (61, 64))	('HET0016', 'Var', (48, 55))
30371	28139732	Overall, the response was better in GBM811 model than HF2303 model and may be attributed to difference in growth and genetic characteristics.	('HF2303', 'CellLine', 'CVCL:M656', (54, 60))	('GBM811 model', 'Var', (36, 48))	('response', 'MPA', (13, 21))	('better', 'PosReg', (26, 32))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
30375	28139732	There was significantly reduced tumor volume in animals treated with IV HET0016 (54.33 +- 12.37 mm3) compared to that of vehicle treated animals (131.70 +- 19.45 mm3) (p < 0.007) (Supplementary Figure 1).	('HET0016', 'Var', (72, 79))	('reduced', 'NegReg', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
30380	28139732	IV administration of HPssCD-HET0016 in a rat model of human GBM significantly reduced tumor growth in developing or developed tumors as compared to IP HET0016 treatment.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', (86, 91))	('HPssCD-HET0016', 'Var', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('rat', 'Species', '10116', (41, 44))	('reduced', 'NegReg', (78, 85))	('rat', 'Species', '10116', (11, 14))	('HPssCD', 'Chemical', '-', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('human', 'Species', '9606', (54, 59))	('tumor', 'Disease', (126, 131))
30381	28139732	It appears that the IV formulation facilitated increased delivery of HET0016 to the hypervascular and hypoxic tumor sites, due to EPR effects.	('hypoxic tumor', 'Disease', 'MESH:D009369', (102, 115))	('HET0016', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('hypoxic tumor', 'Disease', (102, 115))	('delivery', 'MPA', (57, 65))	('increased', 'PosReg', (47, 56))	('hypervascular', 'Disease', 'None', (84, 97))	('hypervascular', 'Disease', (84, 97))
30382	28139732	Moreover, the effect of IV HET0016 was not cell specific and showed similar reduced tumor growth in syngeneic tumor (GL261) models.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('HET0016', 'Var', (27, 34))	('GL261', 'Chemical', '-', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('syngeneic tumor', 'Disease', (100, 115))	('tumor', 'Disease', (84, 89))	('reduced', 'NegReg', (76, 83))	('syngeneic tumor', 'Disease', 'MESH:D009369', (100, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
30389	28139732	Unfortunately, majority of the primary and recurrent GBMs have unmethylated or active high level of MGMT, which make TMZ treatment unresponsive.	('GBMs', 'Disease', (53, 57))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('unmethylated', 'Var', (63, 75))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('MGMT', 'MPA', (100, 104))
30392	28139732	Therefore, HET0016 plus TMZ combination may prolong survival and reduce therapy resistance.	('TMZ', 'Chemical', 'MESH:D000077204', (24, 27))	('HET0016', 'Var', (11, 18))	('prolong', 'PosReg', (44, 51))	('survival', 'CPA', (52, 60))	('reduce', 'NegReg', (65, 71))	('therapy resistance', 'MPA', (72, 90))
30393	28139732	The synergistic effect may be due to the role of HET0016 in sensitizing the action of TMZ and irradiation by reducing DNA repair mechanisms.	('HET0016', 'Var', (49, 56))	('DNA repair mechanisms', 'MPA', (118, 139))	('TMZ', 'Chemical', 'MESH:D000077204', (86, 89))	('reducing', 'NegReg', (109, 117))	('sensitizing', 'MPA', (60, 71))
30396	28139732	The anti-tumor effect of HPssCD-HET0016 was supported by decreased tumor cell proliferation, migration, and neovascularization.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('migration', 'CPA', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('neovascularization', 'CPA', (108, 126))	('HPssCD-HET0016', 'Var', (25, 39))	('rat', 'Species', '10116', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (9, 14))	('HPssCD', 'Chemical', '-', (25, 31))	('tumor', 'Disease', (67, 72))	('rat', 'Species', '10116', (96, 99))	('decreased', 'NegReg', (57, 66))
30399	28139732	In addition, we suggest that the effect of HET0016 on tumor growth may be attributed to the reduced basic fibroblast growth factor expression (bFGF or FGF-2) after early and delayed treatment.	('bFGF', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('bFGF', 'Gene', '54250', (143, 147))	('basic fibroblast growth factor expression', 'MPA', (100, 141))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('reduced', 'NegReg', (92, 99))	('FGF-2', 'Gene', (151, 156))	('tumor', 'Disease', (54, 59))	('HET0016', 'Var', (43, 50))
30403	28139732	We found overall fewer vessels in both early and delayed IV treatment group, with reduced EES, laminin, and alphaSMA staining, especially at the invasive margin of the tumor indicating the role of HET0016 in inhibiting the growth of new blood vessels.	('fewer', 'NegReg', (17, 22))	('laminin', 'Protein', (95, 102))	('vessels', 'CPA', (23, 30))	('tumor', 'Disease', (168, 173))	('growth of new blood vessels', 'CPA', (223, 250))	('alphaSMA staining', 'Protein', (108, 125))	('HET0016', 'Var', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('reduced', 'NegReg', (82, 89))	('inhibiting', 'NegReg', (208, 218))	('EES', 'MPA', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
30405	28139732	We suggest that HPssCD-HET0016 has a primary effect on blood vessels, which by normalization increased the bioavailability of drug to the hypoxic tumor sites.	('hypoxic tumor', 'Disease', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('bioavailability of drug', 'MPA', (107, 130))	('hypoxic tumor', 'Disease', 'MESH:D009369', (138, 151))	('HPssCD', 'Chemical', '-', (16, 22))	('increased', 'PosReg', (93, 102))	('blood vessels', 'MPA', (55, 68))	('HPssCD-HET0016', 'Var', (16, 30))
30408	28139732	In our study, we observed that HET0016 reduced expression of the pro-angiogenic proteins but increased the expression of anti-angiogenic proteins expression to achieve equilibrium to reduce tumor growth.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('HET0016', 'Var', (31, 38))	('increased', 'PosReg', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('expression', 'MPA', (107, 117))	('tumor', 'Disease', (190, 195))	('reduced', 'NegReg', (39, 46))	('expression', 'MPA', (47, 57))	('reduce', 'NegReg', (183, 189))
30412	28139732	Moreover, HET0016 treatment reduces the expression of MCP-1 and SDF-1alpha, key chemokines responsible for trafficking and activation of monocytes/macrophages and have been involved in inflammation and angiogenesis.	('expression', 'MPA', (40, 50))	('MCP-1', 'Gene', (54, 59))	('reduces', 'NegReg', (28, 35))	('HET0016', 'Var', (10, 17))	('SDF-1alpha', 'Gene', (64, 74))	('inflammation', 'Disease', 'MESH:D007249', (185, 197))	('inflammation', 'Disease', (185, 197))
30420	28139732	In present study, we found HET0016 was able to reduce the protein expression of CYP4A11 and COX-1, thereby influencing inflammation, angiogenesis, and MAPK signaling in GBM.	('HET0016', 'Var', (27, 34))	('reduce', 'NegReg', (47, 53))	('inflammation', 'Disease', 'MESH:D007249', (119, 131))	('protein expression', 'MPA', (58, 76))	('CYP4A11', 'Gene', (80, 87))	('angiogenesis', 'CPA', (133, 145))	('influencing', 'Reg', (107, 118))	('inflammation', 'Disease', (119, 131))	('GBM', 'Phenotype', 'HP:0012174', (169, 172))	('MAPK signaling', 'MPA', (151, 165))	('COX', 'Gene', (92, 95))	('COX', 'Gene', '304024', (92, 95))
30425	28139732	We demonstrated reduced levels of p-NFkappaB after HET0016 treatment suggesting an anti-proliferative effect in glioma.	('p-NFkappaB', 'Protein', (34, 44))	('HET0016', 'Var', (51, 58))	('rat', 'Species', '10116', (95, 98))	('reduced', 'NegReg', (16, 23))	('glioma', 'Disease', (112, 118))	('anti-proliferative effect', 'CPA', (83, 108))	('levels', 'MPA', (24, 30))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('rat', 'Species', '10116', (10, 13))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
30429	28139732	We found that HPssCD-HET0016 treatment also reduced the levels of pSTAT1, indicating HET0016 can improve overall prognosis in glioma.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('levels of pSTAT1', 'MPA', (56, 72))	('reduced', 'NegReg', (44, 51))	('glioma', 'Disease', (126, 132))	('improve', 'PosReg', (97, 104))	('HET0016', 'Var', (85, 92))	('HPssCD', 'Chemical', '-', (14, 20))
30431	28139732	Our results showed that HET0016 in combination with TMZ and radiation enhanced the anti-tumor efficacy and prolonged survival in GBM xenograft models as compared to TMZ alone.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('HET0016', 'Var', (24, 31))	('prolonged', 'PosReg', (107, 116))	('enhanced', 'PosReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('survival', 'CPA', (117, 125))	('tumor', 'Disease', (88, 93))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
30432	28139732	Anti-tumor properties of HPssCD-HET0016 resulted in decreasing proliferation, hypoxia, migration, stemness, and vasculatures in glioma by altering the balance of pro-angiogenic and anti-angiogenic balance, PI3K/Akt, p38/MAPK and inflammation pathways (Summary model in Fig.	('migration', 'CPA', (87, 96))	('proliferation', 'CPA', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('HPssCD-HET0016', 'Var', (25, 39))	('inflammation', 'Disease', (229, 241))	('decreasing', 'NegReg', (52, 62))	('stemness', 'Disease', 'MESH:D020295', (98, 106))	('stemness', 'Disease', (98, 106))	('altering', 'Reg', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('rat', 'Species', '10116', (70, 73))	('hypoxia', 'Disease', (78, 85))	('glioma', 'Disease', (128, 134))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('HPssCD', 'Chemical', '-', (25, 31))	('rat', 'Species', '10116', (90, 93))	('inflammation', 'Disease', 'MESH:D007249', (229, 241))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('tumor', 'Disease', (5, 10))	('PI3K/Akt', 'Pathway', (206, 214))
30465	28139732	Two different PDX models were developed using HF2303 (n = 11) and GBM811 (n = 13).	('GBM811', 'Gene', (66, 72))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('HF2303', 'Var', (46, 52))	('HF2303', 'CellLine', 'CVCL:M656', (46, 52))
30467	28139732	Prior to the start of treatment, animals underwent MRI at 6 weeks for GBM811 and 10 weeks for HF2303 before the start of treatment to confirm the presence of a 3 mm3 tumor.	('HF2303', 'CellLine', 'CVCL:M656', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('GBM811', 'Var', (70, 76))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))
30482	28139732	Our previous experience showed that HF2303 GBM bearing animals die by 16-20 weeks and GBM811 tumor bearing animals die in 12-16 weeks if not treated.	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('HF2303', 'CellLine', 'CVCL:M656', (36, 42))	('tumor', 'Disease', (93, 98))	('GBM', 'Phenotype', 'HP:0012174', (86, 89))	('HF2303', 'Var', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
30489	26908439	When compared to the normal human astrocytes (NHAs) and hNSCs, hNSCs-BMP4 could significantly inhibit the invasive growth of hGSCs, promote their differentiation and apoptosis by activating Smad1/5/8 signaling, and prolong the survival time of the tumor-bearing nude mice.	('hNSCs-BMP4', 'Var', (63, 73))	('tumor', 'Disease', (248, 253))	('activating', 'PosReg', (179, 189))	('invasive growth', 'CPA', (106, 121))	('human', 'Species', '9606', (28, 33))	('prolong', 'PosReg', (215, 222))	('differentiation', 'CPA', (146, 161))	('survival time', 'CPA', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('Smad1/5', 'Gene', '4086;4090', (190, 197))	('Smad1/5', 'Gene', (190, 197))	('promote', 'PosReg', (132, 139))	('inhibit', 'NegReg', (94, 101))	('nude mice', 'Species', '10090', (262, 271))	('apoptosis', 'CPA', (166, 175))
30512	26908439	In this matter, Lee and colleagues also found that BMPs promoted apparent glial differentiation in BTSCs in some patient-derived samples.	('promoted', 'PosReg', (56, 64))	('patient', 'Species', '9606', (113, 120))	('apparent glial differentiation', 'CPA', (65, 95))	('BMPs', 'Var', (51, 55))
30532	26908439	The results showed that after addition of NSCs-BMP4/CM at the 48th huor, the expression of phospho-Smad1 had increased and the latter accumulated in the nucleus of hGSCs (Figure 2D).	('expression', 'MPA', (77, 87))	('Smad1', 'Gene', (99, 104))	('Smad1', 'Gene', '17125', (99, 104))	('accumulated', 'PosReg', (134, 145))	('increased', 'PosReg', (109, 118))	('NSCs-BMP4/CM', 'Var', (42, 54))
30534	26908439	Consistently, Ki67 staining in hGSCs, cultured with BMP4 (20ng/ml) and NSCs-BMP4/CM, was reduced significantly then it was cultured with Con/CM and NSCs/CM groups (Figure 3A, P < 0.05, student's t-test).	('Ki67', 'Gene', '17345', (14, 18))	('staining', 'MPA', (19, 27))	('NSCs-BMP4/CM', 'Var', (71, 83))	('reduced', 'NegReg', (89, 96))	('Ki67', 'Gene', (14, 18))
30554	26908439	We found that the mice that received hNSCs-BMP4 survived for a significant longer time than those that were inoculated with NHAs group (the log-rank test P < 0.005) (Figure 5C).	('longer', 'PosReg', (75, 81))	('hNSCs-BMP4', 'Var', (37, 47))	('mice', 'Species', '10090', (18, 22))
30590	26908439	Briefly, the dissociated cells were placed into culture plates with a serum-free medium that was supplemented with mitogens (20ng/ml EGF, 20ng/ml b-FGF, and 10ng/ml LIF) (Invitrogen, CA, USA).	('20ng/ml', 'Var', (125, 132))	('b-FGF', 'Gene', '14173', (146, 151))	('LIF', 'Gene', (165, 168))	('LIF', 'Gene', '16878', (165, 168))	('b-FGF', 'Gene', (146, 151))
30660	27152253	Cancer cell phenotype must be regulated by its microenvironment, given that oncogenic mutations present in the genotype of every cell of a patient only manifests as cancer in specific tissues and regions.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('patient', 'Species', '9606', (139, 146))	('men', 'Species', '9606', (59, 62))
30681	27152253	The T4-2 line is characterized by aberrantly high expression of beta1 and beta4 integrins, and disruption of cell-matrix interactions using beta1 and beta4 integrin inhibitors caused massive apoptosis in the non-malignant cultures and a reversion to a non-malignant phenotype in the malignant cultures.	('apoptosis', 'CPA', (191, 200))	('non-malignant phenotype', 'CPA', (252, 275))	('disruption', 'Var', (95, 105))	('beta1 and beta4', 'Gene', '10678;10381', (64, 79))	('beta1 and beta4', 'Gene', '10678;10381', (140, 155))	('expression', 'MPA', (50, 60))
30755	27152253	U373-MG and U87-MG glioblastoma multiforme (GBM) cells were cultured as multicellular spheroids and embedded within functionalized HA gels, and compared with parallel cultures on HA-coated tissue culture plates and in 3D collagen hydrogels.	('U87-MG glioblastoma multiforme', 'Disease', 'MESH:D005909', (12, 42))	('HA', 'Chemical', 'MESH:D006820', (179, 181))	('U87-MG glioblastoma multiforme', 'Disease', (12, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('HA', 'Chemical', 'MESH:D006820', (131, 133))	('U373-MG', 'Var', (0, 7))
30773	27152253	Similarly, the Zhao group used commercially available RADA16-I peptides, capable of generating nanofibrous (d = 10 nm) hydrogels with pore size ranging from 5 to 200 nm, for a 3D tumor model of ovarian cancer (A2780, A2780/DDP, SK-OV-3).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ovarian cancer', 'Disease', (194, 208))	('rat', 'Species', '10116', (88, 91))	('A2780', 'Var', (210, 215))	('3D tumor', 'Disease', 'MESH:D009369', (176, 184))	('A2780/DDP', 'Var', (217, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('3D tumor', 'Disease', (176, 184))	('ovarian cancer', 'Disease', 'MESH:D010051', (194, 208))
30964	25279461	Because of the functional role of miRNAs in a wide array of biological processes, including cell proliferation, differentiation and apoptosis, deregulation of miRNA expression represents a hallmark of cancer, where they can act either as oncogenes or tumour suppressors contributing to initiation and progression of cancer.	('apoptosis', 'CPA', (132, 141))	('deregulation', 'Var', (143, 155))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('miR', 'Gene', '220972', (34, 37))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('miR', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumour', 'Disease', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('miR', 'Gene', (159, 162))	('miR', 'Gene', '220972', (159, 162))	('cancer', 'Disease', (316, 322))	('differentiation', 'CPA', (112, 127))
30980	25279461	Single-stranded cDNA was synthesized from 5.5 ng of total RNA using 50 nM specific stem-loop RT primers for selected miRNAs (Life Technologies, Foster City, CA) and endogenous control RNU48 (P/N 4373383, Life Technologies, Foster City, CA), according to manufacturer's instructions (Table S1).	('P/N 4373383', 'Var', (191, 202))	('RNU48', 'Gene', '26801', (184, 189))	('RNU48', 'Gene', (184, 189))	('P/N 4373383', 'SUBSTITUTION', 'None', (191, 202))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))
31006	25279461	IDH1-R132H/C mutations were found in 7 out of 8 WHO II grade tumours (88%, R132H in six samples and R132C in one sample), 1 out of the 2 anaplastic astrocytomas (50%, R132C), and as expected by the low frequencies reported in literature in none of the GBMs (0%).	('R132C', 'Var', (167, 172))	('R132C', 'Mutation', 'rs121913499', (167, 172))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('R132H', 'Var', (5, 10))	('IDH1', 'Gene', (0, 4))	('anaplastic astrocytomas', 'Disease', 'MESH:D001254', (137, 160))	('R132H', 'Var', (75, 80))	('R132H', 'SUBSTITUTION', 'None', (5, 10))	('IDH1', 'Gene', '3417', (0, 4))	('anaplastic astrocytomas', 'Disease', (137, 160))	('R132C', 'Var', (100, 105))	('R132C', 'Mutation', 'rs121913499', (100, 105))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('R132H', 'SUBSTITUTION', 'None', (75, 80))	('tumours', 'Disease', (61, 68))	('found', 'Reg', (28, 33))	('astrocytoma', 'Phenotype', 'HP:0009592', (148, 159))	('R132H', 'Mutation', 'rs121913500', (75, 80))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
31009	25279461	MGMT status was previously determined by using Quantitative Methylation Specific PCR (QMSP): aberrant promoter methylation was found in the 68.75% of the 32 glioma patients.	('MGMT', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('aberrant', 'Var', (93, 101))	('patients', 'Species', '9606', (164, 172))	('glioma', 'Disease', (157, 163))	('found', 'Reg', (127, 132))	('promoter methylation', 'MPA', (102, 122))	('MGMT', 'Gene', '4255', (0, 4))
31019	25279461	The remaining miRNAs (miR-519d, miR-326, miR-139-3p, miR-767-5p, let7d-star, miR-342-3p, and miR-383) were differentially expressed only in grade II gliomas as compared with NBT (Mann Whitney Test).	('miR', 'Gene', (77, 80))	('miR-139-3p', 'Gene', (41, 51))	('miR', 'Gene', '220972', (53, 56))	('II gliomas', 'Disease', 'MESH:D005910', (146, 156))	('miR-326', 'Gene', (32, 39))	('miR-139-3p', 'Gene', '406931', (41, 51))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('miR-326', 'Gene', '442900', (32, 39))	('miR', 'Gene', (14, 17))	('miR-342', 'Gene', (77, 84))	('miR', 'Gene', (93, 96))	('miR', 'Gene', (53, 56))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('miR', 'Gene', '220972', (41, 44))	('NBT', 'Chemical', '-', (174, 177))	('miR', 'Gene', '220972', (32, 35))	('miR-342', 'Gene', '442909', (77, 84))	('miR', 'Gene', (41, 44))	('let7d-star', 'Var', (65, 75))	('II gliomas', 'Disease', (146, 156))	('miR', 'Gene', '220972', (77, 80))	('miR', 'Gene', (32, 35))	('miR', 'Gene', '220972', (22, 25))	('miR-383', 'Gene', '494332', (93, 100))	('miR-519d', 'Gene', '574480', (22, 30))	('miR-383', 'Gene', (93, 100))	('miR-519d', 'Gene', (22, 30))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (22, 25))
31027	25279461	Multivariable Cox regression analysis was performed by stratifying patients according to age and using MGMT methylation status, IDH1 mutations, pre-treatment, recurrence, and TCGA prognostic classification as covariates (n = 185).	('MGMT', 'Gene', '4255', (103, 107))	('IDH1', 'Gene', '3417', (128, 132))	('patients', 'Species', '9606', (67, 75))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('mutations', 'Var', (133, 142))	('IDH1', 'Gene', (128, 132))	('MGMT', 'Gene', (103, 107))
31033	25279461	Multivariable Cox regression analysis was performed including the three miRNAs, age and IDH1 mutational status.	('IDH1', 'Gene', (88, 92))	('mutational', 'Var', (93, 103))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('IDH1', 'Gene', '3417', (88, 92))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))
31034	25279461	This analysis demonstrated an association between age (HR 1.072; 95%CI 1.015-1.13, p = 0.013) and worse OS, while IDH1 mutations were associated with better survival (HR 0.014; 0.001-0.216, p = 0.002).	('better', 'PosReg', (150, 156))	('IDH1', 'Gene', (114, 118))	('IDH1', 'Gene', '3417', (114, 118))	('mutations', 'Var', (119, 128))	('worse OS', 'Disease', (98, 106))
31080	24066922	Although there are marked genomic differences between primary (de novo pathway) and secondary (progressive pathway) glioblastoma, a physiological adaptation to hypoxia and critical genetic mutations commonly converge on a final tumor angiogenesis pathway.	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('glioblastoma', 'Disease', (116, 128))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('tumor', 'Disease', (228, 233))	('mutations', 'Var', (189, 198))	('converge', 'Reg', (208, 216))
31110	24066922	U87MG cells (1.0 x 107 cells) were plated in 96-well plates, incubated in MEM containing 5% fetal bovine serum and 1% antibiotics at 37 C in a humidified atmosphere with 5% CO2, and treated with carboxylated MNC or Apt-MNC at various concentrations for 24 h. An MTT assay was performed and the relative percentage of cell viability was calculated as the ratio of formazan intensity in cells treated with carboxylated MNC or Apt-MNC to the formazan intensity in non-treated cells.	('formazan', 'Chemical', 'MESH:D005562', (363, 371))	('CO2', 'Chemical', '-', (173, 176))	('bovine', 'Species', '9913', (98, 104))	('carboxylate', 'Chemical', '-', (404, 415))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('carboxylate', 'Chemical', '-', (195, 206))	('carboxylated MNC', 'Var', (404, 420))	('formazan', 'Chemical', 'MESH:D005562', (439, 447))	('MTT', 'Chemical', 'MESH:C070243', (262, 265))	('Apt', 'Chemical', '-', (424, 427))	('Apt', 'Chemical', '-', (215, 218))	('Apt-MNC', 'Var', (424, 431))
31130	24066922	The oxyethylene chains (-OCH2CH2-) in the carboxyl polysorbate 80 can increase biocompatibility, and carboxyl groups can be readily conjugated with the amine-functionalized targeting moieties .	('-OCH2CH2-', 'Var', (24, 33))	('increase', 'PosReg', (70, 78))	('carboxyl polysorbate 80', 'Chemical', '-', (42, 65))	('conjugated', 'Interaction', (132, 142))	('oxyethylene', 'Chemical', '-', (4, 15))	('amine', 'Chemical', 'MESH:D000588', (152, 157))	('biocompatibility', 'MPA', (79, 95))
31134	24066922	The dimer structure of carboxylic acid in a condensed undiluted solution weakened the C=O binding, thus C=O stretching vibration in carboxylic acid appeared to have a lower wave number than the C=O stretching vibration in ester.	('lower', 'NegReg', (167, 172))	('wave number', 'MPA', (173, 184))	('carboxylic acid', 'Chemical', 'MESH:D002264', (23, 38))	('dimer structure', 'MPA', (4, 19))	('C=O binding', 'Interaction', (86, 97))	('C=O stretching vibration', 'Var', (104, 128))	('weakened', 'NegReg', (73, 81))	('carboxylic acid', 'Chemical', 'MESH:D002264', (132, 147))	('ester', 'Chemical', 'MESH:D004952', (222, 227))
31141	24066922	The hydrodynamic diameter of Apt-MNC (34.0 +- 5.8 nm) was slightly increased compared with that of carboxylated MNC (31.5 +- 2.2 nm) due to Apt conjugation (Figure  2c).	('carboxylate', 'Chemical', '-', (99, 110))	('Apt', 'Chemical', '-', (140, 143))	('increased', 'PosReg', (67, 76))	('Apt conjugation', 'Var', (140, 155))	('Apt-MNC', 'Var', (29, 36))	('hydrodynamic diameter', 'MPA', (4, 25))	('Apt', 'Chemical', '-', (29, 32))
31155	24066922	PAE/KDR cells treated with Apt-fluorescein exhibited fluorescence levels of 76.8% (green) when compared with that of non-treated PAE/KDR cells (control, 0.5% fluorescence level, black).	('KDR', 'Gene', (4, 7))	('KDR', 'Gene', '16542', (4, 7))	('KDR', 'Gene', '16542', (133, 136))	('fluorescence levels', 'MPA', (53, 72))	('KDR', 'Gene', (133, 136))	('Apt-fluorescein', 'Var', (27, 42))	('Apt-fluorescein', 'Chemical', '-', (27, 42))
31167	24066922	However, the tumor sites treated with Apt-MNC were darker than those treated with carboxylated MNC (red arrow) because Apt-MNC effectively targeted and bound to VEGFR2 of the tumor tissue, whereas carboxylated MNC was washed out in time .	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (175, 180))	('Apt', 'Chemical', '-', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('carboxylate', 'Chemical', '-', (82, 93))	('bound', 'Interaction', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('carboxylate', 'Chemical', '-', (197, 208))	('Apt', 'Chemical', '-', (119, 122))	('Apt-MNC', 'Var', (119, 126))
31177	24066922	Tumor tissues treated with carboxylated MNC showed red (nuclei) and pink (cytoplasm) pigments, but lacked blue pigment.	('carboxylated MNC', 'Var', (27, 43))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carboxylate', 'Chemical', '-', (27, 38))	('lacked', 'NegReg', (99, 105))
31178	24066922	These results demonstrated that the tumor regions, which were identified in the in vivo MR imaging, were successfully targeted by Apt-MNC.	('Apt', 'Chemical', '-', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Apt-MNC', 'Var', (130, 137))	('tumor', 'Disease', (36, 41))
31192	22977194	FoxM1 knockdown inhibited Rad51 expression and sensitized recurrent GBM cells to TMZ cytotoxicity.	('inhibited', 'NegReg', (16, 25))	('recurrent GBM cells', 'CPA', (58, 77))	('cytotoxicity', 'Disease', (85, 97))	('FoxM1', 'Gene', (0, 5))	('TMZ', 'Chemical', 'MESH:D000077204', (81, 84))	('knockdown', 'Var', (6, 15))	('expression', 'MPA', (32, 42))	('sensitized', 'Reg', (47, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('Rad51', 'Protein', (26, 31))
31203	22977194	Several studies have shown that Rad51 expression levels are elevated in GBM cell lines and that targeting Rad51 with Rad51 antisense or imatinib can effectively sensitize cancer cells to radiation therapy.	('expression levels', 'MPA', (38, 55))	('Rad51', 'Gene', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('elevated', 'PosReg', (60, 68))	('Rad51', 'Gene', (32, 37))	('cancer', 'Disease', (171, 177))	('targeting', 'Var', (96, 105))	('sensitize', 'Reg', (161, 170))	('Rad51', 'Gene', (106, 111))	('imatinib', 'Chemical', 'MESH:D000068877', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
31204	22977194	More recently, targeting Rad51 was found to increase GBM cells' sensitivity to TMZ.	('targeting', 'Var', (15, 24))	('Rad51', 'Gene', (25, 30))	('sensitivity to TMZ', 'MPA', (64, 82))	('increase', 'PosReg', (44, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (79, 82))
31210	22977194	In addition, FoxM1 transcriptionally regulated Rad51, and re-expressing Rad51 in FoxM1-knockdown cells partially rescued TMZ resistance.	('Rad51', 'Gene', (72, 77))	('TMZ', 'Chemical', 'MESH:D000077204', (121, 124))	('rescued', 'PosReg', (113, 120))	('FoxM1', 'Gene', (13, 18))	('Rad51', 'Gene', (47, 52))	('TMZ resistance', 'MPA', (121, 135))	('re-expressing', 'Var', (58, 71))
31237	22977194	The Rad51 mutant promoter constructs were generated using the QuikChange site-directed mutagenesis kit (Stratagene).	('Rad51', 'Gene', (4, 9))	('rat', 'Species', '10116', (46, 49))	('mutant', 'Var', (10, 16))	('rat', 'Species', '10116', (106, 109))
31239	22977194	An immunohistochemical analysis of human GBM specimens was performed using anti-FoxM1 or anti-Rad51 antibody.	('human', 'Species', '9606', (35, 40))	('anti-Rad51', 'Var', (89, 99))	('anti-FoxM1', 'Var', (75, 85))
31267	22977194	Previous studies indicated that Rad51 forms repair-associated foci after DNA damage at sites of replication fork collapse and that high Rad51 levels are predictive of stronger radiation therapy or chemotherapy resistance in human cancers.	('stronger', 'PosReg', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Rad51', 'Gene', (32, 37))	('human', 'Species', '9606', (224, 229))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('chemotherapy resistance', 'CPA', (197, 220))	('Rad51', 'Gene', (136, 141))	('cancers', 'Disease', (230, 237))	('repair-associated foci', 'MPA', (44, 66))	('radiation therapy', 'CPA', (176, 193))	('high', 'Var', (131, 135))
31270	22977194	To screen the downstream genes of FoxM1, a microarray analysis was performed after FoxM1 knockdown by siRNA in the U87 glioma cell line.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('FoxM1', 'Gene', (83, 88))	('U87', 'CellLine', 'CVCL:0022', (115, 118))	('glioma', 'Disease', (119, 125))	('knockdown', 'Var', (89, 98))
31271	22977194	To further test this result, we generated two stable cell lines of FoxM1 knockdown using recurrent GBM1 and GBM2 cells, referred to as shFoxM1-1 and shFoxM1-2, respectively.	('rat', 'Species', '10116', (36, 39))	('FoxM1', 'Gene', (67, 72))	('knockdown', 'Var', (73, 82))
31273	22977194	By using the 2.6-kb Rad 51 promoter plasmid, we found that silencing FoxM1 in GBM1 and GBM2 cells dramatically reduced Rad51 promoter activity (Fig.	('Rad 51', 'Gene', (20, 26))	('Rad 51', 'Gene', '5888', (20, 26))	('reduced', 'NegReg', (111, 118))	('Rad51 promoter activity', 'MPA', (119, 142))	('FoxM1', 'Gene', (69, 74))	('silencing', 'Var', (59, 68))
31276	22977194	To determine the functional role of FoxM1-binding sites in Rad51 gene regulation, various mutant reporters harboring different predicted mutant binding sites of FoxM1 were generated from the wild-type Rad51 promoter construct, including site 1 (mutation 1) and site 2 (mutation 2) and site 1 plus site 2 (Fig.	('FoxM1', 'Gene', (161, 166))	('rat', 'Species', '10116', (176, 179))	('mutant', 'Var', (137, 143))
31279	22977194	FoxM1 induction by TMZ was significantly attenuated in FoxM1 knockdown cells (Fig.	('attenuated', 'NegReg', (41, 51))	('TMZ', 'Chemical', 'MESH:D000077204', (19, 22))	('knockdown', 'Var', (61, 70))	('FoxM1', 'Gene', (0, 5))	('FoxM1', 'Gene', (55, 60))
31285	22977194	To determine whether TMZ resistance in recurrent GBM tumor cells is dependent on Rad51, we inhibited Rad51 expression by sh-Rad51 in GBM cells (Fig.	('Rad51', 'Gene', (101, 106))	('inhibited', 'NegReg', (91, 100))	('expression', 'MPA', (107, 117))	('GBM tumor', 'Disease', 'MESH:D005910', (49, 58))	('GBM tumor', 'Disease', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sh-Rad51', 'Var', (121, 129))	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))
31286	22977194	Rad51 knockdown significantly decreased the number of Rad51 foci induced by TMZ treatment (Fig.	('TMZ', 'Chemical', 'MESH:D000077204', (76, 79))	('Rad51', 'Gene', (54, 59))	('Rad51', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('decreased', 'NegReg', (30, 39))
31287	22977194	Moreover, re-expression of Rad51 in FoxM1-silenced GBM cells resulted in increased levels of BRCA2 and Chk2 expression (Fig.	('increased', 'PosReg', (73, 82))	('Rad51', 'Gene', (27, 32))	('levels', 'MPA', (83, 89))	('BRCA2', 'Gene', '675', (93, 98))	('FoxM1-silenced', 'Gene', (36, 50))	('Chk2', 'Gene', '11200', (103, 107))	('re-expression', 'Var', (10, 23))	('Chk2', 'Gene', (103, 107))	('BRCA2', 'Gene', (93, 98))
31291	22977194	These data suggest that Rad51 partially rescues TMZ resistance after FoxM1 knockdown.	('TMZ', 'Chemical', 'MESH:D000077204', (48, 51))	('TMZ resistance', 'MPA', (48, 62))	('knockdown', 'Var', (75, 84))	('FoxM1', 'Gene', (69, 74))	('Rad51', 'Gene', (24, 29))	('rescues', 'PosReg', (40, 47))
31293	22977194	Glioma cells expressing sh-FoxM1, sh-Rad51, or sh-FoxM1 with re-expression of Rad51 were intracranially injected into nude mice.	('sh-FoxM1', 'Var', (24, 32))	('nude mice', 'Species', '10090', (118, 127))	('sh-Rad51', 'Var', (34, 42))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Rad51', 'Gene', (78, 83))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))
31295	22977194	5, FoxM1 or Rad51 knockdown led to decreased tumor formation and prolonged mouse survival and Rad51 re-expression partially rescued the processes mediated by knockdown of FoxM1.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Rad51', 'Gene', (94, 99))	('tumor', 'Disease', (45, 50))	('FoxM1', 'Gene', (171, 176))	('prolonged', 'PosReg', (65, 74))	('decreased', 'NegReg', (35, 44))	('knockdown', 'Var', (158, 167))	('mouse', 'Species', '10090', (75, 80))	('FoxM1', 'Gene', (3, 8))	('mouse survival', 'CPA', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
31296	22977194	Moreover, TMZ treatment increased the mouse survival of Rad51 knockdown group as compared with untreated group, whereas TMZ treatment did not shown any effect in FoxM1 knockdown plus Rad51 re-expression group (Supplementary Fig.	('mouse', 'Species', '10090', (38, 43))	('Rad51', 'Gene', (56, 61))	('mouse survival', 'CPA', (38, 52))	('TMZ', 'Chemical', 'MESH:D000077204', (120, 123))	('TMZ', 'Chemical', 'MESH:D000077204', (10, 13))	('increased', 'PosReg', (24, 33))	('knockdown', 'Var', (62, 71))
31298	22977194	However, the FoxM1 protein level was not correlated with MGMT promoter methylation status or IDH1 R132 mutation in patient samples (Supplementary Tables 5 and 6).	('IDH1 R132', 'Gene', (93, 102))	('MGMT', 'Gene', '4255', (57, 61))	('MGMT', 'Gene', (57, 61))	('mutation', 'Var', (103, 111))	('patient', 'Species', '9606', (115, 122))
31299	22977194	In this study, we found that FoxM1 expression levels were higher in recurrent than in original GBM tumors and that targeting FoxM1 sensitized recurrent GBM cells to TMZ cytotoxicity.	('FoxM1', 'Gene', (29, 34))	('cytotoxicity', 'Disease', (169, 181))	('original GBM tumors', 'Disease', 'MESH:D005910', (86, 105))	('recurrent', 'Disease', (68, 77))	('original GBM tumors', 'Disease', (86, 105))	('expression levels', 'MPA', (35, 52))	('sensitized', 'Reg', (131, 141))	('cytotoxicity', 'Disease', 'MESH:D064420', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('higher', 'PosReg', (58, 64))	('targeting', 'Var', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('FoxM1', 'Gene', (125, 130))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
31307	22977194	Primary GBM cells were sensitized to TMZ cytotoxicity after FoxM1 knockdown.	('FoxM1', 'Gene', (60, 65))	('cytotoxicity', 'Disease', (41, 53))	('TMZ', 'Chemical', 'MESH:D000077204', (37, 40))	('knockdown', 'Var', (66, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
31311	22977194	Further, when Rad51 was overexpressed in FoxM1-knockdown GBM cells, the cells became resistant to TMZ, indicating that the FoxM1-Rad51 axis plays a critical role in TMZ resistance.	('overexpressed', 'PosReg', (24, 37))	('FoxM1-knockdown', 'Var', (41, 56))	('FoxM1-knockdown', 'Gene', (41, 56))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('TMZ', 'Chemical', 'MESH:D000077204', (165, 168))
31313	22977194	Furthermore, Rad51 re-expression partially rescued the tumor inhibition mediated by FoxM1 knockdown and Rad51 knockdown increased the TMZ sensitivity of recurrent GBM cells in vivo, although animal experiments with different doses of TMZ are needed in future studies.	('knockdown', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TMZ sensitivity', 'MPA', (134, 149))	('knockdown', 'Var', (90, 99))	('FoxM1', 'Gene', (84, 89))	('Rad51', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('TMZ', 'Chemical', 'MESH:D000077204', (134, 137))	('increased', 'PosReg', (120, 129))	('TMZ', 'Chemical', 'MESH:D000077204', (234, 237))
31316	22977194	Other studies have reported that inhibition of several FoxM1 downstream genes, such as survivin and PLK1, can sensitize breast cancer cells to chemotherapy.	('inhibition', 'Var', (33, 43))	('PLK1', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('sensitize', 'Reg', (110, 119))	('breast cancer', 'Disease', (120, 133))	('PLK1', 'Gene', '5347', (100, 104))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('survivin', 'Gene', (87, 95))	('FoxM1', 'Gene', (55, 60))
31318	22977194	Moreover, FoxM1 inhibition can impair the self-renewal of glioma-initiated cells.	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('impair', 'NegReg', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('FoxM1', 'Gene', (10, 15))	('glioma', 'Disease', (58, 64))	('inhibition', 'Var', (16, 26))
31319	22977194	These results indicate that FoxM1 plays a key role in tumor cell resistance and that targeting it is an effective method of increasing tumor cells' chemosensitivity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (135, 140))	('targeting', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('FoxM1', 'Gene', (28, 33))	('tumor', 'Disease', (54, 59))	('increasing', 'PosReg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
31323	22977194	Further, Rad51 re-expression in FoxM1-knockdown GBM cells partially rescued their TMZ resistance.	('FoxM1-knockdown', 'Gene', (32, 47))	('re-expression', 'Var', (15, 28))	('TMZ resistance', 'MPA', (82, 96))	('Rad51', 'Gene', (9, 14))	('rescued', 'PosReg', (68, 75))	('TMZ', 'Chemical', 'MESH:D000077204', (82, 85))
31324	22977194	Our findings demonstrate that the FoxM1-Rad51 axis plays an important role in GBM chemotherapy resistance and that targeting FoxM1 may be an efficient method to enhance TMZ sensitivity.	('enhance', 'PosReg', (161, 168))	('TMZ', 'Chemical', 'MESH:D000077204', (169, 172))	('TMZ sensitivity', 'MPA', (169, 184))	('rat', 'Species', '10116', (20, 23))	('targeting', 'Var', (115, 124))	('FoxM1', 'Gene', (125, 130))
31352	33070557	In a period of 10 years, a total of 115,050 patients were diagnosed with PCNSTs according to the ICD-O-3: brain (ICD-O-3: C71.0-C71.9); meninges (C70.0-C70.9); spinal cord, cranial nerves, and other parts of the CNS (C72.0-C72.9); pituitary gland and pineal gland (C75.1-C75.3); and olfactory region of the nasal cavity (C30.0 [9522-9523]), along with the World Health Organization (WHO) classification for brain tumors.	('PCNSTs', 'Chemical', '-', (73, 79))	('brain tumors', 'Phenotype', 'HP:0030692', (407, 419))	('patients', 'Species', '9606', (44, 52))	('brain tumors', 'Disease', 'MESH:D001932', (407, 419))	('tumor', 'Phenotype', 'HP:0002664', (413, 418))	('brain tumors', 'Disease', (407, 419))	('tumors', 'Phenotype', 'HP:0002664', (413, 419))	('C70.0-C70.9', 'Var', (146, 157))	('men', 'Species', '9606', (136, 139))
31465	33667282	Effect of treatment was evaluated by MRI and [18F]FDG PET on day 2, 5, 9 and 12 post-treatment and [18F]FCho PET on day 1, 6, 8 and 13 post-treatment.	('PET', 'Gene', '22095', (109, 112))	('F', 'Chemical', 'MESH:D005461', (102, 103))	('PET', 'Gene', (54, 57))	('PET', 'Gene', (109, 112))	('F', 'Chemical', 'MESH:D005461', (48, 49))	('FCho', 'Chemical', 'MESH:C516370', (104, 108))	('FDG', 'Chemical', 'MESH:D019788', (50, 53))	('F', 'Chemical', 'MESH:D005461', (104, 105))	('PET', 'Gene', '22095', (54, 57))	('[18F]FCho', 'Var', (99, 108))	('F', 'Chemical', 'MESH:D005461', (50, 51))
31467	33667282	To detect treatment response, we found that for [18F]FDG PET (SUVmean x MTV) is superior to MTV only.	('F', 'Chemical', 'MESH:D005461', (53, 54))	('se', 'Gene', '29230', (26, 28))	('PET', 'Gene', '22095', (57, 60))	('MTV', 'Chemical', '-', (72, 75))	('PET', 'Gene', (57, 60))	('[18F]FDG', 'Var', (48, 56))	('FDG', 'Chemical', 'MESH:D019788', (53, 56))	('F', 'Chemical', 'MESH:D005461', (51, 52))	('MTV', 'Chemical', '-', (92, 95))
31469	33667282	Importantly, [18F]FDG PET at delayed time intervals (240 min p.i.)	('[18F]FDG', 'Var', (13, 21))	('PET', 'Gene', (22, 25))	('FDG', 'Chemical', 'MESH:D019788', (18, 21))	('F', 'Chemical', 'MESH:D005461', (18, 19))	('PET', 'Gene', '22095', (22, 25))	('F', 'Chemical', 'MESH:D005461', (16, 17))
31500	33667282	For these purposes, multiple PET tracers have been proposed, such as [18F]fluorodeoxyglucose ([18F]FDG), [18F]Fluoroethyltyrosine ([18F]FET), [18F]fluoroazomycin arabinoside ([18F]FAZA), 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F]FDOPA) and [18F]Fluoromethylcholine ([18F]FCho).	('FAZA', 'Chemical', 'MESH:C498052', (180, 184))	('F', 'Chemical', 'MESH:D005461', (280, 281))	('F', 'Chemical', 'MESH:D005461', (136, 137))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('PET', 'Gene', (29, 32))	('F', 'Chemical', 'MESH:D005461', (278, 279))	('F', 'Chemical', 'MESH:D005461', (254, 255))	('F', 'Chemical', 'MESH:D005461', (72, 73))	('se', 'Gene', '29230', (90, 92))	('F', 'Chemical', 'MESH:D005461', (238, 239))	('[18F]fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (69, 92))	('F', 'Chemical', 'MESH:D005461', (134, 135))	('FET', 'Chemical', 'MESH:C545932', (136, 139))	('[18F]', 'Var', (249, 254))	('se', 'Gene', '29230', (56, 58))	('F', 'Chemical', 'MESH:D005461', (206, 207))	('F', 'Chemical', 'MESH:D005461', (110, 111))	('F', 'Chemical', 'MESH:D005461', (180, 181))	('F', 'Chemical', 'MESH:D005461', (236, 237))	('FCho', 'Chemical', 'MESH:C516370', (280, 284))	('F', 'Chemical', 'MESH:D005461', (252, 253))	('se', 'Gene', '29230', (7, 9))	('FDG', 'Chemical', 'MESH:D019788', (99, 102))	('F', 'Chemical', 'MESH:D005461', (108, 109))	('PET', 'Gene', '22095', (29, 32))	('se', 'Gene', '29230', (15, 17))	('[18F]Fluoromethylcholine', 'Chemical', 'MESH:C516370', (249, 273))	('F', 'Chemical', 'MESH:D005461', (99, 100))	('F', 'Chemical', 'MESH:D005461', (178, 179))	('F', 'Chemical', 'MESH:D005461', (97, 98))	('F', 'Chemical', 'MESH:D005461', (145, 146))
31501	33667282	Currently only two of these are frequently used in the clinic, namely [18F]FDG and [18F]FET.	('FET', 'Chemical', 'MESH:C545932', (88, 91))	('[18F]FET', 'Var', (83, 91))	('se', 'Gene', '29230', (44, 46))	('[18F]FDG', 'Var', (70, 78))	('F', 'Chemical', 'MESH:D005461', (86, 87))	('FDG', 'Chemical', 'MESH:D019788', (75, 78))	('se', 'Gene', '29230', (25, 27))	('F', 'Chemical', 'MESH:D005461', (73, 74))	('F', 'Chemical', 'MESH:D005461', (88, 89))	('F', 'Chemical', 'MESH:D005461', (75, 76))
31521	33667282	In this study, this methodology was applied to investigate the potential of [18F]FDG and [18F]FCho PET, compared to contrast-enhanced MRI, to detect the early effect of combined radiation and TMZ treatment in the F98 GB rat model.	('F', 'Chemical', 'MESH:D005461', (92, 93))	('F', 'Chemical', 'MESH:D005461', (81, 82))	('PET', 'Gene', '22095', (99, 102))	('[18F]', 'Var', (76, 81))	('F', 'Chemical', 'MESH:D005461', (213, 214))	('PET', 'Gene', (99, 102))	('F', 'Chemical', 'MESH:D005461', (79, 80))	('FDG', 'Chemical', 'MESH:D019788', (81, 84))	('TMZ', 'Chemical', 'MESH:D000077204', (192, 195))	('rat', 'Species', '10116', (220, 223))	('F', 'Chemical', 'MESH:D005461', (94, 95))	('[18F]FCho', 'Var', (89, 98))	('FCho', 'Chemical', 'MESH:C516370', (94, 98))
31551	33667282	The assessment of the biological response was evaluated by small animal PET using [18F]FDG and [18F]FCho.	('[18F]FDG', 'Var', (82, 90))	('F', 'Chemical', 'MESH:D005461', (98, 99))	('F', 'Chemical', 'MESH:D005461', (85, 86))	('FDG', 'Chemical', 'MESH:D019788', (87, 90))	('F', 'Chemical', 'MESH:D005461', (87, 88))	('FCho', 'Chemical', 'MESH:C516370', (100, 104))	('PET', 'Gene', '22095', (72, 75))	('F', 'Chemical', 'MESH:D005461', (100, 101))	('se', 'Gene', '29230', (6, 8))	('[18F]FCho', 'Var', (95, 104))	('PET', 'Gene', (72, 75))	('se', 'Gene', '29230', (39, 41))
31559	33667282	The total acquisition time was 20 min for [18F]FCho PET due the fast kinetics of [18F]FCho and 60 min for conventional [18F]FDG PET.	('PET', 'Gene', (52, 55))	('FDG', 'Chemical', 'MESH:D019788', (124, 127))	('F', 'Chemical', 'MESH:D005461', (122, 123))	('F', 'Chemical', 'MESH:D005461', (47, 48))	('FCho', 'Chemical', 'MESH:C516370', (47, 51))	('PET', 'Gene', '22095', (52, 55))	('FCho', 'Chemical', 'MESH:C516370', (86, 90))	('F', 'Chemical', 'MESH:D005461', (86, 87))	('F', 'Chemical', 'MESH:D005461', (45, 46))	('F', 'Chemical', 'MESH:D005461', (84, 85))	('F', 'Chemical', 'MESH:D005461', (124, 125))	('PET', 'Gene', '22095', (128, 131))	('[18F]FCho', 'Var', (81, 90))	('PET', 'Gene', (128, 131))
31562	33667282	Identical reconstruction parameters were applied for [18F]FDG and [18F]FCho PET.	('[18F]', 'Var', (66, 71))	('F', 'Chemical', 'MESH:D005461', (71, 72))	('FCho', 'Chemical', 'MESH:C516370', (71, 75))	('F', 'Chemical', 'MESH:D005461', (58, 59))	('[18F]', 'Var', (53, 58))	('F', 'Chemical', 'MESH:D005461', (56, 57))	('PET', 'Gene', '22095', (76, 79))	('F', 'Chemical', 'MESH:D005461', (69, 70))	('FDG', 'Chemical', 'MESH:D019788', (58, 61))	('PET', 'Gene', (76, 79))
31567	33667282	Within this VOI, MTV was defined as all voxels with an uptake >= 60% and >= 50% of the maximum uptake for [18F]FDG and [18F]FCho, respectively.	('F', 'Chemical', 'MESH:D005461', (109, 110))	('F', 'Chemical', 'MESH:D005461', (122, 123))	('[18F]FDG', 'Var', (106, 114))	('FDG', 'Chemical', 'MESH:D019788', (111, 114))	('F', 'Chemical', 'MESH:D005461', (111, 112))	('F', 'Chemical', 'MESH:D005461', (124, 125))	('FCho', 'Chemical', 'MESH:C516370', (124, 128))	('uptake', 'MPA', (55, 61))	('[18F]FCho', 'Var', (119, 128))	('MTV', 'Chemical', '-', (17, 20))
31593	33667282	The ratio of the SUVmax and TBRmax post-therapy (day 2-5-9-12 for [18F]FDG and day 1-6-8-13 for [18F]FCho PET) to the SUVmax and TBRmax pre-therapy was not significantly different between the control group and the treated group, at any time point for both [18F]FDG, at conventional and delayed time point, and for [18F]FCho PET (S1 Fig).	('PET', 'Gene', '22095', (106, 109))	('F', 'Chemical', 'MESH:D005461', (319, 320))	('FDG', 'Chemical', 'MESH:D019788', (71, 74))	('F', 'Chemical', 'MESH:D005461', (317, 318))	('FCho', 'Chemical', 'MESH:C516370', (101, 105))	('F', 'Chemical', 'MESH:D005461', (332, 333))	('F', 'Chemical', 'MESH:D005461', (71, 72))	('FDG', 'Chemical', 'MESH:D019788', (261, 264))	('PET', 'Gene', '22095', (324, 327))	('PET', 'Gene', (106, 109))	('F', 'Chemical', 'MESH:D005461', (261, 262))	('F', 'Chemical', 'MESH:D005461', (101, 102))	('TBRmax', 'Chemical', '-', (28, 34))	('if', 'Gene', '29319', (171, 173))	('F', 'Chemical', 'MESH:D005461', (259, 260))	('[18F]FDG', 'Var', (256, 264))	('F', 'Chemical', 'MESH:D005461', (69, 70))	('rat', 'Species', '10116', (4, 7))	('PET', 'Gene', (324, 327))	('if', 'Gene', '29319', (160, 162))	('F', 'Chemical', 'MESH:D005461', (99, 100))	('FCho', 'Chemical', 'MESH:C516370', (319, 323))	('TBRmax', 'Chemical', '-', (129, 135))
31595	33667282	Evolution of the normalized MTV and (SUVmean x normalized MTV) for [18F]FDG (early and delayed) and [18F]FCho PET are shown in Fig 4.	('FCho', 'Chemical', 'MESH:C516370', (105, 109))	('F', 'Chemical', 'MESH:D005461', (105, 106))	('MTV', 'Chemical', '-', (28, 31))	('F', 'Chemical', 'MESH:D005461', (127, 128))	('[18F]FCho', 'Var', (100, 109))	('FDG', 'Chemical', 'MESH:D019788', (72, 75))	('PET', 'Gene', '22095', (110, 113))	('F', 'Chemical', 'MESH:D005461', (72, 73))	('F', 'Chemical', 'MESH:D005461', (103, 104))	('F', 'Chemical', 'MESH:D005461', (70, 71))	('PET', 'Gene', (110, 113))	('MTV', 'Chemical', '-', (58, 61))	('[18F]FDG', 'Var', (67, 75))
31599	33667282	No significant MTV differences were found between control and therapy group for [18F]FCho PET at any time point.	('F', 'Chemical', 'MESH:D005461', (85, 86))	('F', 'Chemical', 'MESH:D005461', (83, 84))	('[18F]FCho', 'Var', (80, 89))	('FCho', 'Chemical', 'MESH:C516370', (85, 89))	('PET', 'Gene', '22095', (90, 93))	('MTV', 'Chemical', '-', (15, 18))	('if', 'Gene', '29319', (20, 22))	('if', 'Gene', '29319', (7, 9))	('PET', 'Gene', (90, 93))
31603	33667282	In Fig 5, tumor growth is clearly visible on contrast-enhanced T1-weighted MRI, conventional [18F]FDG, delayed [18F]FDG and [18F]FCho PET.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('F', 'Chemical', 'MESH:D005461', (98, 99))	('F', 'Chemical', 'MESH:D005461', (116, 117))	('FCho', 'Chemical', 'MESH:C516370', (129, 133))	('PET', 'Gene', '22095', (134, 137))	('tumor', 'Disease', (10, 15))	('[18F]FCho', 'Var', (124, 133))	('F', 'Chemical', 'MESH:D005461', (127, 128))	('F', 'Chemical', 'MESH:D005461', (129, 130))	('F', 'Chemical', 'MESH:D005461', (3, 4))	('F', 'Chemical', 'MESH:D005461', (96, 97))	('PET', 'Gene', (134, 137))	('FDG', 'Chemical', 'MESH:D019788', (98, 101))	('F', 'Chemical', 'MESH:D005461', (114, 115))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('FDG', 'Chemical', 'MESH:D019788', (116, 119))
31604	33667282	Evolution of the normalized MTV and (SUVmean x normalized MTV) for [18F]FDG (conventional and delayed) and [18F]FCho PET in a rat receiving control treatment are shown in Fig 4.	('F', 'Chemical', 'MESH:D005461', (112, 113))	('F', 'Chemical', 'MESH:D005461', (171, 172))	('MTV', 'Chemical', '-', (28, 31))	('[18F]FCho', 'Var', (107, 116))	('MTV', 'Chemical', '-', (58, 61))	('FCho', 'Chemical', 'MESH:C516370', (112, 116))	('FDG', 'Chemical', 'MESH:D019788', (72, 75))	('[18F]', 'Var', (67, 72))	('F', 'Chemical', 'MESH:D005461', (72, 73))	('PET', 'Gene', '22095', (117, 120))	('F', 'Chemical', 'MESH:D005461', (70, 71))	('F', 'Chemical', 'MESH:D005461', (110, 111))	('rat', 'Species', '10116', (126, 129))	('PET', 'Gene', (117, 120))
31606	33667282	The autoradiography image showed high [18F]FCho uptake in the F98 GB tumor and very low uptake in normal brain.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GB tumor', 'Disease', (66, 74))	('FCho', 'Chemical', 'MESH:C516370', (43, 47))	('[18F]FCho uptake', 'MPA', (38, 54))	('F', 'Chemical', 'MESH:D005461', (62, 63))	('F', 'Chemical', 'MESH:D005461', (41, 42))	('F98', 'Var', (62, 65))	('GB tumor', 'Disease', 'MESH:D009369', (66, 74))	('F', 'Chemical', 'MESH:D005461', (43, 44))
31608	33667282	The [18F]FCho uptake was clearly lower in the necrotic center of the F98 GB tumor (Fig 6B).	('lower', 'NegReg', (33, 38))	('GB tumor', 'Disease', 'MESH:D009369', (73, 81))	('F', 'Chemical', 'MESH:D005461', (9, 10))	('GB tumor', 'Disease', (73, 81))	('F', 'Chemical', 'MESH:D005461', (83, 84))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('necrotic', 'Disease', (46, 54))	('F', 'Chemical', 'MESH:D005461', (7, 8))	('F98', 'Var', (69, 72))	('F', 'Chemical', 'MESH:D005461', (69, 70))	('necrotic', 'Disease', 'MESH:D009336', (46, 54))	('FCho', 'Chemical', 'MESH:C516370', (9, 13))
31614	33667282	In the F98 GB rat tumor, no gross central tumor necrosis is seen on contrast-enhanced T1-weighted MRI (C) and increased [18F]FCho uptake is present only in the upper left margin of the tumor (20 min post injection; 39.6 MBq injected activity).	('[18F]FCho uptake', 'MPA', (120, 136))	('se', 'Gene', '29230', (60, 62))	('FCho', 'Chemical', 'MESH:C516370', (125, 129))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (18, 23))	('F', 'Chemical', 'MESH:D005461', (7, 8))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('F', 'Chemical', 'MESH:D005461', (125, 126))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('rat', 'Species', '10116', (14, 17))	('tumor necrosis', 'Disease', 'MESH:D009336', (42, 56))	('tumor necrosis', 'Disease', (42, 56))	('se', 'Gene', '29230', (143, 145))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('se', 'Gene', '29230', (116, 118))	('F', 'Chemical', 'MESH:D005461', (123, 124))	('F98 GB', 'Var', (7, 13))
31618	33667282	Diffuse leakage of Gd in the entire tumor volume is seen on MRI (C), while a more localized choline uptake is seen in the upper left margin of the tumor just beneath the skull (D).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('se', 'Gene', '29230', (5, 7))	('if', 'Gene', '29319', (1, 3))	('se', 'Gene', '29230', (52, 54))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('leakage', 'MPA', (8, 15))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('se', 'Gene', '29230', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MRI', 'Var', (60, 63))	('tumor', 'Disease', (36, 41))	('choline', 'Chemical', 'MESH:D002794', (92, 99))
31623	33667282	Hence, for [18F]FDG and [18F]FCho PET, a threshold of >= 60% and >= 50% of the maximum uptake, respectively, was selected based on visual inspection (Fig 3).	('FCho', 'Chemical', 'MESH:C516370', (29, 33))	('[18F]FCho', 'Var', (24, 33))	('F', 'Chemical', 'MESH:D005461', (150, 151))	('PET', 'Gene', '22095', (34, 37))	('se', 'Gene', '29230', (113, 115))	('FDG', 'Chemical', 'MESH:D019788', (16, 19))	('F', 'Chemical', 'MESH:D005461', (14, 15))	('PET', 'Gene', (34, 37))	('[18F]FDG', 'Var', (11, 19))	('F', 'Chemical', 'MESH:D005461', (27, 28))	('se', 'Gene', '29230', (124, 126))	('F', 'Chemical', 'MESH:D005461', (29, 30))	('F', 'Chemical', 'MESH:D005461', (16, 17))
31624	33667282	Based on our results, SUVmax and TBRmax were not able to detect any treatment effects at the chosen time points, nor using [18F]FDG nor [18F]FCho as a PET biomarker.	('FDG', 'Chemical', 'MESH:D019788', (128, 131))	('TBRmax', 'Chemical', '-', (33, 39))	('PET', 'Gene', '22095', (151, 154))	('F', 'Chemical', 'MESH:D005461', (126, 127))	('F', 'Chemical', 'MESH:D005461', (128, 129))	('se', 'Gene', '29230', (96, 98))	('PET', 'Gene', (151, 154))	('[18F', 'Var', (123, 127))	('F', 'Chemical', 'MESH:D005461', (141, 142))	('F', 'Chemical', 'MESH:D005461', (139, 140))	('FCho', 'Chemical', 'MESH:C516370', (141, 145))	('se', 'Gene', '29230', (2, 4))
31627	33667282	In case of [18F]FDG, the (SUVmean x MTV) is also referred to as total lesion glycolysis (TLG), which is a well-known volumetric parameter that enables to capture the glycolytic phenotype and overall tumor burden.	('tumor', 'Disease', (199, 204))	('se', 'Gene', '29230', (5, 7))	('FDG', 'Chemical', 'MESH:D019788', (16, 19))	('F', 'Chemical', 'MESH:D005461', (14, 15))	('[18F]FDG', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('MTV', 'Chemical', '-', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('total lesion glycolysis', 'Disease', 'MESH:C564972', (64, 87))	('total lesion glycolysis', 'Disease', (64, 87))	('F', 'Chemical', 'MESH:D005461', (16, 17))
31628	33667282	In this study, using (SUVmean x MTV), [18F]FDG PET acquired 40-60 minutes post-injection, was able to detect treatment response as early as 5 days post-therapy.	('PET', 'Gene', '22095', (47, 50))	('MTV', 'Chemical', '-', (32, 35))	('PET', 'Gene', (47, 50))	('F', 'Chemical', 'MESH:D005461', (41, 42))	('se', 'Gene', '29230', (125, 127))	('FDG', 'Chemical', 'MESH:D019788', (43, 46))	('[18F]', 'Var', (38, 43))	('F', 'Chemical', 'MESH:D005461', (43, 44))
31636	33667282	For those centers having access to amino-acid PET tracers, [11C]Methionine ([11C]MET) and [18F]FET PET have been suggested to be better suited than [18F]FDG for brain tumor imaging and monitoring therapy response in brain tumor patients.	('F', 'Chemical', 'MESH:D005461', (0, 1))	('PET', 'Gene', (99, 102))	('FDG', 'Chemical', 'MESH:D019788', (153, 156))	('se', 'Gene', '29230', (210, 212))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('brain tumor', 'Phenotype', 'HP:0030692', (216, 227))	('brain tumor', 'Phenotype', 'HP:0030692', (161, 172))	('FET', 'Chemical', 'MESH:C545932', (95, 98))	('F', 'Chemical', 'MESH:D005461', (95, 96))	('brain tumor', 'Disease', (161, 172))	('patients', 'Species', '9606', (228, 236))	('[18F]FET', 'Var', (90, 98))	('brain tumor', 'Disease', (216, 227))	('F', 'Chemical', 'MESH:D005461', (151, 152))	('F', 'Chemical', 'MESH:D005461', (93, 94))	('brain tumor', 'Disease', 'MESH:D001932', (161, 172))	('brain tumor', 'Disease', 'MESH:D001932', (216, 227))	('PET', 'Gene', '22095', (46, 49))	('[11C]', 'Var', (59, 64))	('Methionine', 'Chemical', 'MESH:D008715', (64, 74))	('se', 'Gene', '29230', (7, 9))	('PET', 'Gene', (46, 49))	('PET', 'Gene', '22095', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('F', 'Chemical', 'MESH:D005461', (153, 154))
31639	33667282	reported that, for [11C]Choline PET, a tumor-to-normal-brain ratio (TBR) <= 1.4 might predict a longer overall survival in patients with suspected recurrent glioma after treatment.	('PET', 'Gene', (32, 35))	('overall survival', 'MPA', (103, 119))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('patients', 'Species', '9606', (123, 131))	('glioma', 'Disease', (157, 163))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('longer', 'PosReg', (96, 102))	('PET', 'Gene', '22095', (32, 35))	('tumor', 'Disease', (39, 44))	('Choline', 'Chemical', 'MESH:D002794', (24, 31))	('[11C]Choline', 'Var', (19, 31))
31646	33667282	In a previous clinical study, we investigated the potential of [18F]FCho PET compared to state-of-the art conventional MRI using RANO criteria for early therapy response assessment in GB patients.	('patients', 'Species', '9606', (187, 195))	('[18F]FCho', 'Var', (63, 72))	('se', 'Gene', '29230', (167, 169))	('FCho', 'Chemical', 'MESH:C516370', (68, 72))	('F', 'Chemical', 'MESH:D005461', (68, 69))	('se', 'Gene', '29230', (172, 174))	('F', 'Chemical', 'MESH:D005461', (66, 67))	('PET', 'Gene', '22095', (73, 76))	('PET', 'Gene', (73, 76))
31673	33667282	With regard to the choice of PET biomarker, [18F]FDG (and particularly acquired 4 hours post-injection) is preferred over [18F]FCho.	('FDG', 'Chemical', 'MESH:D019788', (49, 52))	('PET', 'Gene', (29, 32))	('F', 'Chemical', 'MESH:D005461', (47, 48))	('FCho', 'Chemical', 'MESH:C516370', (127, 131))	('F', 'Chemical', 'MESH:D005461', (127, 128))	('F', 'Chemical', 'MESH:D005461', (125, 126))	('F', 'Chemical', 'MESH:D005461', (49, 50))	('PET', 'Gene', '22095', (29, 32))	('[18F]FDG', 'Var', (44, 52))
31675	33667282	5 Jan 2021  PONE-D-20-36019 Assessment of the effect of therapy in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI.	('se', 'Gene', '29230', (30, 32))	('glioblastoma', 'Disease', (82, 94))	('F', 'Chemical', 'MESH:D005461', (106, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('PONE-D-20-36019', 'Chemical', '-', (12, 27))	('FCho', 'Chemical', 'MESH:C516370', (119, 123))	('F', 'Chemical', 'MESH:D005461', (119, 120))	('[18F]FDG', 'Var', (101, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('PET', 'Gene', '22095', (124, 127))	('[18F]FCho', 'Var', (114, 123))	('F', 'Chemical', 'MESH:D005461', (117, 118))	('F', 'Chemical', 'MESH:D005461', (104, 105))	('PET', 'Gene', (124, 127))	('FDG', 'Chemical', 'MESH:D019788', (106, 109))	('rat', 'Species', '10116', (69, 72))
31678	33667282	The article describes the results of a pre-clinical study in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI"  for the early detection of treatment response.	('PET', 'Gene', (118, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('FCho', 'Chemical', 'MESH:C516370', (113, 117))	('F', 'Chemical', 'MESH:D005461', (98, 99))	('se', 'Gene', '29230', (201, 203))	('FDG', 'Chemical', 'MESH:D019788', (100, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('F', 'Chemical', 'MESH:D005461', (113, 114))	('[18F]FCho', 'Var', (108, 117))	('F', 'Chemical', 'MESH:D005461', (100, 101))	('F', 'Chemical', 'MESH:D005461', (111, 112))	('PET', 'Gene', '22095', (118, 121))	('glioblastoma', 'Disease', (76, 88))	('rat', 'Species', '10116', (63, 66))	('[18F]FDG', 'Var', (95, 103))
31693	33667282	Kind regards, Pierpaolo Alongi Academic Editor PLOS ONE Additional Editor Comments: The article describes the results of a pre-clinical study in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI" for the early detection of treatment response.	('glioblastoma', 'Disease', (160, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('se', 'Gene', '29230', (284, 286))	('F', 'Chemical', 'MESH:D005461', (195, 196))	('FCho', 'Chemical', 'MESH:C516370', (197, 201))	('PET', 'Gene', '22095', (202, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('[18F]FDG', 'Var', (179, 187))	('FDG', 'Chemical', 'MESH:D019788', (184, 187))	('F', 'Chemical', 'MESH:D005461', (182, 183))	('PET', 'Gene', (202, 205))	('rat', 'Species', '10116', (147, 150))	('F', 'Chemical', 'MESH:D005461', (184, 185))	('F', 'Chemical', 'MESH:D005461', (197, 198))	('[18F]FCho', 'Var', (192, 201))
31779	33667282	Additional Editor Comments: The article describes the results of a pre-clinical study in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI" for the early detection of treatment response.	('PET', 'Gene', (146, 149))	('[18F]FDG', 'Var', (123, 131))	('FDG', 'Chemical', 'MESH:D019788', (128, 131))	('rat', 'Species', '10116', (91, 94))	('F', 'Chemical', 'MESH:D005461', (126, 127))	('F', 'Chemical', 'MESH:D005461', (128, 129))	('glioblastoma', 'Disease', (104, 116))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('PET', 'Gene', '22095', (146, 149))	('F', 'Chemical', 'MESH:D005461', (141, 142))	('[18F]FCho', 'Var', (136, 145))	('F', 'Chemical', 'MESH:D005461', (139, 140))	('FCho', 'Chemical', 'MESH:C516370', (141, 145))	('se', 'Gene', '29230', (228, 230))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))
31794	33667282	For the use of [18F]FCho PET for the detection of bone metastasis in prostate cancer patients, delayed imaging is recommended.	('se', 'Gene', '29230', (9, 11))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('bone metastasis', 'CPA', (50, 65))	('F', 'Chemical', 'MESH:D005461', (20, 21))	('PET', 'Gene', '22095', (25, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('[18F]FCho', 'Var', (15, 24))	('PET', 'Gene', (25, 28))	('F', 'Chemical', 'MESH:D005461', (18, 19))	('patients', 'Species', '9606', (85, 93))	('FCho', 'Chemical', 'MESH:C516370', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', (69, 84))
31842	33667282	Figure 8 is published in our previous PLoS One publication: 2016;11(8):e0161845, Fig S2 and S4.	('F', 'Chemical', 'MESH:D005461', (81, 82))	('PLoS', 'Disease', (38, 42))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('e0161845', 'Var', (71, 79))	('PLoS', 'Disease', 'MESH:C536329', (38, 42))
31851	33667282	5) authors indicated other specific doses.-4 We agree to include the mean injected activity of all [18F]FDG and [18F]FCho scans in the M&M.	('FDG', 'Chemical', 'MESH:D019788', (104, 107))	('F', 'Chemical', 'MESH:D005461', (102, 103))	('[18F]FDG', 'Var', (99, 107))	('se', 'Gene', '29230', (38, 40))	('F', 'Chemical', 'MESH:D005461', (117, 118))	('F', 'Chemical', 'MESH:D005461', (104, 105))	('F', 'Chemical', 'MESH:D005461', (115, 116))	('FCho', 'Chemical', 'MESH:C516370', (117, 121))	('if', 'Gene', '29319', (31, 33))	('[18F]FCho', 'Var', (112, 121))
31872	33667282	The contrast range of the images selected in Figure 5 was (0-850 kBq/cc) for early FDG, (0-220 kBq/cc) for delayed FDG and (0-350 kBq/cc) for FCho.	('0-220 kBq/cc', 'Var', (89, 101))	('se', 'Gene', '29230', (33, 35))	('FCho', 'Disease', (142, 146))	('FDG', 'Chemical', 'MESH:D019788', (83, 86))	('F', 'Chemical', 'MESH:D005461', (83, 84))	('FDG', 'Chemical', 'MESH:D019788', (115, 118))	('0-850 kBq/cc', 'Var', (59, 71))	('F', 'Chemical', 'MESH:D005461', (142, 143))	('F', 'Chemical', 'MESH:D005461', (45, 46))	('0-350 kBq/cc', 'Var', (124, 136))	('delayed FDG', 'Disease', (107, 118))	('FCho', 'Chemical', 'MESH:C516370', (142, 146))	('F', 'Chemical', 'MESH:D005461', (115, 116))	('early FDG', 'Disease', (77, 86))
31895	33667282	In comparison with other PET tracers, FDG and non-FDG tracers alike, [18F]FCho has certain advantages of which a very low uptake in normal white and grey matter of the brain is of major interest because it enhances the contrast between tumour and normal brain tissue.	('low', 'NegReg', (118, 121))	('contrast', 'MPA', (219, 227))	('tumour', 'Disease', 'MESH:D009369', (236, 242))	('se', 'Gene', '29230', (200, 202))	('[18F]FCho', 'Var', (69, 78))	('tumour', 'Disease', (236, 242))	('FDG', 'Chemical', 'MESH:D019788', (38, 41))	('FCho', 'Chemical', 'MESH:C516370', (74, 78))	('PET', 'Gene', '22095', (25, 28))	('F', 'Chemical', 'MESH:D005461', (38, 39))	('uptake', 'MPA', (122, 128))	('PET', 'Gene', (25, 28))	('F', 'Chemical', 'MESH:D005461', (72, 73))	('FDG', 'Chemical', 'MESH:D019788', (50, 53))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('enhances', 'PosReg', (206, 214))	('F', 'Chemical', 'MESH:D005461', (74, 75))	('F', 'Chemical', 'MESH:D005461', (50, 51))
31897	33667282	Although [18F]FCho PET has been studied for glioma imaging before by other groups, the number of studies is still limited compared to the number of publications on amino acid and hypoxia PET biomarkers.	('PET', 'Gene', (19, 22))	('F', 'Chemical', 'MESH:D005461', (14, 15))	('[18F]FCho', 'Var', (9, 18))	('hypoxia', 'Disease', (179, 186))	('hypoxia', 'Disease', 'MESH:D000860', (179, 186))	('FCho', 'Chemical', 'MESH:C516370', (14, 18))	('glioma', 'Disease', (44, 50))	('PET', 'Gene', '22095', (187, 190))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('F', 'Chemical', 'MESH:D005461', (12, 13))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('PET', 'Gene', (187, 190))	('PET', 'Gene', '22095', (19, 22))
31902	33667282	[18F]FAZA has advantages compared to [18F]FMISO due to better pharmacokinetic properties but [18F]FMISO can cross the blood-brain barrier because of its lipophilic nature while [18F]FAZA and [18F]DiFA can not (Hirata et al.	('F', 'Chemical', 'MESH:D005461', (98, 99))	('F', 'Chemical', 'MESH:D005461', (40, 41))	('F', 'Chemical', 'MESH:D005461', (5, 6))	('F', 'Chemical', 'MESH:D005461', (198, 199))	('FMISO', 'Chemical', 'MESH:C031843', (42, 47))	('FAZA', 'Chemical', 'MESH:C498052', (5, 9))	('lipophilic nature', 'MPA', (153, 170))	('F', 'Chemical', 'MESH:D005461', (3, 4))	('F', 'Chemical', 'MESH:D005461', (42, 43))	('F', 'Chemical', 'MESH:D005461', (182, 183))	('se', 'Gene', '29230', (143, 145))	('F', 'Chemical', 'MESH:D005461', (96, 97))	('rat', 'Species', '10116', (212, 215))	('F', 'Chemical', 'MESH:D005461', (180, 181))	('FAZA', 'Chemical', 'MESH:C498052', (182, 186))	('F', 'Chemical', 'MESH:D005461', (194, 195))	('FMISO', 'Chemical', 'MESH:C031843', (98, 103))	('[18F]FMISO', 'Var', (93, 103))
31908	33667282	Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model.	('rat', 'Species', '10116', (94, 97))	('glioblastoma', 'Disease', (81, 93))	('[18F]', 'Var', (25, 30))	('radiotherapy', 'CPA', (59, 71))	('FET', 'Chemical', 'MESH:C545932', (30, 33))	('F', 'Chemical', 'MESH:D005461', (77, 78))	('F', 'Chemical', 'MESH:D005461', (30, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('F', 'Chemical', 'MESH:D005461', (28, 29))	('PET', 'Gene', '22095', (48, 51))	('FAZA', 'Chemical', 'MESH:C498052', (43, 47))	('F', 'Chemical', 'MESH:D005461', (41, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('PET', 'Gene', (48, 51))	('[18F]', 'Var', (38, 43))	('F', 'Chemical', 'MESH:D005461', (43, 44))
31920	33667282	22 Feb 2021  Assessment of the effect of therapy in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI.	('se', 'Gene', '29230', (15, 17))	('PET', 'Gene', '22095', (109, 112))	('glioblastoma', 'Disease', (67, 79))	('F', 'Chemical', 'MESH:D005461', (91, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('F', 'Chemical', 'MESH:D005461', (89, 90))	('F', 'Chemical', 'MESH:D005461', (102, 103))	('PET', 'Gene', (109, 112))	('rat', 'Species', '10116', (54, 57))	('F', 'Chemical', 'MESH:D005461', (3, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('FDG', 'Chemical', 'MESH:D019788', (91, 94))	('FCho', 'Chemical', 'MESH:C516370', (104, 108))	('F', 'Chemical', 'MESH:D005461', (104, 105))	('[18F]FDG', 'Var', (86, 94))	('[18F]', 'Var', (99, 104))
31930	33667282	23 Feb 2021  PONE-D-20-36019R1  Assessment of the effect of therapy in a rat model of glioblastoma using [18F]FDG and [18F]FCho PET compared to contrast-enhanced MRI.	('FDG', 'Chemical', 'MESH:D019788', (110, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))	('F', 'Chemical', 'MESH:D005461', (123, 124))	('FCho', 'Chemical', 'MESH:C516370', (123, 127))	('F', 'Chemical', 'MESH:D005461', (3, 4))	('se', 'Gene', '29230', (34, 36))	('[18F]FCho', 'Var', (118, 127))	('F', 'Chemical', 'MESH:D005461', (121, 122))	('PONE-D-20-36019', 'Chemical', '-', (13, 28))	('PET', 'Gene', '22095', (128, 131))	('glioblastoma', 'Disease', (86, 98))	('F', 'Chemical', 'MESH:D005461', (110, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('F', 'Chemical', 'MESH:D005461', (108, 109))	('[18F]FDG', 'Var', (105, 113))	('PET', 'Gene', (128, 131))	('rat', 'Species', '10116', (73, 76))
31960	31614431	Recently, measured binding affinity values, Ki (nM), for central nervous system G protein coupled receptors (GPCRs) and transporters related to the efficacy and side effects of penfluridol were 356 (5-hydroxytryptamine [serotonin] receptor 1A; 5HT1A), 3560 (5HT1D), 361 (5HT2A), 184 (5HT2B), 881 (5HT2C), 10,000 (5HT5A), 10,000 (5HT6), 280 (5HT7), 147 (dopamine receptor D1), 159 (D2), 136 (D3), 10,000 (D4), 125 (D5), 10,000 (kappa-opioid receptor), 867 (mu-opioid receptor), 1714 (delta-opioid receptor), 10,000 (histamine receptor 1 H1), 10,000 (H2), 588 (norepinephrine transporter), 10,000 (serotonin transporter), 1714 (dopamine transporter), 602 (alpha1D-adrenoreceptor), 401 (alpha2B), 455 (alpha2C), and 515 nM (beta3).	('5-hydroxytryptamine [serotonin] receptor 1A; 5HT1A', 'Gene', (199, 249))	('beta3', 'Gene', '1934', (721, 726))	('norepinephrine', 'Chemical', 'MESH:D009638', (559, 573))	('penfluridol', 'Chemical', 'MESH:D010395', (177, 188))	('1714', 'Var', (620, 624))	('alpha2C', 'Chemical', 'MESH:C023714', (699, 706))	('5-hydroxytryptamine [serotonin] receptor 1A; 5HT1A', 'Gene', '3350', (199, 249))	('alpha2B', 'Chemical', 'MESH:C023623', (684, 691))	('dopamine receptor D1', 'Gene', (353, 373))	('dopamine transporter', 'Gene', (626, 646))	('5HT5A', 'Gene', (313, 318))	('5HT2C', 'Gene', (297, 302))	('5HT2A', 'Gene', '3356', (271, 276))	('5HT2A', 'Gene', (271, 276))	('serotonin transporter', 'Gene', (596, 617))	('5HT2B', 'Gene', (284, 289))	('HT6', 'CellLine', 'CVCL:X634', (330, 333))	('5HT1D', 'Gene', (258, 263))	('5HT1D', 'Gene', '3352', (258, 263))	('H2', 'Chemical', 'MESH:D006859', (549, 551))	('alpha1D-adrenoreceptor', 'Gene', '146', (654, 676))	('5HT2C', 'Gene', '3358', (297, 302))	('alpha1D-adrenoreceptor', 'Gene', (654, 676))	('5HT2B', 'Gene', '3357', (284, 289))	('beta3', 'Gene', (721, 726))	('dopamine receptor D1', 'Gene', '1812', (353, 373))	('histamine', 'Chemical', 'MESH:D006632', (515, 524))	('5HT5A', 'Gene', '3361', (313, 318))	('dopamine transporter', 'Gene', '6531', (626, 646))	('serotonin transporter', 'Gene', '6532', (596, 617))
31996	31614431	One recent study evaluated lysis of U87MG tumours derived from nonobese diabetic/severe combined immunodeficiency mice injected with human peripheral blood mononuclear cells.	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (88, 113))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('immunodeficiency', 'Phenotype', 'HP:0002721', (97, 113))	('lysis', 'MPA', (27, 32))	('immunodeficiency', 'Disease', (97, 113))	('immunodeficiency', 'Disease', 'MESH:D007153', (97, 113))	('U87MG', 'CellLine', 'CVCL:0022', (36, 41))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('diabetic/severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (72, 113))	('U87MG', 'Var', (36, 41))	('diabetic', 'Disease', 'MESH:D003920', (72, 80))	('mice', 'Species', '10090', (114, 118))	('human', 'Species', '9606', (133, 138))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))	('diabetic', 'Disease', (72, 80))
32005	31614431	Normal cells transform into cancerous ones after the accumulation of gene mutations associated with cell growth suppressors and cell division; genome instability and mutations are characteristic of most cancers (Figure 2).	('mutations', 'Var', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancerous', 'Disease', 'MESH:D009369', (28, 37))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancerous', 'Disease', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
32007	31614431	However, penfluridol has shown therapeutic efficacy in adult GBM patients with IDH1 mutations.	('IDH1', 'Gene', '3417', (79, 83))	('GBM', 'Disease', 'MESH:D005909', (61, 64))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (65, 73))	('GBM', 'Disease', (61, 64))	('IDH1', 'Gene', (79, 83))	('penfluridol', 'Chemical', 'MESH:D010395', (9, 20))
32014	31614431	Moreover, D2-receptor agonists increased phosphorylation at threonine 308 of Akt in neurons, and Akt phosphorylation is known to plays a vital role in cell proliferation; this suggests that D2- receptors are associated with tumourigenesis.	('rat', 'Species', '10116', (163, 166))	('Akt', 'Gene', '207', (77, 80))	('threonine', 'Chemical', 'MESH:C061951', (60, 69))	('Akt', 'Gene', (97, 100))	('D2-', 'Var', (190, 193))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('Akt', 'Gene', (77, 80))	('phosphorylation', 'MPA', (41, 56))	('associated', 'Reg', (208, 218))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('increased phosphorylation at threonine', 'Phenotype', 'HP:0003354', (31, 69))	('tumour', 'Disease', (224, 230))	('Akt', 'Gene', '207', (97, 100))
32020	31614431	It is difficult to find a report explaining various mechanisms of anticancer activity involving of D2-receptor antagonism.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('D2-receptor', 'Protein', (99, 110))	('antagonism', 'Var', (111, 121))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
32038	31614431	Integrin dysregulation may drive the formation of breast cancer, although integrins are not thought be bona fide oncogenes.	('Integrin', 'Protein', (0, 8))	('drive', 'Reg', (27, 32))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('dysregulation', 'Var', (9, 22))
32059	31614431	Besides, GLI1 expression decreased in GBM cells treated with a PI3K/Akt inhibitor (LY294002) or Akt knocked down by Akt siRNA.	('GBM', 'Disease', (38, 41))	('LY294002', 'Var', (83, 91))	('Akt', 'Gene', '207', (68, 71))	('decreased', 'NegReg', (25, 34))	('Akt', 'Gene', '207', (116, 119))	('GLI1', 'Gene', (9, 13))	('expression', 'MPA', (14, 24))	('GBM', 'Disease', 'MESH:D005909', (38, 41))	('LY294002', 'Chemical', 'MESH:C085911', (83, 91))	('knocked down', 'NegReg', (100, 112))	('Akt', 'Gene', '207', (96, 99))	('GBM', 'Phenotype', 'HP:0012174', (38, 41))	('Akt', 'Gene', (68, 71))	('Akt', 'Gene', (116, 119))	('Akt', 'Gene', (96, 99))
32062	31614431	Moreover, the use of GLI1 inhibitors, or knocking down GLI1 by using siRNA or GLI1 CRISPR/Cas9, was studied to determine the role of GLI1 in regulating cancer stem cells through downregulation of OCT4 and Nanog by GLI1 silencing.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('GLI1', 'Gene', (55, 59))	('downregulation', 'NegReg', (178, 192))	('Nanog', 'Gene', '79923', (205, 210))	('Nanog', 'Gene', (205, 210))	('OCT4', 'Protein', (196, 200))	('GLI1', 'Gene', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('silencing', 'Var', (219, 228))
32076	31614431	The role of autophagy and LC3 was also confirmed again by LC3 silencing: a reduced penfluridol effect was noted when LC3B was knocked down by LC3B siRNA before treatment with penfluridol.	('LC3B', 'Gene', '81631', (117, 121))	('LC3B', 'Gene', '81631', (142, 146))	('LC3', 'Gene', (58, 61))	('penfluridol effect', 'MPA', (83, 101))	('penfluridol', 'Chemical', 'MESH:D010395', (175, 186))	('LC3B', 'Gene', (117, 121))	('LC3B', 'Gene', (142, 146))	('reduced', 'NegReg', (75, 82))	('LC3', 'Gene', (117, 120))	('knocked', 'Var', (126, 133))	('LC3', 'Gene', (142, 145))	('penfluridol', 'Chemical', 'MESH:D010395', (83, 94))	('LC3', 'Gene', '84557', (142, 145))	('LC3', 'Gene', '84557', (117, 120))	('LC3', 'Gene', '84557', (26, 29))	('LC3', 'Gene', (26, 29))	('LC3', 'Gene', '84557', (58, 61))
32104	31614431	Indeed, Drosophila models showed the influential magnitude of PP2A in regulating cell morphology and cell cycles.	('Drosophila models', 'Disease', (8, 25))	('Drosophila models', 'Disease', 'MESH:D004195', (8, 25))	('PP2A', 'Var', (62, 66))	('cell morphology', 'CPA', (81, 96))	('cell cycles', 'CPA', (101, 112))
32109	31614431	Moreover, the phosphorylation of two proteins (p70S6K and AKT, which play a key role in cancer) was reduced in penfluridol-treated MIAPaCa-2 cells; p70S6K and AKT were identified as substrates of PP2A.	('MIAPaCa-2', 'CellLine', 'CVCL:0428', (131, 140))	('cancer', 'Disease', (88, 94))	('p70S6K', 'Gene', (47, 53))	('rat', 'Species', '10116', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('AKT', 'Gene', (159, 162))	('p70S6K', 'Gene', '6198', (47, 53))	('reduced', 'NegReg', (100, 107))	('phosphorylation', 'MPA', (14, 29))	('PP2A', 'Var', (196, 200))	('penfluridol', 'Chemical', 'MESH:D010395', (111, 122))	('AKT', 'Gene', '207', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('AKT', 'Gene', '207', (159, 162))	('p70S6K', 'Gene', '6198', (148, 154))	('p70S6K', 'Gene', (148, 154))	('AKT', 'Gene', (58, 61))
32110	31614431	Altogether, therefore, PP2A could be considered a potential mechanism for penfluridol action in the treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('PP2A', 'Var', (23, 27))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('penfluridol', 'Chemical', 'MESH:D010395', (74, 85))
32112	31614431	Inhibition of D3 receptor signalling enhances anti-tumour immunity by dendritic cells through increasing antigen cross-presentation for CD8+ T-cells.	('CD8', 'Gene', (136, 139))	('enhances', 'PosReg', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('CD8', 'Gene', '925', (136, 139))	('Inhibition', 'Var', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('D3 receptor', 'Protein', (14, 25))	('tumour', 'Disease', (51, 57))	('increasing', 'PosReg', (94, 104))
32119	31614431	NHEJ inhibitors are believed to substantially enhance tumour radiosensitivity and improve the therapeutic efficiency of radiotherapy.	('therapeutic efficiency of radiotherapy', 'CPA', (94, 132))	('improve', 'PosReg', (82, 89))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('inhibitors', 'Var', (5, 15))	('tumour radiosensitivity', 'Phenotype', 'HP:0010997', (54, 77))	('enhance', 'PosReg', (46, 53))	('NHEJ', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
32167	31616641	GBM is divided into three subgroups based on isocitrate dehydrogenase 1 (IDH1) and IDH2 mutation status: IDH-mutant, IDH-wild-type and NOS (not otherwise specified).	('GBM', 'Disease', (0, 3))	('mutation', 'Var', (88, 96))	('IDH2', 'Gene', '3418', (83, 87))	('GBM', 'Disease', 'MESH:D005909', (0, 3))	('IDH1', 'Gene', '3417', (73, 77))	('IDH', 'Gene', (83, 86))	('IDH', 'Gene', (117, 120))	('IDH', 'Gene', (73, 76))	('IDH', 'Gene', '3417', (83, 86))	('IDH', 'Gene', '3417', (117, 120))	('IDH', 'Gene', '3417', (73, 76))	('IDH', 'Gene', (105, 108))	('IDH1', 'Gene', (73, 77))	('isocitrate dehydrogenase 1', 'Gene', (45, 71))	('IDH2', 'Gene', (83, 87))	('isocitrate dehydrogenase 1', 'Gene', '3417', (45, 71))	('IDH', 'Gene', '3417', (105, 108))
32179	31616641	A variety of genetic and epigenetic alterations have been identified in GBM that influence patient prognosis (Table 1).	('influence', 'Reg', (81, 90))	('GBM', 'Disease', (72, 75))	('GBM', 'Disease', 'MESH:D005909', (72, 75))	('patient', 'Species', '9606', (91, 98))	('epigenetic alterations', 'Var', (25, 47))
32180	31616641	Despite this heterogeneity, a large-scale analysis of genetic aberrations in GBM identified three main signalling pathways that are commonly dysregulated: activation of the receptor tyrosine kinase (RTK)/Ras/phosphoinositide 3-kinase (PI3K) pathway (88%), inhibition of p53 (87%), and retinoblastoma protein (Rb) signalling pathways (78%).	('retinoblastoma', 'Phenotype', 'HP:0009919', (285, 299))	('retinoblastoma', 'Disease', 'MESH:D012175', (285, 299))	('retinoblastoma', 'Disease', (285, 299))	('RTK', 'Gene', '5979', (199, 202))	('receptor tyrosine kinase', 'Gene', (173, 197))	('receptor tyrosine kinase', 'Gene', '5979', (173, 197))	('GBM', 'Disease', (77, 80))	('inhibition', 'NegReg', (256, 266))	('p53', 'Gene', (270, 273))	('p53', 'Gene', '7157', (270, 273))	('GBM', 'Disease', 'MESH:D005909', (77, 80))	('signalling pathways', 'Pathway', (103, 122))	('genetic', 'Var', (54, 61))	('RTK', 'Gene', (199, 202))	('activation', 'PosReg', (155, 165))
32184	31616641	A small molecule inhibitor of the EphA3 receptor, GLPG1790, has demonstrated superior tumour reduction in U251MG and U87MG subcutaneous xenograft models when compared to radiotherapy alone, however, GLPG1790 was not as effective as treatment with radiotherapy and concomitant temozolomide.	('U87MG', 'Var', (117, 122))	('temozolomide', 'Chemical', 'MESH:C047246', (276, 288))	('GLPG1790', 'Chemical', 'MESH:C109641', (199, 207))	('EphA3', 'Gene', '2042', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('EphA3', 'Gene', (34, 39))	('GLPG1790', 'Chemical', 'MESH:C109641', (50, 58))	('tumour reduction', 'Disease', (86, 102))	('tumour reduction', 'Disease', 'MESH:D009369', (86, 102))
32190	31616641	Epidermal Growth Factor Receptor (EGFR) amplifications and mutations are detected in 40-60% of GBM cases (Table 1) and are generally indicative of poor prognosis.	('Epidermal Growth Factor Receptor', 'Gene', '1956', (0, 32))	('Epidermal Growth Factor Receptor', 'Gene', (0, 32))	('EGFR', 'Gene', (34, 38))	('detected', 'Reg', (73, 81))	('GBM', 'Disease', (95, 98))	('mutations', 'Var', (59, 68))	('GBM', 'Disease', 'MESH:D005909', (95, 98))	('EGFR', 'Gene', '1956', (34, 38))	('amplifications', 'Var', (40, 54))
32193	31616641	The overexpression or mutation of EGFR leads to downstream signalling that impairs apoptosis, enhances proliferation, and angiogenesis.	('enhances', 'PosReg', (94, 102))	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', (34, 38))	('proliferation', 'CPA', (103, 116))	('angiogenesis', 'CPA', (122, 134))	('apoptosis', 'CPA', (83, 92))	('overexpression', 'PosReg', (4, 18))	('EGFR', 'Gene', '1956', (34, 38))	('impairs', 'NegReg', (75, 82))
32195	31616641	Due to the high incidence of EGFR amplifications, a variety of EGFR inhibitors have been examined both pre-clinically and clinically (Table 2).	('EGFR', 'Gene', '1956', (63, 67))	('amplifications', 'Var', (34, 48))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))
32214	31616641	With the largely disappointing clinical results for EGFR inhibitors, additional targets are being investigated, including vascular endothelial growth factor (VEGF), which is highly expressed in glioma cells.	('vascular endothelial growth factor', 'Gene', (122, 156))	('inhibitors', 'Var', (57, 67))	('glioma', 'Disease', (194, 200))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('vascular endothelial growth factor', 'Gene', '7422', (122, 156))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))
32224	31616641	Of note, a decline in neurocognitive function is more frequently observed following bevacizumab treatment, as bevacizumab impairs hippocampal synaptic plasticity and decreases dendritic spine number and length.	('bevacizumab', 'Var', (110, 121))	('impairs', 'NegReg', (122, 129))	('decreases dendritic spine number', 'Disease', 'MESH:D007635', (166, 198))	('decreases dendritic spine number', 'Disease', (166, 198))	('neurocognitive function', 'MPA', (22, 45))	('hippocampal synaptic plasticity', 'MPA', (130, 161))
32244	31616641	More than 50 PI3K inhibitors have been designed and are under investigation as treatments for a range of cancers.	('PI3K', 'Var', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
32259	31616641	Additionally, amuvatinib (MP470) is a small molecule inhibitor that acts on multiple tyrosine kinases, including MET, has been shown to radiosensitise GBM cell lines both in vitro and in vivo (Table 2).	('MP470', 'Var', (26, 31))	('GBM', 'Disease', (151, 154))	('GBM', 'Disease', 'MESH:D005909', (151, 154))	('amuvatinib', 'Chemical', 'MESH:C521047', (14, 24))	('tyrosine', 'Chemical', 'None', (85, 93))
32261	31616641	However, in a subcutaneous xenograft model using Mayo39 and Mayo59 GBM cell lines, crizotinib was only effective at reducing tumour burden and vascular density when used in combination with the EGFR inhibitor erlotinib.	('Mayo', 'Species', '162683', (49, 53))	('reducing', 'NegReg', (116, 124))	('crizotinib', 'Var', (83, 93))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('GBM', 'Disease', (67, 70))	('tumour burden', 'Disease', (125, 138))	('crizotinib', 'Chemical', 'MESH:C551994', (83, 93))	('EGFR', 'Gene', '1956', (194, 198))	('Mayo', 'Species', '162683', (60, 64))	('EGFR', 'Gene', (194, 198))	('tumour burden', 'Disease', 'MESH:D009369', (125, 138))	('GBM', 'Disease', 'MESH:D005909', (67, 70))	('erlotinib', 'Chemical', 'MESH:C400278', (209, 218))
32276	28934149	Importantly, knock-out cell lines for specific autophagy-related genes revealed that the expression of Atg3 and Atg5 but not Atg13 facilitates reovirus replication.	('Atg5', 'Gene', (112, 116))	('Atg3', 'Gene', '67841', (103, 107))	('Atg13', 'Gene', '51897', (125, 130))	('expression', 'Var', (89, 99))	('Atg13', 'Gene', (125, 130))	('Atg3', 'Gene', (103, 107))	('facilitates', 'PosReg', (131, 142))	('reovirus', 'Species', '10891', (143, 151))	('reovirus', 'Protein', (143, 151))
32291	28934149	The presence of a distinct set but not all of the autophagy-related proteins seems to facilitate reovirus replication.	('presence', 'Var', (4, 12))	('reovirus', 'Species', '10891', (97, 105))	('facilitate', 'PosReg', (86, 96))	('reovirus replication', 'CPA', (97, 117))
32352	28934149	For the different knock-outs, minor effects were seen on reovirus-induced cytolysis.	('reovirus-induced cytolysis', 'MPA', (57, 83))	('knock-outs', 'Var', (18, 28))	('reovirus', 'Species', '10891', (57, 65))
32353	28934149	However, sigma3 protein expression and virus titers were markedly decreased in MEFs lacking Atg3 or Atg5 compared to the corresponding wild-type and rescued cells (Figure 3 and Figure 4).	('Atg3', 'Gene', (92, 96))	('decreased', 'NegReg', (66, 75))	('Atg5', 'Var', (100, 104))	('lacking', 'Var', (84, 91))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))	('Atg3', 'Gene', '67841', (92, 96))	('sigma3 protein', 'Protein', (9, 23))	('virus titers', 'CPA', (39, 51))
32354	28934149	A knock-out for Atg13 affected neither the reovirus sigma3 expression nor the titer (Figure 5).	('titer', 'MPA', (78, 83))	('knock-out', 'Var', (2, 11))	('expression', 'MPA', (59, 69))	('reovirus', 'Species', '10891', (43, 51))	('Atg13', 'Gene', '51897', (16, 21))	('Atg13', 'Gene', (16, 21))	('reovirus sigma3', 'Protein', (43, 58))
32355	28934149	Altogether, these results indicate that the expression of Atg3 and Atg5 but not Atg13 facilitates the replication of reovirus in SV40 transformed MEFs.	('reovirus', 'Species', '10891', (117, 125))	('Atg3', 'Gene', '67841', (58, 62))	('Atg13', 'Gene', '51897', (80, 85))	('facilitates', 'PosReg', (86, 97))	('reovirus', 'Protein', (117, 125))	('replication', 'MPA', (102, 113))	('expression', 'Var', (44, 54))	('Atg13', 'Gene', (80, 85))	('MEFs', 'CellLine', 'CVCL:9115', (146, 150))	('Atg3', 'Gene', (58, 62))	('Atg5', 'Gene', (67, 71))
32356	28934149	With the finding that reovirus induces several autophagic features in SV40 transformed MEFs, the question remains whether the same holds true for human cell lines.	('SV40', 'Var', (70, 74))	('autophagic features', 'CPA', (47, 66))	('induces', 'Reg', (31, 38))	('human', 'Species', '9606', (146, 151))	('MEFs', 'CellLine', 'CVCL:9115', (87, 91))	('reovirus', 'Species', '10891', (22, 30))
32366	28934149	As for the Atg5 and LC3 expression, acidic vesicles were detected in U251-MG upon Rapa treatment and jin-1 but not R124 infection, as expected.	('R124', 'Gene', (115, 119))	('U251-MG', 'CellLine', 'CVCL:0021', (69, 76))	('R124', 'Gene', '68929', (115, 119))	('Rapa', 'Chemical', 'MESH:D020123', (82, 86))	('U251-MG', 'Var', (69, 76))	('acidic vesicles', 'MPA', (36, 51))
32392	28934149	This process relies on the activity of PI3K, Atg3, and Atg5.	('Atg3', 'Gene', '67841', (45, 49))	('Atg3', 'Gene', (45, 49))	('PI3K', 'Var', (39, 43))
32422	28934149	Though our results indicate that a productive reovirus infection facilitates the induction of autophagy, the replication process itself seems dispensable as we find that exposure of cells to a much higher MOI* (200 or 1000) of UV-inactivated virus is able to induce autophagic features.	('reovirus infection', 'Disease', (46, 64))	('autophagic features', 'CPA', (266, 285))	('pen', 'Gene', '27344', (145, 148))	('200', 'Var', (211, 214))	('autophagy', 'CPA', (94, 103))	('facilitates', 'PosReg', (65, 76))	('reovirus infection', 'Disease', 'MESH:D012088', (46, 64))	('pen', 'Gene', (145, 148))
32432	28656196	Moreover, CK suppressed the self-renewal capacity as well as the invasiveness of U87MG and U373MG GBM stem-like cells (GSCs) by inducing a reduction in the expression of GSC markers, such as CD133, Nanog, Oct4 and Sox2.	('Oct4', 'Gene', '5460', (205, 209))	('U373MG', 'Var', (91, 97))	('suppressed', 'NegReg', (13, 23))	('reduction', 'NegReg', (139, 148))	('Nanog', 'Gene', '79923', (198, 203))	('U373MG', 'CellLine', 'CVCL:2219', (91, 97))	('Sox2', 'Gene', '6657', (214, 218))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('Oct4', 'Gene', (205, 209))	('CD133', 'Gene', (191, 196))	('U87MG', 'CellLine', 'CVCL:0022', (81, 86))	('CD133', 'Gene', '8842', (191, 196))	('CK', 'Chemical', 'MESH:C112772', (10, 12))	('Sox2', 'Gene', (214, 218))	('Nanog', 'Gene', (198, 203))	('expression', 'MPA', (156, 166))	('invasiveness', 'CPA', (65, 77))	('self-renewal capacity', 'CPA', (28, 49))
32457	28656196	Anti-MMP-2 (64 kDa), anti-MMP-9 (84 kDa), anti-cyclin D1 (36 kDa), anti-cyclin D3 (31 kDa), anti-PARP (89, 116 kDa), anti-cleaved caspase-3 (Asp175, 17, 19 kDa), anti-cleaved caspase-9 (Asp330, 37 kDa), anti-phospho-PI3K [p85 (Tyr458)/p55 (Tyr199), 60 and 85 kDa], anti-PI3K (p85, 85 kDa), anti-phospho-Akt (Ser473, 60 kDa), anti-Akt (60 kDa), anti-phospho-mTOR (Ser2448, 289 kDa), anti-mTOR (289 kDa), anti-Nanog (42 kDa), anti-Sox2 (35 kDa), anti-Oct4 (45 kDa) and anti-beta-actin (45 kDa) antibodies were obtained from Cell Signaling Technology (Danvers, MA, USA).	('p55', 'Gene', (235, 238))	('Sox2', 'Gene', (429, 433))	('p85', 'Gene', (222, 225))	('MMP-2', 'Gene', '4313', (5, 10))	('p55', 'Gene', '8503', (235, 238))	('Akt', 'Gene', (330, 333))	('cyclin D3', 'Gene', (72, 81))	('beta-actin', 'Gene', (472, 482))	('cyclin D1', 'Gene', (47, 56))	('Akt', 'Gene', '207', (330, 333))	('Sox2', 'Gene', '6657', (429, 433))	('mTOR', 'Gene', (357, 361))	('MMP-2', 'Gene', (5, 10))	('PARP', 'Gene', '142', (97, 101))	('Ser2448', 'Var', (363, 370))	('Oct4', 'Gene', '5460', (449, 453))	('caspase-9', 'Gene', '842', (175, 184))	('cyclin D1', 'Gene', '595', (47, 56))	('p85', 'Gene', '5296', (276, 279))	('PARP', 'Gene', (97, 101))	('MMP-9', 'Gene', '4318', (26, 31))	('mTOR', 'Gene', '2475', (357, 361))	('mTOR', 'Gene', (387, 391))	('cyclin D3', 'Gene', '896', (72, 81))	('Nanog', 'Gene', '79923', (408, 413))	('p85', 'Gene', '5296', (222, 225))	('MMP-9', 'Gene', (26, 31))	('Nanog', 'Gene', (408, 413))	('caspase-3', 'Gene', '836', (130, 139))	('beta-actin', 'Gene', '728378', (472, 482))	('Akt', 'Gene', (303, 306))	('caspase-3', 'Gene', (130, 139))	('mTOR', 'Gene', '2475', (387, 391))	('Akt', 'Gene', '207', (303, 306))	('caspase-9', 'Gene', (175, 184))	('p85', 'Gene', (276, 279))	('Oct4', 'Gene', (449, 453))
32505	28656196	3A and B, CK induced G0/G1 phase arrest (an increase in the proportion of arrested cells from 68.6 to 80.7% for U87MG cells and from 66.0 to 77.3% for U373MG cells) along with a decrease of S and G2/M phases when compared with the control cells.	('U87MG', 'CellLine', 'CVCL:0022', (112, 117))	('G2/M phases', 'CPA', (196, 207))	('decrease', 'NegReg', (178, 186))	('U87MG cells', 'Var', (112, 123))	('U373MG', 'Var', (151, 157))	('increase', 'PosReg', (44, 52))	('CK', 'Chemical', 'MESH:C112772', (10, 12))	('U373MG', 'CellLine', 'CVCL:2219', (151, 157))	('G0/G1 phase arrest', 'CPA', (21, 39))
32512	28656196	When U87MG and U373MG cells were treated with CK at either 50 or 75 microM for 24 h, the total amount of early and late apoptotic cells were markedly increased in a dose-dependent manner after CK treatment in comparison with controls (from 2.36 to 26.92% for U87MG cells and from 1.34 to 47.8% for U373MG cells; Fig.	('U373MG', 'CellLine', 'CVCL:2219', (15, 21))	('U87MG', 'CellLine', 'CVCL:0022', (5, 10))	('U87MG', 'CellLine', 'CVCL:0022', (259, 264))	('U87MG', 'Var', (259, 264))	('U373MG', 'CellLine', 'CVCL:2219', (298, 304))	('increased', 'PosReg', (150, 159))	('CK', 'Chemical', 'MESH:C112772', (193, 195))	('CK', 'Chemical', 'MESH:C112772', (46, 48))
32561	28656196	CK treatment significantly reduced both the self-renewal capacity, including cell growth and clonogenicity, and the invasive potential of GSCs derived from U87MG and U373MG cells.	('reduced', 'NegReg', (27, 34))	('U373MG', 'CellLine', 'CVCL:2219', (166, 172))	('U87MG', 'CellLine', 'CVCL:0022', (156, 161))	('cell growth', 'CPA', (77, 88))	('CK', 'Chemical', 'MESH:C112772', (0, 2))	('U87MG', 'Var', (156, 161))	('clonogenicity', 'CPA', (93, 106))	('invasive potential of GSCs derived', 'CPA', (116, 150))	('U373MG', 'Var', (166, 172))	('self-renewal capacity', 'CPA', (44, 65))
32654	26337424	Wnt pathway antagonists, SFRP1, SFRP2, SOX17, and PPP2R2B, are methylated in gliomas and SFRP1 methylation predicts shorter survival The deregulation of Wnt signaling is observed in various cancers, including gliomas, and might be related to the methylation of the genes encoding antagonists of this signaling pathway.	('SFRP1', 'Gene', (89, 94))	('methylation', 'Var', (95, 106))	('SOX17', 'Gene', '64321', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Disease', (209, 216))	('SFRP1', 'Gene', (25, 30))	('PPP2R2B', 'Gene', (50, 57))	('PPP2R2B', 'Gene', '5521', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('shorter', 'NegReg', (116, 123))	('Wnt signaling', 'Pathway', (153, 166))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('deregulation', 'MPA', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gliomas', 'Disease', 'MESH:D005910', (209, 216))	('SOX17', 'Gene', (39, 44))	('SFRP1', 'Gene', '6422', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('SFRP1', 'Gene', '6422', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('gliomas', 'Phenotype', 'HP:0009733', (209, 216))	('SFRP2', 'Gene', '6423', (32, 37))	('gliomas', 'Disease', (77, 84))	('SFRP2', 'Gene', (32, 37))
32657	26337424	Promoter methylation in at least one of the analyzed genes was found in 81.3 % of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('Promoter methylation', 'Var', (0, 20))	('found', 'Reg', (63, 68))
32660	26337424	The most frequently methylated genes were SFRP1 and SFRP2 (73.4 % and 46.9 %, respectively), followed by SOX17 (20.3 %) and PPP2R2B (10.9 %); DKK1 and DACH1 were basically unmethylated (1.6 %).	('SFRP1', 'Gene', '6422', (42, 47))	('methylated', 'Var', (20, 30))	('PPP2R2B', 'Gene', '5521', (124, 131))	('PPP2R2B', 'Gene', (124, 131))	('SFRP1', 'Gene', (42, 47))	('SOX17', 'Gene', '64321', (105, 110))	('SFRP2', 'Gene', '6423', (52, 57))	('SFRP2', 'Gene', (52, 57))	('DKK1', 'Gene', '22943', (142, 146))	('DKK1', 'Gene', (142, 146))	('DACH1', 'Gene', (151, 156))	('DACH1', 'Gene', '1602', (151, 156))	('SOX17', 'Gene', (105, 110))
32661	26337424	SFRP1 methylation negatively correlated with patients' survival time, and was significantly more frequent in older patients and those with higher grade tumors.	('patients', 'Species', '9606', (115, 123))	('SFRP1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('negatively', 'NegReg', (18, 28))	('methylation', 'Var', (6, 17))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Disease', (152, 158))	('SFRP1', 'Gene', '6422', (0, 5))	('frequent', 'Reg', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
32662	26337424	Overall, the results of this study indicate that aberrant promoter methylation of Wnt pathway antagonists is common in gliomas, which may be the possible cause of up-regulation of this signaling pathway often observed in these tumors.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('up-regulation', 'PosReg', (163, 176))	('promoter', 'MPA', (58, 66))	('aberrant', 'Var', (49, 57))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('gliomas', 'Disease', (119, 126))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('common', 'Reg', (109, 115))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
32663	26337424	Moreover, SFRP1 promoter methylation can be regarded as a potential indicator of glioma patients' survival.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('patients', 'Species', '9606', (88, 96))	('SFRP1', 'Gene', (10, 15))	('glioma', 'Disease', (81, 87))	('methylation', 'Var', (25, 36))	('SFRP1', 'Gene', '6422', (10, 15))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
32676	26337424	The imbalance in the structural and signaling properties of beta-catenin often results in deregulated cellular growth related to cancer and metastasis (Kaur et al.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cellular growth', 'CPA', (102, 117))	('beta-catenin', 'Protein', (60, 72))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('imbalance', 'Var', (4, 13))	('results in', 'Reg', (79, 89))	('deregulated', 'MPA', (90, 101))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
32680	26337424	Recent studies supporting a role for a deregulated Wnt/ beta-catenin pathway in malignant glioma also showed that Wnt pathway antagonists such as WIF1 and a family of secreted Frizzled-related proteins, dickkopf, and naked are epigenetically inactivated as a result of their promoters' hypermethylation (Lambiv et al.	('malignant glioma', 'Disease', (80, 96))	('Wnt/ beta-catenin pathway', 'Pathway', (51, 76))	('malignant glioma', 'Disease', 'MESH:D005910', (80, 96))	('WIF1', 'Gene', (146, 150))	('hypermethylation', 'Var', (286, 302))	('WIF1', 'Gene', '11197', (146, 150))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('epigenetically', 'Var', (227, 241))
32685	26337424	We found the hypermethylation of SFRP1 and SFRP2 gene promoters to be the most frequent.	('SFRP2', 'Gene', (43, 48))	('SFRP1', 'Gene', '6422', (33, 38))	('frequent', 'Reg', (79, 87))	('SFRP2', 'Gene', '6423', (43, 48))	('hypermethylation', 'Var', (13, 29))	('SFRP1', 'Gene', (33, 38))
32686	26337424	Moreover, correlation of SFRP1 methylation with tumor grade and patients' survival may suggest its potential as a prognostic biomarker for glioma patients.	('tumor', 'Disease', (48, 53))	('patients', 'Species', '9606', (64, 72))	('SFRP1', 'Gene', '6422', (25, 30))	('glioma', 'Disease', (139, 145))	('SFRP1', 'Gene', (25, 30))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('methylation', 'Var', (31, 42))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('patients', 'Species', '9606', (146, 154))	('correlation', 'Reg', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
32705	26337424	Methylation in at least one of the six analyzed genes occurred in 81.3 % of the tumors, while 46.9 % of the cases showed methylation in at least two genes.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Methylation', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('occurred', 'Reg', (54, 62))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
32714	26337424	However, SFRP1 methylation was found to be significantly more frequent in older patients as compared to younger ones (p = 0.01).	('methylation', 'Var', (15, 26))	('patients', 'Species', '9606', (80, 88))	('SFRP1', 'Gene', '6422', (9, 14))	('frequent', 'Reg', (62, 70))	('SFRP1', 'Gene', (9, 14))
32715	26337424	Almost all of the patients (93.75 %) over 60 years of age showed the presence of SFRP1 promoter methylation, whereas the methylation of this gene was detected less frequently in younger patient groups (41-60 years 75.76 %, <40 years 46.67 %) (Fig.	('SFRP1', 'Gene', (81, 86))	('SFRP1', 'Gene', '6422', (81, 86))	('methylation', 'Var', (96, 107))	('patients', 'Species', '9606', (18, 26))	('patient', 'Species', '9606', (18, 25))	('patient', 'Species', '9606', (186, 193))
32717	26337424	SFRP1 methylation was more frequent in patients with higher grade tumors (III and IV).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SFRP1', 'Gene', (0, 5))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (6, 17))	('frequent', 'Reg', (27, 35))	('SFRP1', 'Gene', '6422', (0, 5))
32718	26337424	Additionally, SFRP1 methylation showed a significant negative correlation with patient survival time (Fig.	('SFRP1', 'Gene', '6422', (14, 19))	('SFRP1', 'Gene', (14, 19))	('methylation', 'Var', (20, 31))	('patient', 'Species', '9606', (79, 86))	('patient survival time', 'CPA', (79, 100))	('negative', 'NegReg', (53, 61))
32719	26337424	All patients with the shortest survival (within 1-3 months after tumor resection) had SFRP1 promoter methylated, whereas the frequency of SFRP1 methylation in patients who survived longer was lower (73 % and 83 % methylated tumor samples in the "3-12 months" and "12-24 months after tumor resection" groups, respectively).	('SFRP1', 'Gene', '6422', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (65, 70))	('SFRP1', 'Gene', '6422', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('shortest', 'NegReg', (22, 30))	('SFRP1', 'Gene', (138, 143))	('tumor', 'Disease', (224, 229))	('SFRP1', 'Gene', (86, 91))	('methylated', 'MPA', (213, 223))	('tumor', 'Disease', (283, 288))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('patients', 'Species', '9606', (159, 167))	('methylated', 'Var', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
32720	26337424	In the long survival group (>24 months), only 43 % of patients showed SFRP1 promoter methylation.	('SFRP1', 'Gene', (70, 75))	('SFRP1', 'Gene', '6422', (70, 75))	('methylation', 'Var', (85, 96))	('patients', 'Species', '9606', (54, 62))
32722	26337424	Deregulation of the Wnt pathway, as shown in several reports, is associated with malignant tumor behavior (Fodde and Brabletz; Delic et al.	('malignant tumor', 'Disease', 'MESH:D018198', (81, 96))	('Deregulation', 'Var', (0, 12))	('Wnt pathway', 'Pathway', (20, 31))	('associated', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('malignant tumor', 'Disease', (81, 96))
32723	26337424	In gliomas, modulation of Wnt signaling has been shown to affect cell growth and motility (Lu et al.	('cell growth', 'CPA', (65, 76))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('modulation', 'Var', (12, 22))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))	('motility', 'CPA', (81, 89))	('affect', 'Reg', (58, 64))
32724	26337424	Importantly, epigenetic silencing of genes encoding proteins known to act as antagonists of the Wnt network was proposed as one of the mechanisms of up-regulation of the Wnt pathway in malignant gliomas (Foltz et al.).	('epigenetic silencing', 'Var', (13, 33))	('malignant gliomas', 'Disease', (185, 202))	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('up-regulation', 'PosReg', (149, 162))	('malignant gliomas', 'Disease', 'MESH:D005910', (185, 202))	('Wnt pathway', 'Pathway', (170, 181))	('gliomas', 'Phenotype', 'HP:0009733', (195, 202))
32725	26337424	Beside the genes, which were described earlier as possible targets of epigenetic silencing in gliomas (SFRP1, SFRP2, DKK1), the methylation of PPP2R2B, SOX17, and DACH1 was also assessed.	('gliomas', 'Disease', 'MESH:D005910', (94, 101))	('SFRP1', 'Gene', '6422', (103, 108))	('DACH1', 'Gene', '1602', (163, 168))	('gliomas', 'Disease', (94, 101))	('PPP2R2B', 'Gene', (143, 150))	('gliomas', 'Phenotype', 'HP:0009733', (94, 101))	('SOX17', 'Gene', (152, 157))	('epigenetic silencing', 'Var', (70, 90))	('SFRP1', 'Gene', (103, 108))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('DKK1', 'Gene', '22943', (117, 121))	('DKK1', 'Gene', (117, 121))	('SFRP2', 'Gene', '6423', (110, 115))	('SFRP2', 'Gene', (110, 115))	('PPP2R2B', 'Gene', '5521', (143, 150))	('SOX17', 'Gene', '64321', (152, 157))	('DACH1', 'Gene', (163, 168))
32727	26337424	The high prevalence of methylation of the promoter regions of genes encoding Wnt pathway antagonists in higher grade gliomas indicates that this epigenetic mechanism contributes to the malignant behavior of these CNS tumors.	('gliomas', 'Disease', 'MESH:D005910', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('gliomas', 'Phenotype', 'HP:0009733', (117, 124))	('gliomas', 'Disease', (117, 124))	('methylation', 'Var', (23, 34))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('contributes', 'Reg', (166, 177))	('malignant behavior', 'CPA', (185, 203))
32735	26337424	As mentioned previously, SFRP1 methylation was found to be related to tumor aggressiveness and, more importantly, negatively correlated with patients' survival time.	('correlated', 'Reg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SFRP1', 'Gene', '6422', (25, 30))	('negatively', 'NegReg', (114, 124))	('tumor aggressiveness', 'Disease', (70, 90))	('SFRP1', 'Gene', (25, 30))	('methylation', 'Var', (31, 42))	('related', 'Reg', (59, 66))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (70, 90))	('aggressiveness', 'Phenotype', 'HP:0000718', (76, 90))	('patients', 'Species', '9606', (141, 149))	('men', 'Species', '9606', (3, 6))
32736	26337424	While hypermethylation of this gene in malignant astrocytic gliomas has already been described (Gotze et al.	('hypermethylation', 'Var', (6, 22))	('malignant astrocytic gliomas', 'Disease', 'MESH:D001254', (39, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('malignant astrocytic gliomas', 'Disease', (39, 67))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
32737	26337424	), the above-mentioned correlations are novel findings in relation to glioma and may suggest a potential prognostic value of SFRP1 methylation in this subtype of cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('glioma', 'Disease', (70, 76))	('SFRP1', 'Gene', '6422', (125, 130))	('cancer', 'Disease', (162, 168))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('SFRP1', 'Gene', (125, 130))	('men', 'Species', '9606', (13, 16))	('methylation', 'Var', (131, 142))
32740	26337424	Our results indirectly indicate that the hypermethylation of SFRP1 promoter sequence may be the main mechanism for the decrease in the level of its expression.	('hypermethylation', 'Var', (41, 57))	('decrease', 'NegReg', (119, 127))	('SFRP1', 'Gene', (61, 66))	('level of', 'MPA', (135, 143))	('SFRP1', 'Gene', '6422', (61, 66))	('expression', 'MPA', (148, 158))
32741	26337424	Taking into consideration the possible clinical application of these findings, reversal of aberrant gene methylation through the use of epigenome modifying agents opens the possibility to restore the expression of SFRP1 or other SFRP family members and, therefore, antagonize deleterious Wnt signaling (Surana et al.).	('antagonize', 'NegReg', (265, 275))	('restore', 'PosReg', (188, 195))	('SFRP', 'Gene', (229, 233))	('rat', 'Species', '10116', (19, 22))	('clinical', 'Species', '191496', (39, 47))	('SFRP1', 'Gene', '6422', (214, 219))	('expression', 'MPA', (200, 210))	('aberrant', 'Var', (91, 99))	('SFRP1', 'Gene', (214, 219))
32749	26337424	The SRY-box containing gene 17 (SOX17) was methylated in around one fifth (20.31 %) of patients.	('SOX17', 'Gene', '64321', (32, 37))	('patients', 'Species', '9606', (87, 95))	('SOX17', 'Gene', (32, 37))	('methylated', 'Var', (43, 53))
32751	26337424	or 93 %, 100 %, and 94 % methylated samples of nonpolypoid adenomas, polypoid adenomas, and colorectal carcinomas, respectively (Voorham et al.	('polypoid adenomas', 'Disease', 'MESH:D000236', (50, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('colorectal carcinomas', 'Disease', (92, 113))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (92, 113))	('nonpolypoid adenomas', 'Disease', (47, 67))	('methylated', 'Var', (25, 35))	('polypoid adenomas', 'Disease', 'MESH:D000236', (69, 86))	('polypoid adenomas', 'Disease', (69, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('nonpolypoid adenomas', 'Disease', 'MESH:D000236', (47, 67))
32754	26337424	Sox17 knockdown increased the levels of cyclin D1, Axin2, and activated beta-catenin (Chew et al.).	('Sox17', 'Gene', (0, 5))	('beta-catenin', 'Protein', (72, 84))	('Axin2', 'Gene', (51, 56))	('Axin2', 'Gene', '8313', (51, 56))	('cyclin D1', 'Gene', '595', (40, 49))	('increased', 'PosReg', (16, 25))	('cyclin D1', 'Gene', (40, 49))	('knockdown', 'Var', (6, 15))	('levels', 'MPA', (30, 36))	('activated', 'PosReg', (62, 71))
32756	26337424	However, in our study, SOX17 was found methylated in anaplastic oligodendroglioma samples, so we speculate that epigenetic silencing of this gene may function as a factor up-regulating the Wnt pathway or deregulating the cell cycle in these tumors.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('SOX17', 'Gene', '64321', (23, 28))	('oligodendroglioma', 'Disease', 'MESH:D009837', (64, 81))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('oligodendroglioma', 'Disease', (64, 81))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('up-regulating', 'PosReg', (171, 184))	('SOX17', 'Gene', (23, 28))	('Wnt pathway', 'Pathway', (189, 200))	('deregulating', 'Reg', (204, 216))	('cell cycle', 'CPA', (221, 231))	('epigenetic silencing', 'Var', (112, 132))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
32760	26337424	Here, we report that, also, roughly one tenth of glioma tumor samples (10.9 %) is characterized by this epigenetic change.	('glioma tumor', 'Disease', 'MESH:D005910', (49, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('characterized', 'Reg', (82, 95))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('epigenetic change', 'Var', (104, 121))	('glioma tumor', 'Disease', (49, 61))
32761	26337424	We also show that DACH1 and DKK1 methylation is an infrequent event in glioma.	('methylation', 'Var', (33, 44))	('glioma', 'Disease', (71, 77))	('DACH1', 'Gene', (18, 23))	('DKK1', 'Gene', '22943', (28, 32))	('DKK1', 'Gene', (28, 32))	('DACH1', 'Gene', '1602', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
32762	26337424	Mechanisms other than epigenetic were proposed for DACH1 silencing, e.g., homozygous deletion of the chromosomal region containing DACH1 gene sequence (13q21) (Watanabe et al.).	('silencing', 'NegReg', (57, 66))	('DACH1', 'Gene', (131, 136))	('deletion', 'Var', (85, 93))	('DACH1', 'Gene', (51, 56))	('DACH1', 'Gene', '1602', (51, 56))	('DACH1', 'Gene', '1602', (131, 136))
32763	26337424	Interestingly, the induction of the expression of DACH1 decreased cell proliferation in a series of glioma cell lines, whereas loss of DACH1 increased the number of tumor-initiating cells through transcriptional activation of bFGF (Watanabe et al.).	('bFGF', 'Gene', '2247', (226, 230))	('glioma', 'Disease', (100, 106))	('bFGF', 'Gene', (226, 230))	('DACH1', 'Gene', (50, 55))	('increased', 'PosReg', (141, 150))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('DACH1', 'Gene', '1602', (50, 55))	('decreased', 'NegReg', (56, 65))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('DACH1', 'Gene', '1602', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('rat', 'Species', '10116', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('DACH1', 'Gene', (135, 140))	('loss', 'Var', (127, 131))	('activation', 'PosReg', (212, 222))	('tumor', 'Disease', (165, 170))
32764	26337424	In contrast to DACH1, epigenetic changes were reported to play a role in reducing DKK1 expression in gliomas.	('DACH1', 'Gene', '1602', (15, 20))	('DKK1', 'Gene', (82, 86))	('epigenetic changes', 'Var', (22, 40))	('gliomas', 'Disease', (101, 108))	('gliomas', 'Disease', 'MESH:D005910', (101, 108))	('DKK1', 'Gene', '22943', (82, 86))	('gliomas', 'Phenotype', 'HP:0009733', (101, 108))	('reducing', 'NegReg', (73, 81))	('expression', 'MPA', (87, 97))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('DACH1', 'Gene', (15, 20))
32766	26337424	), our study showed negligible frequency of DKK1 methylation.	('DKK1', 'Gene', (44, 48))	('methylation', 'Var', (49, 60))	('DKK1', 'Gene', '22943', (44, 48))
32768	26337424	have found DKK1 hypermethylation in 50 % of secondary but not primary glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('secondary', 'Disease', (44, 53))	('hypermethylation', 'Var', (16, 32))	('DKK1', 'Gene', '22943', (11, 15))	('DKK1', 'Gene', (11, 15))	('glioblastoma', 'Disease', (70, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))
32769	26337424	The overall results of our current study, together with the hypermethylation of RUNX3 observed in our earlier investigation, indicate that epigenetic silencing of Wnt antagonists may constitute a crucial mechanism of abnormal up-regulation of this signaling pathway which is often observed in gliomas.	('gliomas', 'Disease', 'MESH:D005910', (293, 300))	('gliomas', 'Phenotype', 'HP:0009733', (293, 300))	('RUNX3', 'Gene', (80, 85))	('RUNX3', 'Gene', '864', (80, 85))	('epigenetic silencing', 'Var', (139, 159))	('glioma', 'Phenotype', 'HP:0009733', (293, 299))	('up-regulation', 'PosReg', (226, 239))	('gliomas', 'Disease', (293, 300))
32770	26337424	Moreover, SFRP1 methylation can be regarded as a potential indicator of glioma patient survival.	('glioma', 'Disease', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('SFRP1', 'Gene', (10, 15))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('patient', 'Species', '9606', (79, 86))	('methylation', 'Var', (16, 27))	('SFRP1', 'Gene', '6422', (10, 15))
32823	26320940	Of these miRNAs, miR-30d was identified as dysregulated in canine models of HF (with improvement after biventricular pacing).	('miR-30d', 'Var', (17, 24))	('canine', 'Species', '9615', (59, 65))	('improvement', 'PosReg', (85, 96))
32824	26320940	Furthermore, in a cohort of over 50 patients with HF undergoing biventricular pacing, miR-30d was independently associated with favourable response in cardiac function after biventricular pacing.	('miR-30d', 'Var', (86, 93))	('patients', 'Species', '9606', (36, 44))	('cardiac function', 'MPA', (151, 167))
32833	26320940	In addition, further mechanistic studies on miR-30d have confirmed its role in cardioprotection (against apoptosis and hypoxia-mediated cardiac stress).	('miR-30d', 'Var', (44, 51))	('hypoxia', 'Disease', (119, 126))	('hypoxia', 'Disease', 'MESH:D000860', (119, 126))
32890	26320940	These include epidermal growth factor receptor variant III (EGFRvIII, a highly specific deletion mutation found in 20-25% of GBMs) and isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations (found in 10% of GBMs).	('IDH1/2', 'Gene', (169, 175))	('mutations', 'Var', (177, 186))	('epidermal growth factor receptor', 'Gene', (14, 46))	('EGFR', 'Gene', '1956', (60, 64))	('IDH1/2', 'Gene', '3417;3418', (169, 175))	('epidermal growth factor receptor', 'Gene', '1956', (14, 46))	('EGFR', 'Gene', (60, 64))
32893	26320940	EGFRvIII deletions and IDH1.132 point mutations) which may be scored and analyzed as "present" versus "absent" and (b) wild-type EV genes known to be quantitatively differentially expressed in GBM, such as EGFR, IDH1 and promoter methylated proteins.	('IDH1', 'Gene', '3417', (212, 216))	('EGFR', 'Gene', (206, 210))	('EGFR', 'Gene', (0, 4))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', (212, 216))	('IDH1', 'Gene', '3417', (23, 27))	('EGFR', 'Gene', '1956', (0, 4))	('deletions', 'Var', (9, 18))	('EGFR', 'Gene', '1956', (206, 210))
32897	26320940	These methods identified mutant IDH1 mRNA in CSF-derived EVs from patients with mutant IDH1 gliomas, and established that patients with tumours have higher levels of CSF and serum EV mutant IDH1 mRNA than healthy controls.	('IDH1', 'Gene', (32, 36))	('tumours', 'Disease', (136, 143))	('IDH1', 'Gene', (87, 91))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('higher', 'PosReg', (149, 155))	('CSF', 'MPA', (166, 169))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('IDH1', 'Gene', (190, 194))	('mutant', 'Var', (80, 86))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('IDH1', 'Gene', '3417', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('IDH1', 'Gene', '3417', (87, 91))	('levels', 'MPA', (156, 162))	('IDH1', 'Gene', '3417', (190, 194))	('IDH1 gliomas', 'Disease', (87, 99))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (66, 74))	('IDH1 gliomas', 'Disease', 'MESH:D005910', (87, 99))
32964	25304031	Additionally, in the TCGA cohort, TCTN1 expression was dramatically decreased in patients within the proneural subtype compared to other subtypes, and significantly influenced by the status of several genetic aberrations such as CDKN2A/B deletion, EGFR amplification, PTEN deletion and TP53 mutation.	('expression', 'MPA', (40, 50))	('decreased', 'NegReg', (68, 77))	('PTEN', 'Gene', (268, 272))	('EGFR', 'Gene', '1956', (248, 252))	('TCTN1', 'Gene', (34, 39))	('CDKN2A', 'Gene', (229, 235))	('PTEN', 'Gene', '5728', (268, 272))	('mutation', 'Var', (291, 299))	('EGFR', 'Gene', (248, 252))	('deletion', 'Var', (273, 281))	('TP53', 'Gene', '7157', (286, 290))	('TP53', 'Gene', (286, 290))	('CDKN2A', 'Gene', '1029', (229, 235))	('patients', 'Species', '9606', (81, 89))	('influenced by', 'Reg', (165, 178))
32965	25304031	The prognostic value of TCTN1 was more pronounced in proneural and mesenchymal subtypes, and was also affected by several genetic alterations particularly PTEN deletion.	('TCTN1', 'Gene', (24, 29))	('PTEN', 'Gene', (155, 159))	('PTEN', 'Gene', '5728', (155, 159))	('affected', 'Reg', (102, 110))	('deletion', 'Var', (160, 168))	('more', 'PosReg', (34, 38))	('proneural', 'CPA', (53, 62))
32970	25304031	There are several different genetic alterations of important genes that may contribute to the pathogenesis of GBM, and these aberrations may differ from patient to patient.	('genetic alterations', 'Var', (28, 47))	('patient', 'Species', '9606', (164, 171))	('GBM', 'Disease', (110, 113))	('GBM', 'Phenotype', 'HP:0012174', (110, 113))	('patient', 'Species', '9606', (153, 160))	('contribute', 'Reg', (76, 86))
32976	25304031	Over the past several years, the primary cilium was found to be a complex signalling center where Hedgehog signalling was regulated, and its disregulation was associated closely to tumorigenesis.	('disregulation', 'Var', (141, 154))	('tumor', 'Disease', (181, 186))	('associated', 'Reg', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
33000	25304031	Briefly, 293 T cells were co-transfected with the lentiviral expression vector pCDH-TCTN1 (pCDH empty vector as a control) together with packaging plasmids pLP/VSVG, pLP1 and pLP2 for overexpression, and with lentiviral vector pLL3.7-shTCTN1 (or shControl) and corresponding packaging vectors psPAX2 and pMD2.G for gene silencing, using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions.	('pLP2', 'Gene', '5355', (175, 179))	('gene', 'Var', (315, 319))	('pLP', 'Gene', '5354', (175, 178))	('pLP2', 'Gene', (175, 179))	('pLP1', 'Gene', '5354', (166, 170))	('pLP', 'Gene', (166, 169))	('pLP', 'Gene', (156, 159))	('pLP1', 'Gene', (166, 170))	('pLP', 'Gene', '5354', (156, 159))	('pLP', 'Gene', '5354', (166, 169))	('293 T', 'CellLine', 'CVCL:0063', (9, 14))	('pLP', 'Gene', (175, 178))
33009	25304031	As shown in Figure 1C and D, high TCTN1 expressers had significantly shorter overall survival (OS) and progression-free survival (PFS) than those with low TCTN1 expression (Log rank P =0.027 and 0.029 for OS and PFS respectively).	('high', 'Var', (29, 33))	('TCTN1', 'Gene', (34, 39))	('progression-free survival', 'CPA', (103, 128))	('OS', 'Chemical', '-', (205, 207))	('shorter', 'NegReg', (69, 76))	('overall survival', 'CPA', (77, 93))	('OS', 'Chemical', '-', (95, 97))
33012	25304031	To further explore the expression profile of TCTN1 gene, we examined associations between its expression and common genetic alterations in GBM, including mutations in TP53, PTEN, NF1, EGFR, RB1, PIK3R1, IDH1, PIK3CA, SPTA1, ATRX, KEL, GABRA6, LZTR1, CTNND2, BRAF, amplifications of EGFR, CDK4, PDGFRA, MDM2, MET, MDM4, CDK6, MYCN, CCND2, PIK3CA, AKT3, and deletions of CDKN2A, CDKN2B, PTEN, CDKN2C, RB1, PARK2 and NF1.	('PIK3R1', 'Gene', (195, 201))	('CDKN2A', 'Gene', (369, 375))	('LZTR1', 'Gene', (243, 248))	('CDKN2B', 'Gene', '1030', (377, 383))	('PDGFRA', 'Gene', '5156', (294, 300))	('NF1', 'Gene', (414, 417))	('EGFR', 'Gene', (282, 286))	('PTEN', 'Gene', (173, 177))	('RB1', 'Gene', (190, 193))	('CDKN2C', 'Gene', (391, 397))	('TP53', 'Gene', '7157', (167, 171))	('CDK6', 'Gene', '1021', (319, 323))	('PIK3CA', 'Gene', (338, 344))	('LZTR1', 'Gene', '8216', (243, 248))	('MDM2', 'Gene', '4193', (302, 306))	('CTNND2', 'Gene', (250, 256))	('PTEN', 'Gene', (385, 389))	('AKT3', 'Gene', '10000', (346, 350))	('KEL', 'Gene', (230, 233))	('PIK3CA', 'Gene', (209, 215))	('CDKN2A', 'Gene', '1029', (369, 375))	('CDK4', 'Gene', (288, 292))	('PARK2', 'Gene', '5071', (404, 409))	('SPTA1', 'Gene', '6708', (217, 222))	('CDK6', 'Gene', (319, 323))	('EGFR', 'Gene', (184, 188))	('PTEN', 'Gene', '5728', (173, 177))	('CTNND2', 'Gene', '1501', (250, 256))	('AKT3', 'Gene', (346, 350))	('RB1', 'Gene', '5925', (190, 193))	('PIK3R1', 'Gene', '5295', (195, 201))	('NF1', 'Gene', '4763', (179, 182))	('PTEN', 'Gene', '5728', (385, 389))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))	('CDKN2C', 'Gene', '1031', (391, 397))	('EGFR', 'Gene', '1956', (282, 286))	('MYCN', 'Gene', '4613', (325, 329))	('SPTA1', 'Gene', (217, 222))	('RB1', 'Gene', (399, 402))	('ATRX', 'Gene', (224, 228))	('KEL', 'Gene', '3792', (230, 233))	('PARK2', 'Gene', (404, 409))	('CDK4', 'Gene', '1019', (288, 292))	('BRAF', 'Gene', '673', (258, 262))	('IDH1', 'Gene', (203, 207))	('CDKN2B', 'Gene', (377, 383))	('NF1', 'Gene', (179, 182))	('ATRX', 'Gene', '546', (224, 228))	('BRAF', 'Gene', (258, 262))	('TP53', 'Gene', (167, 171))	('MDM2', 'Gene', (302, 306))	('CCND2', 'Gene', (331, 336))	('PIK3CA', 'Gene', '5290', (338, 344))	('MDM4', 'Gene', '4194', (313, 317))	('GABRA6', 'Gene', '2559', (235, 241))	('associations', 'Interaction', (69, 81))	('EGFR', 'Gene', '1956', (184, 188))	('MDM4', 'Gene', (313, 317))	('deletions', 'Var', (356, 365))	('CCND2', 'Gene', '894', (331, 336))	('PIK3CA', 'Gene', '5290', (209, 215))	('NF1', 'Gene', '4763', (414, 417))	('RB1', 'Gene', '5925', (399, 402))	('mutations', 'Var', (154, 163))	('PDGFRA', 'Gene', (294, 300))	('GABRA6', 'Gene', (235, 241))	('IDH1', 'Gene', '3417', (203, 207))	('MYCN', 'Gene', (325, 329))
33013	25304031	Consequently, we found that TCTN1 expression was significantly associated with mutations of TP53, IDH1 and ATRX, amplifications of EGFR, PDGFRA and MYCN, and deletions of CDKN2A, CDKN2B, PTEN and PARK2 (Figure 2C-H, Additional file 1: Figure S2), but not other aberrations.	('amplifications', 'Var', (113, 127))	('CDKN2B', 'Gene', '1030', (179, 185))	('expression', 'MPA', (34, 44))	('PARK2', 'Gene', (196, 201))	('PTEN', 'Gene', (187, 191))	('MYCN', 'Gene', (148, 152))	('EGFR', 'Gene', (131, 135))	('CDKN2A', 'Gene', '1029', (171, 177))	('TP53', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (98, 102))	('mutations', 'Var', (79, 88))	('associated', 'Reg', (63, 73))	('PTEN', 'Gene', '5728', (187, 191))	('ATRX', 'Gene', (107, 111))	('ATRX', 'Gene', '546', (107, 111))	('EGFR', 'Gene', '1956', (131, 135))	('MYCN', 'Gene', '4613', (148, 152))	('TP53', 'Gene', '7157', (92, 96))	('CDKN2B', 'Gene', (179, 185))	('PDGFRA', 'Gene', '5156', (137, 143))	('PDGFRA', 'Gene', (137, 143))	('TCTN1', 'Gene', (28, 33))	('PARK2', 'Gene', '5071', (196, 201))	('deletions', 'Var', (158, 167))	('CDKN2A', 'Gene', (171, 177))	('IDH1', 'Gene', (98, 102))
33015	25304031	Cases with TP53 mutation had lower levels of TCTN1 expression than wild-type (P =0.004) in non-proneural subtypes, while there was no significant difference in proneural subtype (Figure 2E).	('levels', 'MPA', (35, 41))	('TCTN1 expression', 'MPA', (45, 61))	('mutation', 'Var', (16, 24))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('lower', 'NegReg', (29, 34))
33016	25304031	In contrast, cases with amplification of EGFR or deletion of PTEN or PARK2 had higher levels of TCTN1 expression than cases with no corresponding changes only in proneural subtype (P =0.045, 0.003, 0.014, respectively; Figure 2F-H).	('EGFR', 'Gene', (41, 45))	('PARK2', 'Gene', '5071', (69, 74))	('TCTN1 expression', 'MPA', (96, 112))	('levels', 'MPA', (86, 92))	('PARK2', 'Gene', (69, 74))	('PTEN', 'Gene', (61, 65))	('amplification', 'Var', (24, 37))	('deletion', 'Var', (49, 57))	('PTEN', 'Gene', '5728', (61, 65))	('higher', 'PosReg', (79, 85))	('EGFR', 'Gene', '1956', (41, 45))
33017	25304031	However, the differential expression of TCTN1 according to mutations of IDH1, ATRX or amplification of MYCN and PDGFRA (Additional file 1: Figure S1A-D) lost any statistical significance when we classified all cases into non-proneural and proneural subgroups.	('expression', 'MPA', (26, 36))	('ATRX', 'Gene', (78, 82))	('IDH1', 'Gene', (72, 76))	('MYCN', 'Gene', (103, 107))	('ATRX', 'Gene', '546', (78, 82))	('IDH1', 'Gene', '3417', (72, 76))	('MYCN', 'Gene', '4613', (103, 107))	('mutations', 'Var', (59, 68))	('PDGFRA', 'Gene', '5156', (112, 118))	('PDGFRA', 'Gene', (112, 118))	('lost', 'NegReg', (153, 157))	('TCTN1', 'Gene', (40, 45))
33023	25304031	As a consequence, TCTN1 expression was associated with patients' prognosis only in one specific subgroup classified by the status of 7 genes (PTEN, EGFR, PDGFRA, MYCN, PARK2, CDKN2A, CDKN2B; Figure 3F and Additional file 1: Figure S4).	('PTEN', 'Gene', (142, 146))	('PARK2', 'Gene', '5071', (168, 173))	('PTEN', 'Gene', '5728', (142, 146))	('PARK2', 'Gene', (168, 173))	('CDKN2B', 'Gene', (183, 189))	('TCTN1', 'Gene', (18, 23))	('CDKN2A', 'Gene', (175, 181))	('EGFR', 'Gene', '1956', (148, 152))	('CDKN2B', 'Gene', '1030', (183, 189))	('EGFR', 'Gene', (148, 152))	('MYCN', 'Gene', (162, 166))	('CDKN2A', 'Gene', '1029', (175, 181))	('patients', 'Species', '9606', (55, 63))	('MYCN', 'Gene', '4613', (162, 166))	('associated', 'Reg', (39, 49))	('expression', 'Var', (24, 34))	('PDGFRA', 'Gene', (154, 160))	('PDGFRA', 'Gene', '5156', (154, 160))
33026	25304031	Moreover, high TCTN1 mRNA expression (n =132) could significantly predict a worse overall survival for GBM patients in comparison with low TCTN1 expression (n =49; Log-rank P =0.013; HR =1.54, 95% CI 1.09-2.17; Figure 4B), which could also serve as an independent prognostic factor in a multivariate Cox regression model (HR =1.58, 95% CI =1.09-2.29, P =0.017; Table 2).	('GBM', 'Disease', (103, 106))	('worse', 'NegReg', (76, 81))	('TCTN1', 'Gene', (15, 20))	('Cox', 'Gene', (300, 303))	('high', 'Var', (10, 14))	('overall survival', 'MPA', (82, 98))	('Cox', 'Gene', '1351', (300, 303))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('patients', 'Species', '9606', (107, 115))
33033	25304031	Our TMA analysis and real-time PCR validation of a Chinese GBM cohort revealed that TCTN1 was up-regulated in GBMs compared to normal controls, and high TCTN1 expression could predict shorter overall and progression-free survival for GBM patients, as an independent prognostic factor.	('GBM', 'Phenotype', 'HP:0012174', (234, 237))	('up-regulated', 'PosReg', (94, 106))	('GBMs', 'Disease', (110, 114))	('TCTN1', 'Gene', (84, 89))	('progression-free survival', 'CPA', (204, 229))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('shorter', 'NegReg', (184, 191))	('GBM', 'Phenotype', 'HP:0012174', (110, 113))	('high', 'Var', (148, 152))	('patients', 'Species', '9606', (238, 246))
33040	25304031	The most typical examples were basal cell carcinoma (BCC) and medulloblastoma (MB), in which mutations were identified in the regulatory components of Hedgehog pathway.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (31, 51))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (31, 51))	('basal cell carcinoma', 'Disease', (31, 51))	('mutations', 'Var', (93, 102))	('medulloblastoma', 'Disease', 'MESH:D008527', (62, 77))	('medulloblastoma', 'Phenotype', 'HP:0002885', (62, 77))	('BCC', 'Phenotype', 'HP:0002671', (53, 56))	('MB', 'Phenotype', 'HP:0002885', (79, 81))	('medulloblastoma', 'Disease', (62, 77))	('Hedgehog', 'Pathway', (151, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
33046	25304031	Furthermore, it seems that the observed cilia of a small portion of U251 GBM cells had no effect on cell proliferation, since depletion of Kif3a, a key component of ciliogenesis, did not significantly affect cell growth.	('Kif3a', 'Gene', '11127', (139, 144))	('Kif3a', 'Gene', (139, 144))	('depletion', 'Var', (126, 135))	('cell proliferation', 'CPA', (100, 118))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))
33049	25304031	In addition, they found that depletion of CCRK could restore cilia for a small fraction of U251 glioma cells, and inhibit cell growth in part dependent on cilia.	('depletion', 'Var', (29, 38))	('inhibit', 'NegReg', (114, 121))	('cilia', 'MPA', (61, 66))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('CCRK', 'Protein', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('cell growth', 'CPA', (122, 133))	('restore', 'PosReg', (53, 60))	('glioma', 'Disease', (96, 102))
33052	25304031	mutations of TP53, IDH1 and ATRX, amplifications of EGFR, PDGFRA and MYCN, deletions of CDKN2A, CDKN2B, PTEN and PARK2.	('TP53', 'Gene', (13, 17))	('EGFR', 'Gene', (52, 56))	('MYCN', 'Gene', (69, 73))	('IDH1', 'Gene', '3417', (19, 23))	('mutations', 'Var', (0, 9))	('PARK2', 'Gene', '5071', (113, 118))	('CDKN2A', 'Gene', (88, 94))	('CDKN2B', 'Gene', '1030', (96, 102))	('deletions', 'Var', (75, 84))	('ATRX', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (13, 17))	('ATRX', 'Gene', '546', (28, 32))	('PTEN', 'Gene', (104, 108))	('PARK2', 'Gene', (113, 118))	('PDGFRA', 'Gene', (58, 64))	('EGFR', 'Gene', '1956', (52, 56))	('CDKN2A', 'Gene', '1029', (88, 94))	('PDGFRA', 'Gene', '5156', (58, 64))	('MYCN', 'Gene', '4613', (69, 73))	('PTEN', 'Gene', '5728', (104, 108))	('IDH1', 'Gene', (19, 23))	('CDKN2B', 'Gene', (96, 102))
33053	25304031	Interestingly, for several of them (TP53 mutation, EGFR amplification, PTEN deletion and PARK2 deletion), the association was restricted in non-proneural or proneural subtype.	('deletion', 'Var', (76, 84))	('PARK2', 'Gene', (89, 94))	('EGFR', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (36, 40))	('PARK2', 'Gene', '5071', (89, 94))	('PTEN', 'Gene', (71, 75))	('mutation', 'Var', (41, 49))	('EGFR', 'Gene', '1956', (51, 55))	('PTEN', 'Gene', '5728', (71, 75))	('TP53', 'Gene', (36, 40))	('amplification', 'Var', (56, 69))
33054	25304031	For instance, within non-proneural subgroups, the status of PTEN deletion did not influence the levels of TCTN1 expression.	('PTEN', 'Gene', (60, 64))	('deletion', 'Var', (65, 73))	('PTEN', 'Gene', '5728', (60, 64))
33058	25304031	However, we noted that within the proneural subgroup patients with high TCTN1 expression suffer from especially poor prognosis than those with low TCTN1 expression.	('TCTN1', 'Gene', (72, 77))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))
33062	25304031	Similar results could also be observed for other several alterations, in detail, high expression of TCTN1 could predict poor prognosis for patients with no EGFR change, no PDGFRA change, no MYCN change, PARK2 deletion, CDKN2A deletion or CDKN2B deletion.	('PDGFRA', 'Gene', (172, 178))	('CDKN2B', 'Gene', (238, 244))	('deletion', 'Var', (245, 253))	('PARK2', 'Gene', '5071', (203, 208))	('CDKN2B', 'Gene', '1030', (238, 244))	('PDGFRA', 'Gene', '5156', (172, 178))	('TCTN1', 'Gene', (100, 105))	('PARK2', 'Gene', (203, 208))	('EGFR', 'Gene', '1956', (156, 160))	('patients', 'Species', '9606', (139, 147))	('CDKN2A', 'Gene', (219, 225))	('deletion', 'Var', (209, 217))	('deletion', 'Var', (226, 234))	('EGFR', 'Gene', (156, 160))	('CDKN2A', 'Gene', '1029', (219, 225))	('MYCN', 'Gene', (190, 194))	('MYCN', 'Gene', '4613', (190, 194))
33068	24968753	The aim of this study was to demonstrate the role of fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS) fusion gene in ICC.	('fusion', 'Var', (101, 107))	('fused-in-glioblastoma', 'Gene', '57120', (53, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('ROS', 'Chemical', '-', (96, 99))	('fused-in-glioblastoma', 'Gene', (53, 74))	('ICC', 'Disease', (116, 119))	('FIG-ROS', 'Gene', (92, 99))	('c-ros-oncogene1', 'Gene', (75, 90))	('c-ros-oncogene1', 'Gene', '6098', (75, 90))
33072	24968753	Moreover, the co-inhibition of ROS- and FIG-specific shRNA exhibited stronger effects on HUCCT1 cell proliferation, apoptosis, colony formation, cell cycle progression, migration and invasion, when compared to single inhibition of ROS and FIG.	('shRNA', 'Gene', (53, 58))	('ROS', 'Chemical', '-', (31, 34))	('apoptosis', 'CPA', (116, 125))	('migration', 'CPA', (169, 178))	('stronger effects', 'PosReg', (69, 85))	('cell cycle progression', 'CPA', (145, 167))	('ROS', 'Chemical', '-', (231, 234))	('colony formation', 'CPA', (127, 143))	('HUCCT1', 'CellLine', 'CVCL:0324', (89, 95))	('invasion', 'CPA', (183, 191))	('co-inhibition', 'Var', (14, 27))	('HUCCT1 cell proliferation', 'CPA', (89, 114))
33082	24968753	In various types of cancer, dysregulated RTK activation was found in the process of initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('RTK', 'Protein', (41, 44))	('dysregulated', 'Var', (28, 40))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('activation', 'PosReg', (45, 55))
33141	24968753	2B, the expression of FIG protein was significantly downregulated in HUCCT1 cells transfected with plasmids expressing FIG-363, FIG-475, and FIG-504 shRNAs, respectively, compared to the control HUCCT1 cells without any transfection.	('FIG-363', 'Var', (119, 126))	('HUCCT1', 'CellLine', 'CVCL:0324', (69, 75))	('FIG-475', 'Var', (128, 135))	('downregulated', 'NegReg', (52, 65))	('HUCCT1', 'CellLine', 'CVCL:0324', (195, 201))	('FIG-504', 'Var', (141, 148))	('expression', 'MPA', (8, 18))	('FIG protein', 'Protein', (22, 33))
33146	24968753	Moreover, our findings showed that co-downregulation of ROS and FIG had an improved inhibitory effect on HUCCT1 cell proliferation, compared to the single downregulation of ROS (Fig.	('improved', 'PosReg', (75, 83))	('FIG', 'Gene', (64, 67))	('inhibitory effect', 'MPA', (84, 101))	('HUCCT1 cell proliferation', 'CPA', (105, 130))	('ROS', 'Chemical', '-', (56, 59))	('HUCCT1', 'CellLine', 'CVCL:0324', (105, 111))	('ROS', 'Chemical', '-', (173, 176))	('ROS', 'Gene', (56, 59))	('co-downregulation', 'Var', (35, 52))
33149	24968753	However, single downregulation of ROS or co-inhibition of ROS and FIG induced HUCCT1 cell apoptosis.	('downregulation', 'NegReg', (16, 30))	('ROS', 'Chemical', '-', (58, 61))	('ROS', 'Chemical', '-', (34, 37))	('ROS', 'Protein', (34, 37))	('ROS', 'Gene', (58, 61))	('HUCCT1', 'CellLine', 'CVCL:0324', (78, 84))	('co-inhibition', 'Var', (41, 54))	('HUCCT1 cell apoptosis', 'CPA', (78, 99))
33154	24968753	By contrast, HUCCT1 cells transfected with ROS1-6290 shRNA plasmid or co-transfected with ROS1-6290 and FIG-363 shRNA plasmids showed a different cell cycle distribution compared to the control group, indicating that the inhibition of ROS or ROS-FIG suppressed HUCCT1 cell proliferation partially at least by inducing an abnormal cell cycle progression (Fig.	('suppressed', 'NegReg', (250, 260))	('ROS-FIG', 'Gene', (242, 249))	('inhibition', 'Var', (221, 231))	('ROS1', 'Gene', (43, 47))	('ROS', 'Gene', (235, 238))	('ROS1', 'Gene', '6098', (43, 47))	('cell cycle progression', 'CPA', (330, 352))	('inducing', 'Reg', (309, 317))	('ROS', 'Chemical', '-', (235, 238))	('ROS', 'Chemical', '-', (90, 93))	('ROS', 'Chemical', '-', (242, 245))	('ROS1', 'Gene', (90, 94))	('HUCCT1', 'CellLine', 'CVCL:0324', (13, 19))	('ROS', 'Chemical', '-', (43, 46))	('ROS1', 'Gene', '6098', (90, 94))	('HUCCT1', 'CellLine', 'CVCL:0324', (261, 267))	('HUCCT1 cell proliferation', 'CPA', (261, 286))
33159	24968753	Single inhibition of ROS or co-inhibition of ROS and FIG notably downregulated HUCCT1 cell migration, while single inhibition of FIG had no effect on cell migration (Fig.	('ROS', 'Chemical', '-', (21, 24))	('HUCCT1', 'CellLine', 'CVCL:0324', (79, 85))	('HUCCT1 cell migration', 'CPA', (79, 100))	('ROS', 'Chemical', '-', (45, 48))	('ROS', 'Protein', (21, 24))	('ROS', 'Protein', (45, 48))	('downregulated', 'NegReg', (65, 78))	('co-inhibition', 'Var', (28, 41))
33168	24968753	ROS fusions were identified originally in glioblastoma and non-small cell lung cancer (NSCLC) to promote their progression.	('NSCLC', 'Disease', (87, 92))	('ROS', 'Chemical', '-', (0, 3))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('ROS', 'Gene', (0, 3))	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))	('non-small cell lung cancer', 'Disease', (59, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('progression', 'MPA', (111, 122))	('fusions', 'Var', (4, 11))	('promote', 'PosReg', (97, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
33171	24968753	Dysregulated ROS1 may occur in different types, including ROS1 gene fusion, overexpression, or mutations.	('ROS1', 'Gene', (13, 17))	('ROS1', 'Gene', '6098', (13, 17))	('ROS1', 'Gene', (58, 62))	('gene fusion', 'Var', (63, 74))	('ROS1', 'Gene', '6098', (58, 62))	('mutations', 'Var', (95, 104))	('occur', 'Reg', (22, 27))	('overexpression', 'PosReg', (76, 90))
33172	24968753	In many cases, the ROS1 pathway was activated by interchromosomal translocation or intrachromosomal deletion, which resulted in N-terminal ROS1 fusion genes.	('resulted in', 'Reg', (116, 127))	('interchromosomal translocation', 'Var', (49, 79))	('activated', 'PosReg', (36, 45))	('N-terminal', 'MPA', (128, 138))	('intrachromosomal deletion', 'Var', (83, 108))	('ROS1', 'Gene', (19, 23))	('ROS1', 'Gene', (139, 143))	('ROS1', 'Gene', '6098', (19, 23))	('ROS1', 'Gene', '6098', (139, 143))
33173	24968753	Increasing evidence has shown that ROS1 fusions as a distinct subgroup within various types of cancer promoted the development of ROS1-directed therapeutic strategies.	('ROS1', 'Gene', (130, 134))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('fusions', 'Var', (40, 47))	('ROS1', 'Gene', '6098', (130, 134))	('cancer', 'Disease', (95, 101))	('ROS1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ROS1', 'Gene', '6098', (35, 39))
33179	24968753	In malignant gliomas, the demethylation of ROS promoter enhanced the elevated expression of ROS kinase.	('ROS', 'Protein', (92, 95))	('expression', 'MPA', (78, 88))	('malignant gliomas', 'Disease', (3, 20))	('ROS promoter', 'Protein', (43, 55))	('demethylation', 'Var', (26, 39))	('malignant gliomas', 'Disease', 'MESH:D005910', (3, 20))	('enhanced', 'PosReg', (56, 64))	('elevated', 'PosReg', (69, 77))	('ROS', 'Chemical', '-', (43, 46))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('ROS', 'Chemical', '-', (92, 95))
33183	24968753	Thus, specific ROS inhibitors, such as crizotinib and foretinib, may provide approaches for the treatment of patients with liver cancer harboring ROS fusions.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('crizotinib', 'Chemical', 'MESH:D000077547', (39, 49))	('liver cancer', 'Disease', 'MESH:D006528', (123, 135))	('patients', 'Species', '9606', (109, 117))	('liver cancer', 'Disease', (123, 135))	('fusions', 'Var', (150, 157))	('foretinib', 'Chemical', 'MESH:C544831', (54, 63))	('ROS', 'Chemical', '-', (146, 149))	('ROS', 'Chemical', '-', (15, 18))	('liver cancer', 'Phenotype', 'HP:0002896', (123, 135))
33200	24968753	Aberrant ROS1 kinase activity resulted in the activated downstream signaling of several oncogenic pathways, including AKT/mTOR, RAS-MAPK/ERK, and Src-homology 2 domain-containing phosphatase (SHP)-1 and -2 pathways.	('ROS1', 'Gene', '6098', (9, 13))	('activated', 'PosReg', (46, 55))	('AKT', 'Gene', '207', (118, 121))	('Aberrant', 'Var', (0, 8))	('ROS1', 'Gene', (9, 13))	('AKT', 'Gene', (118, 121))	('downstream signaling', 'MPA', (56, 76))	('ERK', 'Gene', '5594', (137, 140))	('ERK', 'Gene', (137, 140))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('Src-homology 2 domain-containing phosphatase (SHP)-1 and -2', 'Gene', '5777;5781', (146, 205))	('activity', 'MPA', (21, 29))	('oncogenic pathways', 'Pathway', (88, 106))
33219	24884636	Inhibition of Pyk2 phosphorylation might be a potential target to ameliorate the therapeutic efficiency of anti-VEGF treatment.	('Pyk2', 'Protein', (14, 18))	('rat', 'Species', '10116', (72, 75))	('Inhibition', 'Var', (0, 10))
33227	24884636	With the angiogenesis-targeted therapy widely accepted, inevitable recurrence and unexpected tumor resistance, especially increased ability of glioma cell invasion were also observed after anti-VEGF treatment.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('anti-VEGF', 'Var', (189, 198))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('tumor', 'Disease', (93, 98))	('glioma', 'Disease', (143, 149))	('increased', 'PosReg', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
33241	24884636	The aim of this study was to determine whether FAK and/or Pyk2 are involved in glioma cell invasion induced by anti-VEGF therapy.	('involved', 'Reg', (67, 75))	('FAK', 'Var', (47, 50))	('glioma', 'Disease', (79, 85))	('Pyk2', 'Var', (58, 62))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))
33260	24884636	Western blotting was performed to detected protein expression and its phosphorylation statues by using specific antibodies against beta-actin (1:2000), FAK (1:2000), phosphorylated FAK (Tyr397, 1:1000), Pyk2 (1:1000) or phosphorylated Pyk2 (Tyr402, 1:1000).	('1:1000', 'Var', (209, 215))	('beta-actin', 'Gene', '81822', (131, 141))	('Tyr397', 'Chemical', '-', (186, 192))	('Tyr402', 'Chemical', '-', (241, 247))	('phosphorylation', 'MPA', (70, 85))	('Tyr402', 'Var', (241, 247))	('beta-actin', 'Gene', (131, 141))
33282	24884636	The activity of FAK and Pyk2 is regulated by phosphorylation at Tyr397 and Tyr402, respectively.	('Tyr402', 'Chemical', '-', (75, 81))	('Tyr402', 'Var', (75, 81))	('regulated', 'Reg', (32, 41))	('FAK', 'Protein', (16, 19))	('phosphorylation', 'MPA', (45, 60))	('Pyk2', 'Protein', (24, 28))	('Tyr397', 'Chemical', '-', (64, 70))	('activity', 'MPA', (4, 12))
33292	24884636	Furthermore, combined treatment of bevacizumab with Pyk2 siRNA or PP1 significantly inhibited C6 glioma cells invasion when compared to bevacizumab treatment alone or bevacizumab plus siRNA control or vehicle control (Figure 6B and 6D), suggesting the involvement of Pyk2 phosphorylation in bevacizumab-induced C6 giloma cell invasion.	('PP1', 'Gene', (66, 69))	('involvement', 'Reg', (252, 263))	('bevacizumab', 'Chemical', 'MESH:D000068258', (136, 147))	('C6 giloma', 'Disease', 'MESH:C567307', (311, 320))	('Pyk2', 'Var', (52, 56))	('bevacizumab', 'Chemical', 'MESH:D000068258', (291, 302))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('bevacizumab', 'Chemical', 'MESH:D000068258', (167, 178))	('C6 glioma', 'Disease', 'MESH:C567307', (94, 103))	('PP1', 'Gene', '29471', (66, 69))	('C6 glioma', 'Disease', (94, 103))	('bevacizumab', 'Chemical', 'MESH:D000068258', (35, 46))	('C6 giloma', 'Disease', (311, 320))	('inhibited', 'NegReg', (84, 93))
33296	24884636	Although combination of bevacizumab and PP1 decreased glioma cell invasion, there was no difference in the median survival duration of rat with intracranial xenograft between bevacizumab group and bevacizumab plus PP1 group (Figure 8).	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('rat', 'Species', '10116', (125, 128))	('rat', 'Species', '10116', (135, 138))	('bevacizumab', 'Chemical', 'MESH:D000068258', (197, 208))	('PP1', 'Gene', '29471', (40, 43))	('PP1', 'Gene', '29471', (214, 217))	('glioma', 'Disease', (54, 60))	('PP1', 'Gene', (40, 43))	('combination', 'Var', (9, 20))	('PP1', 'Gene', (214, 217))	('bevacizumab', 'Chemical', 'MESH:D000068258', (175, 186))	('bevacizumab', 'Chemical', 'MESH:D000068258', (24, 35))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('decreased', 'NegReg', (44, 53))
33301	24884636	Similarly, other recent studies showed that treatment with anti-VEGFR specific monoclonal antibody caused a striking increase in tumor cell invasion and metastasis.	('increase', 'PosReg', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('anti-VEGFR', 'Var', (59, 69))	('tumor', 'Disease', (129, 134))
33303	24884636	These studies provide evidence supporting the notion that glioma cells can directly be affected by anti-VEGF or anti-VEGFR treatment and disruption of VEGF-VEGFR autocrine loop in tumor cells maybe result in glioma cell phenotypic change.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('glioma', 'Disease', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('result in', 'Reg', (198, 207))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('tumor', 'Disease', (180, 185))	('disruption', 'Var', (137, 147))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('glioma', 'Disease', (58, 64))
33309	24884636	Moreover, Pyk2 expression occurred much more frequently and with higher expression scores within the different world health organization (WHO) grades of astrocytic tumors, although significant co-expression of FAK and Pyk2 in astrocytomas has been demonstrated.	('astrocytomas', 'Disease', 'MESH:D001254', (226, 238))	('Pyk2', 'Var', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('astrocytic tumors', 'Disease', (153, 170))	('astrocytomas', 'Disease', (226, 238))	('expression', 'MPA', (72, 82))	('rat', 'Species', '10116', (255, 258))	('astrocytic tumors', 'Disease', 'MESH:D001254', (153, 170))	('higher', 'PosReg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
33312	24884636	Compared with IgG control treatment, the phosphorylation level of Pyk2 at Tyr402 significantly increased after bevacizumab treatment, although the total levels of Pyk2 protein were similar.	('bevacizumab', 'Chemical', 'MESH:D000068258', (111, 122))	('Tyr402', 'Var', (74, 80))	('phosphorylation level', 'MPA', (41, 62))	('increased', 'PosReg', (95, 104))	('Tyr402', 'Chemical', '-', (74, 80))
33324	24884636	Recently, a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis was demonstrated and stromal-FAK heterozygosity was showed to be sufficient to enhance tumor growth and tumor angiogenesis.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('rat', 'Species', '10116', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('heterozygosity', 'Var', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('enhance', 'PosReg', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
33325	24884636	FAK-heterozygous endothelial cells displayed an imbalance in FAK phosphorylation at Tyr397 and Tyr861 without changes in the activity of Pyk2 or Erk1/2.	('imbalance', 'Phenotype', 'HP:0002172', (48, 57))	('Tyr397', 'Chemical', '-', (84, 90))	('Erk1/2', 'Gene', '50689;116590', (145, 151))	('Tyr861', 'Chemical', '-', (95, 101))	('FAK phosphorylation', 'MPA', (61, 80))	('Erk1/2', 'Gene', (145, 151))	('Tyr861', 'Var', (95, 101))
33329	24884636	Although inhibition of Pyk2 decreased glioma cell invasion, there was no difference in the median survival duration of rat with intracranial xenograft between bevacizumab treatment group and bevacizumab plus PP1 treatment group, suggesting that the development of glioma is a complex process.	('glioma', 'Disease', (264, 270))	('Pyk2', 'Gene', (23, 27))	('PP1', 'Gene', '29471', (208, 211))	('decreased', 'NegReg', (28, 37))	('bevacizumab', 'Chemical', 'MESH:D000068258', (191, 202))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('rat', 'Species', '10116', (119, 122))	('glioma', 'Disease', 'MESH:D005910', (264, 270))	('rat', 'Species', '10116', (109, 112))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('PP1', 'Gene', (208, 211))	('glioma', 'Disease', (38, 44))	('inhibition', 'Var', (9, 19))	('bevacizumab', 'Chemical', 'MESH:D000068258', (159, 170))
33341	24884636	To our knowledge, this is the first study to focus on the role of FAK and Pyk2 in the promotion of glioma cell invasion induced by anti-VEGF treatment.	('promotion', 'PosReg', (86, 95))	('anti-VEGF', 'Var', (131, 140))	('glioma', 'Disease', (99, 105))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('Pyk2', 'Gene', (74, 78))
33396	23826488	Also dysfunction of this transmembrane protein results in an autosomal dominant childhood-onset neurological disease DYT1 Dystonia.	('neurological disease DYT1 Dystonia', 'Disease', 'MESH:C538005', (96, 130))	('neurological disease', 'Phenotype', 'HP:0000707', (96, 116))	('neurological disease DYT1 Dystonia', 'Disease', (96, 130))	('results in', 'Reg', (47, 57))	('Dystonia', 'Phenotype', 'HP:0001332', (122, 130))	('dysfunction', 'Var', (5, 16))
33400	23826488	Additionally, it has been reported that Humanin increases ATP biosynthesis in human rhabdomyosarcoma TE671 cells cultured under serum-free conditions.	('rhabdomyosarcoma', 'Disease', (84, 100))	('increases', 'PosReg', (48, 57))	('ATP biosynthesis', 'MPA', (58, 74))	('Humanin', 'Var', (40, 47))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (84, 100))	('human', 'Species', '9606', (78, 83))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (84, 100))
33413	23826488	Several investigations point to the role of XRCC2 mutations and polymorphisms in various cancers such as breast cancer, colorectal cancer, brain cancer, oral and Lynch syndrome and esophageal adenocarcinoma.	('oral', 'Disease', 'MESH:D020820', (153, 157))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (181, 206))	('cancers', 'Disease', (89, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (181, 206))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Lynch syndrome', 'Disease', (162, 176))	('brain cancer', 'Phenotype', 'HP:0030692', (139, 151))	('colorectal cancer', 'Disease', (120, 137))	('esophageal adenocarcinoma', 'Disease', (181, 206))	('brain cancer', 'Disease', 'MESH:D001932', (139, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('Lynch syndrome', 'Disease', 'MESH:D003123', (162, 176))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('XRCC2', 'Gene', (44, 49))	('mutations', 'Var', (50, 59))	('oral', 'Disease', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('brain cancer', 'Disease', (139, 151))
33414	23826488	Overexpression of X-ray repair cross-complementing group 2(XRCC2) is a hallmark of neoplastic cells and especially in glioblastoma tumor cells leads to resistance against anticancer drugs Temozolomide (TMZ).	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('leads to', 'Reg', (143, 151))	('resistance', 'MPA', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (118, 136))	('XRCC2', 'Gene', (59, 64))	('glioblastoma tumor', 'Disease', (118, 136))	('Overexpression', 'Var', (0, 14))	('Temozolomide', 'Chemical', 'MESH:D000077204', (188, 200))	('TMZ', 'Chemical', 'MESH:D000077204', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
33522	33329726	This happened for GSE14520(U133B), GSE6919(U95B and C), and GSE 6344(U133B).	('GSE', 'Gene', '317782', (18, 21))	('GSE', 'Gene', (18, 21))	('GSE6919', 'Chemical', '-', (35, 42))	('B', 'Chemical', 'MESH:D001895', (73, 74))	('GSE', 'Gene', '317782', (60, 63))	('GSE', 'Gene', (60, 63))	('B', 'Chemical', 'MESH:D001895', (46, 47))	('U133B', 'Var', (27, 32))	('U133B', 'Var', (69, 74))	('GSE', 'Gene', '317782', (35, 38))	('GSE', 'Gene', (35, 38))	('B', 'Chemical', 'MESH:D001895', (31, 32))
33581	33329726	In this sense, the 33 overexpressed genes used as input for the network construction were related to GOs deeply associated to all cancers, like a positive induction of cell cycle, deregulation of DNA repair, proteolysis, and kinase-related signaling pathways (Figure 2C and Supplementary Figure 1, Supplementary Table 16) (Hanahan and Weinberg,; Pickup et al.,; Sanchez-Vega et al.,).	('kinase-related signaling pathways', 'Pathway', (225, 258))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cell cycle', 'CPA', (168, 178))	('to', 'Gene', '6999', (98, 100))	('cancers', 'Disease', (130, 137))	('proteolysis', 'CPA', (208, 219))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('deregulation', 'Var', (180, 192))	('to', 'Gene', '6999', (123, 125))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('DNA repair', 'Protein', (196, 206))
33645	33329726	BRCA patients with high expression of CTHRC1 had shorter lifespans (HR = 1.7) however.	('CTHRC1', 'Gene', (38, 44))	('pan', 'Gene', '51816', (62, 65))	('patients', 'Species', '9606', (5, 13))	('BRCA', 'Gene', (0, 4))	('high expression', 'Var', (19, 34))	('shorter', 'NegReg', (49, 56))	('CTHRC1', 'Gene', '115908', (38, 44))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('pan', 'Gene', (62, 65))	('BRCA', 'Gene', '672', (0, 4))
33683	32110947	LnHS significantly inhibited U-87 cancer cell proliferation, but not that of fibroblasts, and was able to reduce U-87 cell migration, inducing further DNA damage.	('DNA damage', 'MPA', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('U-87', 'Gene', '641648', (29, 33))	('inhibited', 'NegReg', (19, 28))	('inducing', 'Reg', (134, 142))	('U-87', 'Gene', '641648', (113, 117))	('reduce', 'NegReg', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('LnHS', 'Var', (0, 4))	('cancer', 'Disease', (34, 40))	('U-87', 'Gene', (29, 33))	('U-87', 'Gene', (113, 117))
33721	32110947	The N-CO alpha-cleavage, a characteristic fragmentation observed as a common pattern in all natural and synthetic amides, could drive the genesis of the ion at m/z 161.0244, whereas ions at m/z 135.0455 (base peak), 134.0373, and 133.0302, and 132.0217 were attributable to dihydroxycinnamoyl residue (Table 1).	('133.0302', 'Var', (230, 238))	('genesis', 'MPA', (138, 145))	('N', 'Chemical', 'MESH:D009584', (4, 5))	('132.0217', 'Var', (244, 252))	('134.0373', 'Var', (216, 224))	('amides', 'Chemical', 'MESH:D000577', (114, 120))	('dihydroxycinnamoyl', 'Chemical', '-', (274, 292))	('at m/z 161.0244', 'Var', (157, 172))
33725	32110947	The deprotonated molecular ion gave rise to the ion [M - H - H2O]- at m/z 280.0981, which in turn provided the ions at m/z 134.0607 and 119.0502.	('H2O', 'Chemical', '-', (61, 64))	('119.0502', 'Var', (136, 144))	('m/z 280.0981', 'Var', (70, 82))	('m/z 134.0607', 'Var', (119, 131))
33731	32110947	The CH2CO loss likely consisted in the fragment ion at m/z 256.0974 (Figure 2).	('loss', 'NegReg', (10, 14))	('m/z 256.0974', 'Var', (55, 67))	('CH2CO', 'Chemical', '-', (4, 9))	('consisted', 'Reg', (22, 31))
33733	32110947	The TOF-MS2 spectra of the 3d-derived underwent rearrangement to give the ion at m/z 180.0619, whereas the loss of an ethen-1-one-2-d provided the fragment ion at m/z 258.1098.	('m/z 180.0619', 'Var', (81, 93))	('rearrangement', 'MPA', (48, 61))	('MS2', 'Species', '2710868', (8, 11))
33737	32110947	The deprotonated molecular ion underwent in both TOF-MS2 spectra methyl radical loss to achieve the fragment ion at m/z 297.1015(4), which gave rise to fragment ions at m/z 190.0510(3) and 178.0513, or more favorably led to ion at m/z 148.0530(5) (base peak) through CO-Calpha' bond cleavage.	('methyl radical', 'MPA', (65, 79))	('178.0513', 'Var', (189, 197))	('loss', 'NegReg', (80, 84))	('radical', 'Chemical', '-', (72, 79))	('MS2', 'Species', '2710868', (53, 56))
33738	32110947	The CH3  loss generated the radical ion at m/z 134.0373(6), as well as the ion at m/z 135.0452(6).	('m/z 135.0452', 'Var', (82, 94))	('loss', 'NegReg', (9, 13))	('radical', 'Chemical', '-', (28, 35))	('m/z 134.0373', 'Var', (43, 55))	('CH3', 'Gene', (4, 7))
33740	32110947	UV-DAD and TOF-MS/MS spectra were according to N-p-coumaroyltyramine, an antioxidant HAA compound with inhibiting effect on acetylcholinesterase, cell proliferation, platelet aggregation.	('D', 'Chemical', 'MESH:D003903', (3, 4))	('N-p-coumaroyltyramine', 'Var', (47, 68))	('platelet aggregation', 'Disease', (166, 186))	('platelet aggregation', 'Disease', 'MESH:D001791', (166, 186))	('inhibiting', 'NegReg', (103, 113))	('HAA', 'Chemical', '-', (85, 88))	('acetylcholinesterase', 'MPA', (124, 144))	('platelet aggregation', 'Phenotype', 'HP:0003540', (166, 186))	('D', 'Chemical', 'MESH:D003903', (5, 6))	('cell proliferation', 'CPA', (146, 164))	('N-p-coumaroyltyramine', 'Chemical', '-', (47, 68))
33750	32110947	The loss of 163.06 Da, likely corresponding to isocyanic acid (HNCO) + p-hydroxystyrene, also could directly occur from the deprotonated molecular ion supplying the fragment ion at m/z 430.1313.	('p-hydroxystyrene', 'Chemical', 'MESH:C030626', (71, 87))	('HNCO', 'Chemical', '-', (63, 67))	('isocyanic acid', 'Chemical', 'MESH:C005057', (47, 61))	('163.06 Da', 'Var', (12, 21))	('D', 'Chemical', 'MESH:D003903', (19, 20))	('loss', 'NegReg', (4, 8))
33761	32110947	The [M - H]- ion dissociated, as observed in the TOF-MS/MS experiment, providing the ion m/z 458.1262, attributable to a tyramine moiety direct neutral loss, as well as the more abundant ion at m/z 432.1468.	('tyramine', 'Chemical', 'MESH:D014439', (121, 129))	('loss', 'NegReg', (152, 156))	('m/z 458.1262', 'Var', (89, 101))
33762	32110947	This latter could further loss a tyramine unit providing the ion at m/z 295.0616 or also, more favorably supplied the base peak at m/z 269.0828, which was in accordance with a 2-hydroxy-4-(7-hydroxy-5-vinyl-2,3-dihydrobenzofuran-2-yl)phenolate (Figure S9).	('m/z 295.0616', 'Var', (68, 80))	('tyramine unit', 'MPA', (33, 46))	('loss', 'NegReg', (26, 30))	('2-hydroxy-4-(7-hydroxy-5-vinyl-2,3-dihydrobenzofuran-2-yl)phenolate', 'Chemical', '-', (176, 243))	('tyramine', 'Chemical', 'MESH:D014439', (33, 41))	('base peak', 'MPA', (118, 127))
33768	32110947	The most polar compounds 4 and 6 showed the deprotonated molecular ions at m/z 609.1886 and 609.1887, respectively and were distinguishable with the other extract's compounds for their content in octopamine, beyond tyramine, as polyamine moiety.	('octopamine', 'Chemical', 'MESH:D009655', (196, 206))	('deprotonated molecular ions', 'MPA', (44, 71))	('octopamine', 'MPA', (196, 206))	('m/z 609.1886', 'Var', (75, 87))	('tyramine', 'Chemical', 'MESH:D014439', (215, 223))	('609.1887', 'Var', (92, 100))	('polyamine', 'Chemical', 'MESH:D011073', (228, 237))
33769	32110947	In particular, both the [M - H]- ions underwent water neutral loss (likely from the octopamine residue) providing a fragment ion at m/z 591.18 and presented the base peak ion at m/z 456.11 (Figure S11).	('water', 'Chemical', 'MESH:D014867', (48, 53))	('water', 'MPA', (48, 53))	('octopamine', 'Chemical', 'MESH:D009655', (84, 94))	('m/z 591.18', 'Var', (132, 142))
33771	32110947	Furthermore, TOF-MS/MS spectrum of compound 4 also displayed the fragment ion at m/z 472.1058, which could be due to the loss of the tyramine moiety, and further underwent water loss to yield the ion at m/z 454.0944 (Figure S11).	('tyramine', 'Protein', (133, 141))	('loss', 'NegReg', (121, 125))	('water loss', 'Phenotype', 'HP:0000969', (172, 182))	('water', 'Chemical', 'MESH:D014867', (172, 177))	('m/z 454.0944', 'Var', (203, 215))	('yield', 'Reg', (186, 191))	('tyramine', 'Chemical', 'MESH:D014439', (133, 141))
33775	32110947	Both the ions at m/z 595.2080 and 432.1446 could undergo phenyldihydronaphthalene moiety cleavage providing the ions at m/z 475.1864 and 312.1227, respectively.	('312.1227', 'Var', (137, 145))	('432.1446', 'Var', (34, 42))	('m/z 475.1864', 'Var', (120, 132))	('phenyldihydronaphthalene', 'Chemical', '-', (57, 81))
33777	32110947	Furthermore, a dimer of N-caffeoyloctopamine and N-caffeoyltyramine was hypothesized to be compound 26, whose deprotonated molecular ion at m/z 611.2047 gave rise the abundant ions at m/z 314.1044 and 298.1088, attributable to caffeoyloctopamine, and caffeoyltyramine, respectively (Figure S13).	('298.1088', 'Var', (201, 209))	('N-caffeoyloctopamine', 'Chemical', '-', (24, 44))	('caffeoyloctopamine', 'Chemical', '-', (26, 44))	('caffeoyltyramine', 'Chemical', '-', (251, 267))	('caffeoyltyramine', 'Chemical', '-', (51, 67))	('caffeoyloctopamine', 'Chemical', '-', (227, 245))	('m/z 314.1044', 'Var', (184, 196))	('N-caffeoyltyramine', 'Chemical', 'MESH:C481438', (49, 67))
33778	32110947	H2O and CH2O losses were detectable in TOF-MS/MS spectra of peaks related to compounds 19 and 20, which showed the deprotonated molecular ions at m/z 508.1968 and 508.1990, respectively, likely corresponding erythro and threo-diastereoisomers of cannabisin H. The fragment ions at m/z 312.1244 and 312.1248, could be formed following the cleavage of beta-aryl ether moiety, whereas the further methyl radical loss yielded the ions at m/z 297.1015 and 297.1009.	('H2O', 'Chemical', '-', (9, 12))	('H2O', 'Chemical', '-', (0, 3))	('312.1248', 'Var', (298, 306))	('beta-aryl ether moiety', 'Protein', (350, 372))	('CH2O', 'Chemical', '-', (8, 12))	('297.1009', 'Var', (451, 459))	('radical', 'Chemical', '-', (401, 408))	('methyl radical', 'MPA', (394, 408))	('loss', 'NegReg', (409, 413))	('m/z 312.1244', 'Var', (281, 293))
33784	32110947	The aryldihydronaphtalene-type core likely characterized both compounds 23 and 24 which were distinguishable through fragment ions at m/z 499.1891 and 485.1757, respectively, which were in accordance with their relative catechol or guaiacol loss.	('485.1757', 'Var', (151, 159))	('guaiacol', 'Chemical', 'MESH:D006139', (232, 240))	('m/z 499.1891', 'Var', (134, 146))	('aryldihydronaphtalene', 'Chemical', '-', (4, 25))	('catechol', 'Chemical', 'MESH:C034221', (220, 228))
33787	32110947	In fact, also in this case, the [M - H]- ion underwent tyramine neutral loss with the genesis of the ion at m/z 472.1428, whereas the loss of 163.06 Da gave the most abundant ion at m/z 446.1633, which in turn lost a methyl radical, providing the radical anion at m/z 431.1391.	('loss', 'NegReg', (72, 76))	('radical', 'Chemical', '-', (247, 254))	('lost', 'NegReg', (210, 214))	('tyramine', 'Chemical', 'MESH:D014439', (55, 63))	('tyramine', 'MPA', (55, 63))	('D', 'Chemical', 'MESH:D003903', (149, 150))	('radical', 'Chemical', '-', (224, 231))	('methyl radical', 'MPA', (217, 231))	('loss', 'Var', (134, 138))
33789	32110947	This latter, which represented the base peak, also furnished the radical ion at m/z 268.0743 through methyl radical loss (Figure 5).	('methyl radical loss', 'MPA', (101, 120))	('radical', 'Chemical', '-', (65, 72))	('m/z 268.0743', 'Var', (80, 92))	('radical', 'Chemical', '-', (108, 115))
33795	32110947	The deprotonated molecular ion at m/z 490.1875 provided the fragment ions at m/z 472.1769 and 460.1769, following H2O and formaldehyde neutral losses.	('H2O', 'Chemical', '-', (114, 117))	('m/z 472.1769', 'Var', (77, 89))	('formaldehyde', 'Chemical', 'MESH:D005557', (122, 134))	('460.1769', 'Var', (94, 102))
33797	32110947	Both the ions underwent methyl radical loss to achieve ions at m/z 457.1541 and 445.1529, respectively, which, in turn, gave diradical anions at m/z 442.1300 (base peak) and 430.1300.	('m/z 442.1300', 'Var', (145, 157))	('radical', 'Chemical', '-', (127, 134))	('diradical anions', 'MPA', (125, 141))	('445.1529', 'Var', (80, 88))	('radical', 'Chemical', '-', (31, 38))	('methyl radical', 'MPA', (24, 38))	('gave', 'Reg', (120, 124))	('m/z 457.1541', 'Var', (63, 75))
33804	32110947	The presence of the pentose moiety was further suggested for compounds 9 and 10, whose aglycone moiety was kaempferol, as suggested by the [aglycone - H]- and aglycone radical ion at m/z 285.0406(08) and 284.0328(29), as well as the ions at m/z 255.0299(303) and 227.0352(1), which could come from the [aglycone - H] - ion.	('aglycone', 'Chemical', 'MESH:C458179', (303, 311))	('pentose', 'Chemical', 'MESH:D010429', (20, 27))	('aglycone', 'Chemical', 'MESH:C458179', (159, 167))	('aglycone', 'Chemical', 'MESH:C458179', (87, 95))	('227.0352', 'Var', (263, 271))	('m/z', 'Var', (183, 186))	('m/z 255.0299', 'Var', (241, 253))	('radical', 'Chemical', '-', (168, 175))	('284.0328', 'Var', (204, 212))	('kaempferol', 'Chemical', 'MESH:C006552', (107, 117))	('aglycone', 'Chemical', 'MESH:C458179', (140, 148))
33807	32110947	Finally, the detected loss of acetic acid moiety in the TOF-MS/MS spectrum of compound 18 as well as the occurrence of [aglycone-H]-, [aglycone - H] - and [aglycone - 2H] - at m/z 301.0361; 300.0278 and 299.0194, were in accordance with quercetin-7-O-acetyldeoxyhexose.	('acetic acid', 'Chemical', 'MESH:D019342', (30, 41))	('2H', 'Chemical', 'MESH:D003903', (167, 169))	('aglycone', 'Chemical', 'MESH:C458179', (156, 164))	('[aglycone-H', 'MPA', (119, 130))	('aglycone', 'Chemical', 'MESH:C458179', (135, 143))	('299.0194', 'Var', (203, 211))	('loss', 'NegReg', (22, 26))	('acetic acid moiety', 'MPA', (30, 48))	('aglycone', 'Chemical', 'MESH:C458179', (120, 128))	('quercetin', 'Chemical', 'MESH:D011794', (237, 246))	('7-O-acetyldeoxyhexose', 'Chemical', '-', (247, 268))
33822	32110947	U-87 cells showed DNA damage when treated with LnHS 25 and 50 mug/mL (Figure 7A), whereas no genotoxic effects was detectable in human fibroblast cells.	('DNA damage', 'MPA', (18, 28))	('U-87', 'Gene', (0, 4))	('U-87', 'Gene', '641648', (0, 4))	('LnHS 25', 'Var', (47, 54))	('human', 'Species', '9606', (129, 134))
33824	32110947	Both the cell types were subjected to scraped wounds: U-87 cells were treated with five doses (0.5, 2.5, 5, 25 and 50 microg/mL), whereas HF cells with three LnHS doses (5, 25 and 50 microg/mL).	('0.5', 'Var', (95, 98))	('HF', 'CellLine', 'CVCL:M656', (138, 140))	('U-87', 'Gene', (54, 58))	('U-87', 'Gene', '641648', (54, 58))
33908	31106264	After systemic administration, P1C10, the lead brain ECM-targeting VLR candidate, specifically accumulated in brains with mannitol-disrupted BBB and at disrupted BBB regions in two different intracranial glioblastoma models.	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('intracranial glioblastoma', 'Disease', 'MESH:D005909', (191, 216))	('intracranial glioblastoma', 'Disease', (191, 216))	('mannitol', 'Chemical', 'MESH:D008353', (122, 130))	('accumulated', 'PosReg', (95, 106))	('P1C10', 'Var', (31, 36))	('VLR', 'Gene', (67, 70))
33926	31106264	For example, yeast displaying clones P1C10 and P2C7 (ELISA fold change, 4.2 and 4.5, respectively) bound selectively to bEnd.3 ECM compared to 3T3 ECM, whereas a nonbinding VLR clone P1E9 showed very little ECM binding (Fig.	('P2C7', 'Var', (47, 51))	('yeast', 'Species', '4932', (13, 18))	('bound', 'Interaction', (99, 104))	('P1C10', 'Var', (37, 42))
33931	31106264	Direct immunolabeling of murine tissues using VLR-Cy5 conjugates indicated that P1C10-Cy5 had substantial brain ECM selectivity compared to kidney (10.1-fold increase), heart (20.2-fold increase), and liver (5.7-fold increase) tissues (Fig.	('P1C10-Cy5', 'Var', (80, 89))	('Cy5', 'Chemical', 'MESH:C085321', (50, 53))	('brain', 'CPA', (106, 111))	('murine', 'Species', '10090', (25, 31))	('Cy5', 'Chemical', 'MESH:C085321', (86, 89))
33932	31106264	In contrast, P3A8-Cy5 bound both brain and liver ECM with similar intensity but, like P1C10-Cy5, also did not show binding to kidney and heart tissues (fig.	('Cy5', 'Chemical', 'MESH:C085321', (18, 21))	('Cy5', 'Chemical', 'MESH:C085321', (92, 95))	('binding', 'Interaction', (115, 122))	('P3A8-Cy5', 'Var', (13, 21))
33934	31106264	P1C10-Cy5 bound human brain ECM compared with controls, with a pattern similar to that observed in murine brain sections (Fig.	('bound', 'Interaction', (10, 15))	('murine', 'Species', '10090', (99, 105))	('P1C10-Cy5', 'Var', (0, 9))	('Cy5', 'Chemical', 'MESH:C085321', (6, 9))	('human', 'Species', '9606', (16, 21))
33935	31106264	Furthermore, P1C10-Cy5 also bound to ECM in cryosections of freshly resected human GBM specimens (Fig.	('bound', 'Reg', (28, 33))	('Cy5', 'Chemical', 'MESH:C085321', (19, 22))	('P1C10-Cy5', 'Var', (13, 22))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('human', 'Species', '9606', (77, 82))
33942	31106264	Mice treated with P1C10-IR800 had a significant, 3.3-fold increase in accumulated brain fluorescence compared to RBC36-IR800 and a 7.6-fold increase compared to saline-treated animals.	('increase', 'PosReg', (58, 66))	('saline', 'Chemical', 'MESH:D012965', (161, 167))	('P1C10-IR800', 'Var', (18, 29))	('Mice', 'Species', '10090', (0, 4))	('accumulated brain fluorescence', 'MPA', (70, 100))
33946	31106264	The mean fluorescence intensity of the GL261 tumor region for mice treated with P1C10-IR800 was 112-fold higher than that of the contralateral brain region (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('higher', 'PosReg', (105, 111))	('tumor', 'Disease', (45, 50))	('mice', 'Species', '10090', (62, 66))	('GL261', 'Chemical', '-', (39, 44))	('P1C10-IR800', 'Var', (80, 91))	('fluorescence intensity', 'MPA', (9, 31))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
33947	31106264	By contrast, the fluorescence intensity of the GL261 tumor region for mice treated with control RBC36-IR800 was only increased ninefold compared with contralateral brain.	('GL261', 'Chemical', '-', (47, 52))	('increased', 'PosReg', (117, 126))	('fluorescence intensity', 'MPA', (17, 39))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Disease', (53, 58))	('RBC36-IR800', 'Var', (96, 107))
33948	31106264	Moreover, the accumulated P1C10-IR800 in tumor was 13-fold higher than that observed for control RBC36-IR800.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('higher', 'PosReg', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('P1C10-IR800', 'Var', (26, 37))
33949	31106264	Together, these data indicate that P1C10-IR800 selectively accumulated within GL261 orthotopic tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('ether', 'Chemical', 'MESH:D004986', (3, 8))	('GL261', 'Chemical', '-', (78, 83))	('P1C10-IR800', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
33952	31106264	P1C10, 192, and RBC36 were fused to a rabbit Fc region (VLR-Fc) to facilitate avidity and detection while minimizing renal clearance.	('rabbit', 'Species', '9986', (38, 44))	('P1C10', 'Var', (0, 5))	('facilitate', 'PosReg', (67, 77))	('minimizing', 'NegReg', (106, 116))	('RBC36', 'Gene', (16, 21))	('detection', 'MPA', (90, 99))	('minimizing renal clearance', 'Phenotype', 'HP:0012213', (106, 132))	('renal clearance', 'MPA', (117, 132))	('avidity', 'MPA', (78, 85))
33953	31106264	Both VLR clones P1C10-Fc and 192-Fc accumulated within the margins of the GBM, with P1C10-Fc being distributed throughout the tumor ECM (Fig.	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('P1C10-Fc', 'Var', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('P1C10-Fc', 'Var', (16, 24))	('tumor', 'Disease', (126, 131))
33958	31106264	Quantitatively, P1C10-Fc demonstrated a 21.2-fold increase in U87 tumor compared to contralateral controls, as well as increases of 21.2-fold compared to kidney, 15.9-fold compared to liver, and 29.6-fold compared to heart.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('increases', 'PosReg', (119, 128))	('tumor', 'Disease', (66, 71))	('increase', 'PosReg', (50, 58))	('P1C10-Fc', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
33959	31106264	Both P1C10-Fc (25.4-fold) and 192-Fc (11.9-fold) yielded increased accumulation in U87 tumor regions compared to the RBC36-Fc control.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('P1C10-Fc', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('accumulation', 'PosReg', (67, 79))
33960	31106264	Together, both P1C10-Fc and 192-Fc specifically target and preferentially accumulate at regions of vascular disruption in GBM, with P1C10-Fc displaying more brain specificity.	('preferentially', 'PosReg', (59, 73))	('P1C10-Fc', 'Var', (132, 140))	('GBM', 'Phenotype', 'HP:0012174', (122, 125))	('ether', 'Chemical', 'MESH:D004986', (3, 8))	('accumulate', 'PosReg', (74, 84))
33968	31106264	Last, VLRs retained their binding activity after immobilization on the liposome surface as demonstrated by a 4.5-fold increase in doxorubicin signal for P1C10-targeted liposomes binding to murine brain sections compared to RBC36-targeted control liposomes (Fig.	('doxorubicin signal', 'MPA', (130, 148))	('increase', 'PosReg', (118, 126))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('P1C10-targeted', 'Var', (153, 167))	('murine', 'Species', '10090', (189, 195))	('binding', 'Interaction', (26, 33))	('binding', 'Interaction', (178, 185))
33969	31106264	To demonstrate the feasibility of performing treatment studies with VLR-targeted doxorubicin-loaded liposomes, we incubated U87 GBM cells cultured on bEnd.3 ECM with P1C10- or RBC36-targeted doxorubicin-loaded liposomes in vitro (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (191, 202))	('RBC36-targeted', 'Protein', (176, 190))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('P1C10-', 'Var', (166, 172))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))
33970	31106264	To demonstrate the potential therapeutic utility of targeting pathologically exposed brain ECM, we treated SCID mice bearing intracranial U87 GBM with P1C10-, 192-, or RBC36-targeted doxorubicin-loaded liposomes.	('doxorubicin', 'Chemical', 'MESH:D004317', (183, 194))	('RBC36-targeted', 'Var', (168, 182))	('SCID', 'Disease', 'MESH:D053632', (107, 111))	('GBM', 'Phenotype', 'HP:0012174', (142, 145))	('SCID', 'Disease', (107, 111))	('mice', 'Species', '10090', (112, 116))	('P1C10-', 'Var', (151, 157))
33972	31106264	Whole-brain images of doxorubicin signal from mice treated with either P1C10- or RBC36-targeted doxorubicin liposomes show enhanced doxorubicin uptake with P1C10-targeted liposomes (Fig.	('enhanced', 'PosReg', (123, 131))	('doxorubicin', 'Chemical', 'MESH:D004317', (22, 33))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('mice', 'Species', '10090', (46, 50))	('P1C10-', 'Var', (71, 77))	('doxorubicin uptake', 'MPA', (132, 150))	('RBC36-targeted', 'Gene', (81, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (132, 143))
33974	31106264	Higher-resolution fluorescent images indicate that P1C10 mediates an elevated doxorubicin accumulation within the tumor region compared to control contralateral brain tissue (7.6-fold increase) or the signal observed within the tumor region after exposure to control RBC36 (7.9-fold increase) (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('doxorubicin', 'Chemical', 'MESH:D004317', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (228, 233))	('P1C10', 'Var', (51, 56))	('elevated', 'PosReg', (69, 77))	('doxorubicin accumulation', 'MPA', (78, 102))
33975	31106264	4), indicating that P1C10 mediates doxorubicin accumulation at the tumor site.	('doxorubicin accumulation', 'MPA', (35, 59))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('P1C10', 'Var', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('mediates', 'Reg', (26, 34))
33977	31106264	Four weekly therapeutic doses of 12 mg doxorubicin/kg of doxorubicin-loaded liposomes targeted by P1C10, 192, or RBC36 were administered by intraperitoneal injection at days 7, 14, 21, and 28.	('doxorubicin', 'Chemical', 'MESH:D004317', (39, 50))	('P1C10', 'Var', (98, 103))	('RBC36', 'Gene', (113, 118))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
33978	31106264	Median survivals after tumor implantation were 43, 30, and 28 days for P1C10-, 192-, and RBC36-targeted groups, respectively.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('P1C10-', 'Var', (71, 77))	('tumor', 'Disease', (23, 28))	('RBC36-targeted', 'Gene', (89, 103))
33994	31106264	However, the unoptimized doxorubicin dosing and administration in our study is different from the previous IL-13 work, and IL-13 may also result in tumor cell endocytosis, which may confer superior efficacy compared to an ECM-targeted doxorubicin payload.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('IL-13', 'Var', (123, 128))	('doxorubicin', 'Chemical', 'MESH:D004317', (235, 246))	('efficacy', 'MPA', (198, 206))	('tumor', 'Disease', (148, 153))	('doxorubicin', 'Chemical', 'MESH:D004317', (25, 36))	('result in', 'Reg', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
33996	31106264	Thus, the therapeutic benefit observed with P1C10 VLR is directly related to its specific targeting of disrupted BBB regions, and the biodistribution data suggest that the therapeutic benefit results from enhanced accumulation of doxorubicin selectively within the GBM.	('enhanced accumulation', 'PosReg', (205, 226))	('doxorubicin', 'MPA', (230, 241))	('P1C10', 'Var', (44, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (230, 241))	('GBM', 'Phenotype', 'HP:0012174', (265, 268))
34001	31106264	In addition, rather than targeting doxorubicin as in this proof-of-principle study, P1C10 VLR could be used to target and deliver more clinically relevant anti-GBM treatments such as temozolomide-loaded liposomes or immune checkpoint inhibitors.	('GBM', 'Phenotype', 'HP:0012174', (160, 163))	('anti-GBM', 'Disease', (155, 163))	('temozolomide', 'Chemical', 'MESH:D000077204', (183, 195))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('P1C10', 'Var', (84, 89))
34018	31106264	For VLR surface display assays, EBY100 yeast were grown in SD-CAA medium [dextrose (20.0 g/liter), yeast nitrogen base (6.7 g/liter), casamino acids (5.0 g/liter), Na2HPO4 7 H2O (10.19 g/liter), and NaH2HPO4 H2O (8.56 g/liter)] as previously described and induced when the culture reached an optical density at 600 nm (OD600nm) between 0.8 and 0.9 using SG-CAA medium.	('NaH2HPO4', 'CellLine', 'CVCL:U766', (199, 207))	('yeast', 'Species', '4932', (39, 44))	('Na2HPO4', 'Var', (164, 171))	('yeast', 'Species', '4932', (99, 104))	('NaH2HPO4 H2O', 'Var', (199, 211))
34088	31106264	To directly quantify VLR-doxorubicin binding to murine sections, P1C10-RBC36, or nontargeted doxorubicin-loaded liposomes were incubated with murine sections, washed and then imaged on a Zeiss Imager Z2 upright fluorescent microscope.	('murine', 'Species', '10090', (142, 148))	('binding', 'Interaction', (37, 44))	('P1C10-RBC36', 'Var', (65, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (25, 36))	('murine', 'Species', '10090', (48, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (93, 104))
34098	31106264	For survival studies, after confirming tumor engraftment by luminescence, mice were intraperitoneally administered 12 mg/kg doxorubicin of P1C10-targeted (n = 5), 192-targeted (n = 5), or RBC36-targeted (n = 4) doxorubicin-loaded liposomes weekly for four cycles.	('RBC36-targeted', 'Var', (188, 202))	('doxorubicin', 'Chemical', 'MESH:D004317', (211, 222))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('192-targeted', 'Var', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('P1C10-targeted', 'Var', (139, 153))	('tumor', 'Disease', (39, 44))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('mice', 'Species', '10090', (74, 78))
34108	28445150	Knocking-down Kir4.1 expression by siRNA transfection similarly increased both filopodia formation and invasiveness of glioma cells as observed in Boyden chamber assay.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('filopodia formation', 'CPA', (79, 98))	('invasiveness of glioma', 'Disease', (103, 125))	('Knocking-down', 'Var', (0, 13))	('Kir4.1', 'Gene', '3766', (14, 20))	('Kir4.1', 'Gene', (14, 20))	('invasiveness of glioma', 'Disease', 'MESH:D005910', (103, 125))	('increased', 'PosReg', (64, 73))
34109	28445150	MiR-5096 also promotes the release of extracellular vesicles by which it increases its own transfer to surrounding cells, in a Kir4.1-dependent manner in U251 but not in U87.	('MiR-5096', 'Gene', '100616427', (0, 8))	('U251', 'CellLine', 'CVCL:0021', (154, 158))	('increases', 'PosReg', (73, 82))	('U87', 'Gene', (170, 173))	('Kir4.1', 'Gene', '3766', (127, 133))	('Kir4.1', 'Gene', (127, 133))	('U87', 'Gene', '641648', (170, 173))	('promotes', 'PosReg', (14, 22))	('transfer to surrounding cells', 'MPA', (91, 120))	('MiR-5096', 'Gene', (0, 8))	('U251', 'Var', (154, 158))	('release of extracellular vesicles', 'MPA', (27, 60))
34115	28445150	mutation in KCNJ10 gene causes an autosomal recessive disorder associating early onset seizures, ataxia, mental retardation, and electrolyte imbalance while a polymorphism in this gene correlates with seizure susceptibility.	('electrolyte imbalance', 'Phenotype', 'HP:0003111', (129, 150))	('seizure', 'Phenotype', 'HP:0001250', (201, 208))	('causes', 'Reg', (24, 30))	('KCNJ10', 'Gene', '3766', (12, 18))	('seizure', 'Disease', (201, 208))	('seizure', 'Disease', 'MESH:D012640', (87, 94))	('seizures', 'Disease', (87, 95))	('seizure', 'Phenotype', 'HP:0001250', (87, 94))	('imbalance', 'Phenotype', 'HP:0002172', (141, 150))	('mutation', 'Var', (0, 8))	('mental retardation', 'Phenotype', 'HP:0001249', (105, 123))	('seizures', 'Disease', 'MESH:D012640', (87, 95))	('seizure', 'Disease', (87, 94))	('mental retardation', 'Disease', 'MESH:D008607', (105, 123))	('early onset seizures', 'Phenotype', 'HP:0011152', (75, 95))	('ataxia', 'Phenotype', 'HP:0001251', (97, 103))	('seizures', 'Phenotype', 'HP:0001250', (87, 95))	('electrolyte imbalance', 'MPA', (129, 150))	('seizure', 'Disease', 'MESH:D012640', (201, 208))	('mental retardation', 'Disease', (105, 123))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (34, 62))	('KCNJ10', 'Gene', (12, 18))	('ataxia', 'Disease', 'MESH:D001259', (97, 103))	('autosomal recessive disorder', 'Disease', (34, 62))	('ataxia', 'Disease', (97, 103))
34139	28445150	Because cell membrane depolarization promotes the secretion of both neurotransmitters and cell-derived vesicles, we next examined the contribution of Kir4.1 current to the release of exosomes in our culture conditions.	('Kir4.1', 'Gene', (150, 156))	('Kir4.1', 'Gene', '3766', (150, 156))	('secretion of', 'MPA', (50, 62))	('depolarization', 'Var', (22, 36))	('promotes', 'PosReg', (37, 45))
34164	28445150	Such an increase was also observed by knocking down Kir4.1 (i.e.	('knocking down', 'Var', (38, 51))	('increase', 'PosReg', (8, 16))	('Kir4.1', 'Gene', (52, 58))	('Kir4.1', 'Gene', '3766', (52, 58))
34165	28445150	The U87 cells typically showed finger-like projections (filopodia) and an accelerated cell growth in a "rosary" induced by silencing Kir4.1 expression (Figure 3E).	('Kir4.1', 'Gene', '3766', (133, 139))	('Kir4.1', 'Gene', (133, 139))	('accelerated', 'PosReg', (74, 85))	('finger-like projections', 'CPA', (31, 54))	('cell growth in', 'CPA', (86, 100))	('U87', 'Gene', (4, 7))	('silencing', 'Var', (123, 132))	('U87', 'Gene', '641648', (4, 7))
34168	28445150	A slight but significant increase in cell proliferation was observed 48 h after transfection in U87 (Figure 3E), whereas a two-fold decrease was in U251 cells (Figure 3F).	('U251', 'CellLine', 'CVCL:0021', (148, 152))	('increase', 'PosReg', (25, 33))	('U87', 'Gene', (96, 99))	('cell proliferation', 'CPA', (37, 55))	('transfection', 'Var', (80, 92))	('U87', 'Gene', '641648', (96, 99))
34169	28445150	Clearly Kir4.1 knockdown differently affected proliferation of the two glioma cell lines, suggesting that additional mechanisms are involved.	('affected', 'Reg', (37, 45))	('knockdown', 'Var', (15, 24))	('glioma', 'Disease', (71, 77))	('proliferation', 'CPA', (46, 59))	('Kir4.1', 'Gene', (8, 14))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('Kir4.1', 'Gene', '3766', (8, 14))	('glioma', 'Disease', 'MESH:D005910', (71, 77))
34182	28445150	by miR-5096 loading, barium blockage or siRNA knockdown, on the invasion rate of the two cell lines by using Boyden chamber with matrigel-precoated filter inserts (Figure 5B).	('invasion rate', 'CPA', (64, 77))	('barium', 'Chemical', 'MESH:D001464', (21, 27))	('knockdown', 'Var', (46, 55))	('miR-5096', 'Gene', '100616427', (3, 11))	('miR-5096', 'Gene', (3, 11))
34183	28445150	Over a 24-hour period, the invasiveness of U87 and U251 was increased by two-fold following Kir4.1 depletion.	('U251', 'CellLine', 'CVCL:0021', (51, 55))	('Kir4.1', 'Gene', '3766', (92, 98))	('U87', 'Gene', (43, 46))	('depletion', 'Var', (99, 108))	('U251', 'Var', (51, 55))	('U87', 'Gene', '641648', (43, 46))	('invasiveness', 'CPA', (27, 39))	('Kir4.1', 'Gene', (92, 98))	('increased', 'PosReg', (60, 69))
34192	28445150	Increased chloride conductivity could increase cell mobility (see); indeed, the reverse potential of the current was depolarized in miR-5096 loaded cells (  -40 mV; i.e.	('reverse potential of the current', 'MPA', (80, 112))	('cell mobility', 'CPA', (47, 60))	('increase', 'PosReg', (38, 46))	('chloride conductivity', 'MPA', (10, 31))	('miR-5096', 'Gene', (132, 140))	('Increased', 'PosReg', (0, 9))	('chloride', 'Chemical', 'MESH:D002712', (10, 18))	('miR-5096', 'Gene', '100616427', (132, 140))	('depolarized', 'NegReg', (117, 128))	('  -40 mV', 'Var', (155, 163))
34196	28445150	The genetic deletion of TREK-1 alone or together with TWIK-1 produced no obvious alteration in the basic electrophysiological properties of astrocytes.	('TREK-1', 'Gene', '3776', (24, 30))	('deletion', 'Var', (12, 20))	('TWIK-1', 'Gene', '3775', (54, 60))	('TREK-1', 'Gene', (24, 30))	('TWIK-1', 'Gene', (54, 60))
34209	28445150	Moreover, a slight but significant decrease in U251 cell invasion was induced by the miR-5096 inhibitor, suggesting a contribution of the endogenous miR5096 to this cell type behavior.	('miR5096', 'Gene', '100616427', (149, 156))	('U251 cell invasion', 'CPA', (47, 65))	('miR-5096', 'Gene', '100616427', (85, 93))	('decrease', 'NegReg', (35, 43))	('inhibitor', 'Var', (94, 103))	('miR5096', 'Gene', (149, 156))	('miR-5096', 'Gene', (85, 93))	('U251', 'CellLine', 'CVCL:0021', (47, 51))
34222	28445150	Such an increase in exosome release was also induced by silencing Kir4.1 with siRNA but not by external barium, suggesting that blocking Kir4.1 membrane channels was not involved.	('silencing', 'Var', (56, 65))	('Kir4.1', 'Gene', (137, 143))	('increase', 'PosReg', (8, 16))	('barium', 'Chemical', 'MESH:D001464', (104, 110))	('Kir4.1', 'Gene', '3766', (137, 143))	('Kir4.1', 'Gene', (66, 72))	('exosome release', 'MPA', (20, 35))	('Kir4.1', 'Gene', '3766', (66, 72))
34233	28445150	Human hsa-miR-5096 mimic (mirVana TM miRNA, 4464066-MC22429) and hsa-miR-5096 inhibitor (4464084-MH22429) were purchased from Ambion (Invitrogen; Life Technologies).	('Human', 'Species', '9606', (0, 5))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('miR-5096', 'Gene', '100616427', (10, 18))	('4464084-MH22429', 'Var', (89, 104))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('miR', 'Gene', (69, 72))	('miR-5096', 'Gene', '100616427', (69, 77))	('miR', 'Gene', '220972', (69, 72))	('miR-5096', 'Gene', (10, 18))	('miR-5096', 'Gene', (69, 77))
34235	28445150	For some exosome analysis, HMEC were also transfected with human hsa-miR-145-5p mimic (mirVana TM miRNA, 4464066-MC11480) or hsa-miR-145-5p inhibitor (4464084-MH11480).	('4464084-MH11480', 'Var', (151, 166))	('miR', 'Gene', '220972', (129, 132))	('human', 'Species', '9606', (59, 64))	('miR', 'Gene', (129, 132))	('miR-145', 'Gene', '406937', (69, 76))	('MH11480', 'Chemical', '-', (159, 166))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('miR-145', 'Gene', (129, 136))	('miR-145', 'Gene', '406937', (129, 136))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('HMEC', 'Chemical', '-', (27, 31))	('miR-145', 'Gene', (69, 76))
34260	28198667	Pan-cancer analysis of frequent DNA co-methylation patterns reveals consistent epigenetic landscape changes in multiple cancers DNA methylation is the major form of epigenetic modifications through which the cell regulates the gene expression and silencing.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('silencing', 'MPA', (247, 256))	('Pan-cancer', 'Disease', (0, 10))	('DNA', 'Var', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('regulates', 'Reg', (213, 222))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('methylation', 'Var', (132, 143))
34266	28198667	We also found that genes commonly believed to be silenced via hypermethylation in cancers may still display highly variable methylation levels among cancer cells, and should be considered while using them as epigenetic biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (149, 155))	('hypermethylation', 'Var', (62, 78))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancer', 'Disease', (82, 88))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('methylation levels', 'MPA', (124, 142))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
34268	28198667	Aberrant DNA methylation pattern is a hallmark of cancer, and it has been speculated that DNA methylation change may play a role in cancer initiation, development, and drug resistance.	('play', 'Reg', (117, 121))	('role', 'Reg', (124, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (168, 183))	('hallmark of cancer', 'Disease', 'MESH:D009369', (38, 56))	('Aberrant', 'Var', (0, 8))	('cancer initiation', 'Disease', (132, 149))	('cancer initiation', 'Disease', 'MESH:D009369', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('hallmark of cancer', 'Disease', (38, 56))
34270	28198667	It is generally believed that in cancer cells tumor suppressor genes are hypermethylated in the promoter region and are repressed, while oncogenes are hypomethylated and abnormally active.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('abnormally active', 'Phenotype', 'HP:0000752', (170, 187))	('hypermethylated', 'Var', (73, 88))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
34286	28198667	These frequently identified co-methylation clusters may indicate common gene regulations in different cancer types.	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('co-methylation', 'Var', (28, 42))
34306	28198667	Figure 1c shows the highly correlated beta values of DNA methylation from Cluster 4 among COAD-450 patients, with each color line representing one gene from Cluster 4.	('patients', 'Species', '9606', (99, 107))	('methylation', 'Var', (57, 68))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('COAD', 'Disease', (90, 94))
34337	28198667	It is widely accepted that tumor suppressors are hypermethylated in their promoter region and repressed in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('hypermethylated', 'Var', (49, 64))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
34338	28198667	The hypermethylation usually leads to silencing of the genes and a list of commonly repressed and silenced genes from five types of cancer (BRCA, LUCA, PC, Leukemia and CRC) can be found in literature.	('BRCA', 'Gene', '672', (140, 144))	('cancer', 'Disease', (132, 138))	('CRC', 'Disease', (169, 172))	('Leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('silencing', 'MPA', (38, 47))	('BRCA', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('LUCA', 'Disease', (146, 150))	('Leukemia', 'Disease', 'MESH:D007938', (156, 164))	('CRC', 'Disease', 'MESH:D015179', (169, 172))	('leads to', 'Reg', (29, 37))	('Leukemia', 'Disease', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('hypermethylation', 'Var', (4, 20))
34343	28198667	One of the major finings in this study is the existence of pan-cancer co-methylation clusters.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('co-methylation', 'Var', (70, 84))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
34348	28198667	There are four major co-methylation clusters among the 11 types of cancer studied.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('co-methylation', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
34351	28198667	Among them, only CDH1 was previously considered to be cancer epigenetic-biomarkers, and reported silenced by hypermethylation in breast, colon, lung, leukemia and prostate cancer (Table 2,).	('lung', 'Disease', (144, 148))	('silenced', 'NegReg', (97, 105))	('CDH1', 'Gene', '999', (17, 21))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('colon', 'Disease', (137, 142))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (54, 60))	('leukemia and prostate cancer', 'Disease', 'MESH:D011471', (150, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))	('hypermethylation', 'Var', (109, 125))	('CDH1', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast', 'Disease', (129, 135))
34361	28198667	The loss of imprinting of IGF2 and H19 from parental alleles were previously linked to cervical cancer; Loss of imprinting of H19 was also linked to lung cancer and hepatoblastoma.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('H19', 'Gene', (126, 129))	('H19', 'Gene', (35, 38))	('IGF2', 'Gene', '3481', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('linked', 'Reg', (139, 145))	('hepatoblastoma', 'Disease', (165, 179))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (165, 179))	('Loss of', 'Var', (104, 111))	('IGF2', 'Gene', (26, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('linked', 'Reg', (77, 83))	('lung cancer', 'Disease', (149, 160))	('cervical cancer', 'Disease', 'MESH:D002583', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('hepatoblastoma', 'Disease', 'MESH:D018197', (165, 179))	('cervical cancer', 'Disease', (87, 102))
34369	28198667	The results from this study lead to interesting biological question on the molecular mechanism for co-methylation, while at the same time will provide insights and new directions for potential cancer epigenetic marker and therapeutic target findings.	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('co-methylation', 'Var', (99, 113))
34423	25613377	We also identified Sck as the molecular link between CD95 and activation of the PI3K and MAPK pathways.	('MAPK pathways', 'Pathway', (89, 102))	('Sck', 'Gene', '25759', (19, 22))	('PI3', 'Gene', (80, 83))	('PI3', 'Gene', '5266', (80, 83))	('Sck', 'Gene', (19, 22))	('CD95', 'Var', (53, 57))
34424	25613377	Neutralization of the CD95L reduces PDAC growth and metastasis.	('CD95L', 'Var', (22, 27))	('PDAC', 'Phenotype', 'HP:0006725', (36, 40))	('reduces', 'NegReg', (28, 35))	('PDAC growth', 'CPA', (36, 47))	('Neutralization', 'Var', (0, 14))	('PDAC', 'Chemical', '-', (36, 40))
34445	25613377	Animals injected with PanD3 cells (containing 9.3% of CD95+, 17.8% CD24+ and 23.6% CD44+ cells; Figures 3b and c) developed tumours that were manually detectable 3 months after the injection.	('PanD3', 'Gene', (22, 27))	('CD24', 'Gene', '100133941', (67, 71))	('CD95+', 'Var', (54, 59))	('PanD3', 'Gene', '677663', (22, 27))	('CD24', 'Gene', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('CD44', 'Gene', '960', (83, 87))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('CD44', 'Gene', (83, 87))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
34447	25613377	Immunohistochemically, both human and mouse tumours displayed a membrane-bound and cytoplasmic expression of CD95 and CD95L in ductal cells.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('mouse', 'Species', '10090', (38, 43))	('CD95', 'Gene', (109, 113))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('human', 'Species', '9606', (28, 33))	('tumours', 'Disease', (44, 51))	('CD95L', 'Var', (118, 123))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
34460	25613377	Interestingly, knockdown (KD) of SCK in Panc1 cells decreased CD95-mediated upregulation of vimentin and E-cadherin protein levels, yet a mild induction of vimentin is still detectable (Supplementary Figure 4).	('SCK', 'Gene', (33, 36))	('CD95-mediated upregulation', 'MPA', (62, 88))	('knockdown', 'Var', (15, 24))	('SCK', 'Gene', '25759', (33, 36))	('vimentin', 'Gene', '7431', (156, 164))	('decreased', 'NegReg', (52, 61))	('E-cadherin', 'Gene', (105, 115))	('vimentin', 'Gene', (156, 164))	('E-cadherin', 'Gene', '999', (105, 115))	('Panc1', 'CellLine', 'CVCL:0480', (40, 45))	('vimentin', 'Gene', '7431', (92, 100))	('vimentin', 'Gene', (92, 100))
34465	25613377	Three and seven days after the orthotopic injection, mice were intravenously treated with either CD95-Fc or NaCl and monitored until the establishment of palpable tumours 105 days later.	('mice', 'Species', '10090', (53, 57))	('tumours', 'Disease', (163, 170))	('CD95-Fc', 'Var', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('NaCl', 'Chemical', 'MESH:D012965', (108, 112))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumours', 'Disease', 'MESH:D009369', (163, 170))
34470	25613377	Animals treated with CD95-Fc showed reduced tumour volumes compared with the saline-treated ones (Figures 4d and g).	('saline', 'Chemical', 'MESH:D012965', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('reduced', 'NegReg', (36, 43))	('CD95-Fc', 'Var', (21, 28))
34471	25613377	Furthermore, treatment with CD95-Fc reduced the incidence of liver metastasis and the size of metastatic tumours as compared with untreated animals (Figures 4e and f).	('CD95-Fc', 'Var', (28, 35))	('liver metastasis', 'Disease', 'MESH:D009362', (61, 77))	('liver metastasis', 'Disease', (61, 77))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('reduced', 'NegReg', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
34473	25613377	PanD3 and PanD24 clones are resistant to CD95-induced apoptosis, even at high doses of CD95L-T4, a recombinant trimerized CD95L (Supplementary Figure 1).	('CD95L-T4', 'Var', (87, 95))	('PanD3', 'Gene', '677663', (0, 5))	('PanD24', 'Gene', (10, 16))	('PanD3', 'Gene', (0, 5))
34474	25613377	Stimulation of PanD24 cells with CD95L-T4 induced both AKT and ERK phosphorylation and led to inhibition of GSK3beta as evidenced by Ser9 phosphorylation (Figure 5a and Supplementary Figures 2 and 3).	('inhibition', 'NegReg', (94, 104))	('AKT', 'Gene', (55, 58))	('CD95L-T4', 'Var', (33, 41))	('GSK3beta', 'Gene', '2932', (108, 116))	('Ser9', 'Chemical', '-', (133, 137))	('Ser9 phosphorylation', 'MPA', (133, 153))	('AKT', 'Gene', '207', (55, 58))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))	('GSK3beta', 'Gene', (108, 116))
34485	25613377	The ITAM/ITIM-like motif surrounding Tyr291 of CD95 offers an alternative-docking site for the allocation of SH2-containing proteins.	('Tyr291', 'Chemical', '-', (37, 43))	('CD95', 'Gene', (47, 51))	('Tyr291', 'Var', (37, 43))
34486	25613377	After incubation of CD95L-stimulated cell lysates of PANC-1 and PanD3 cells with SH2 domain protein arrays, showed the spots corresponding to the SH2 domain of Shc2/Sck demonstrated the strongest CD95 binding (Figure 5c and Supplementary Figure 2).	('CD95', 'Protein', (196, 200))	('PanD3', 'Gene', (64, 69))	('Shc2', 'Gene', (160, 164))	('PANC-1', 'CellLine', 'CVCL:0480', (53, 59))	('Shc2', 'Gene', '25759', (160, 164))	('Sck', 'Gene', '25759', (165, 168))	('PanD3', 'Gene', '677663', (64, 69))	('SH2 domain', 'Var', (146, 156))	('strongest', 'PosReg', (186, 195))	('Sck', 'Gene', (165, 168))
34495	25613377	Cells treated with 20 ng/ml of CD95L-T4 contained a higher fraction of EdU-positive cells as compared with the untreated sample (Figure 6a), thus confirming accelerated entry into the S phase.	('CD95L-T4', 'Var', (31, 39))	('EdU', 'Chemical', '-', (71, 74))	('accelerated', 'PosReg', (157, 168))
34500	25613377	In this study, we show that CD95 expression strongly correlates with stemness and EMT and demonstrates that CD95 drives migration and proliferation in PDACs.	('drives', 'PosReg', (113, 119))	('PDAC', 'Chemical', '-', (151, 155))	('CD95', 'Var', (108, 112))	('migration', 'CPA', (120, 129))	('CD95', 'Gene', (28, 32))	('stemness', 'Disease', (69, 77))	('EMT', 'CPA', (82, 85))	('stemness', 'Disease', 'MESH:D020295', (69, 77))	('correlates', 'Reg', (53, 63))	('PDAC', 'Phenotype', 'HP:0006725', (151, 155))	('proliferation', 'CPA', (134, 147))
34501	25613377	Moreover, blocking the receptor in vivo decreases tumour growth and metastasis.	('blocking', 'Var', (10, 18))	('decreases tumour growth', 'Disease', (40, 63))	('decreases tumour growth', 'Disease', 'MESH:D006130', (40, 63))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
34512	25613377	The relevance of CD95 expression for detection of EMT is further supported by the fact that CD95-positive cells within a tumour exhibit a higher concomitant expression of epithelial and mesenchymal transcripts as compared with CD95-negative tumour cells.	('expression', 'MPA', (157, 167))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('CD95-positive', 'Var', (92, 105))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('epithelial', 'Protein', (171, 181))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('tumour', 'Disease', (121, 127))	('tumour', 'Disease', (241, 247))	('higher', 'PosReg', (138, 144))
34522	25613377	Tyr291 present in CD95 death domain has been shown to undergo phosphorylation upon receptor activation via number of the SKFs.	('Tyr291', 'Chemical', '-', (0, 6))	('phosphorylation', 'MPA', (62, 77))	('Tyr291', 'Var', (0, 6))	('undergo', 'Reg', (54, 61))
34526	25613377	Those results stand in accordance with the observations made for lprcg mice, carrying spontaneous CD95 mutation (I225N) that prevents both FADD binding and induction of apoptosis.	('mice', 'Species', '10090', (71, 75))	('apoptosis', 'CPA', (169, 178))	('CD95', 'Gene', (98, 102))	('I225N', 'Mutation', 'p.I225N', (113, 118))	('FADD', 'Protein', (139, 143))	('mutation', 'Var', (103, 111))	('prevents', 'NegReg', (125, 133))
34527	25613377	This mutation should not affect the ITAM-like motif of CD95, thus still allowing PAC formation.	('allowing', 'Reg', (72, 80))	('PAC', 'Disease', (81, 84))	('PAC', 'Chemical', '-', (81, 84))	('PAC', 'Phenotype', 'HP:0006699', (81, 84))	('mutation', 'Var', (5, 13))
34529	25613377	Moreover, lprcg mice develop liver tumours when transplanted with wild-type bone marrow.	('liver tumours', 'Disease', 'MESH:D008113', (29, 42))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('lprcg', 'Var', (10, 15))	('liver tumours', 'Disease', (29, 42))	('mice', 'Species', '10090', (16, 20))
34532	25613377	Interestingly, it was reported that blocking Shc/Grb2 interaction suppressed the growth of B104-1-1 tumours xenografted in nude mice, showing that cancer treatment might also target the adapter proteins.	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Grb2', 'Gene', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('nude mice', 'Species', '10090', (123, 132))	('B104-1-1 tumours', 'Disease', 'MESH:D010051', (91, 107))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('B104-1-1 tumours', 'Disease', (91, 107))	('suppressed', 'NegReg', (66, 76))	('Shc', 'Gene', (45, 48))	('Shc', 'Gene', '20416', (45, 48))	('interaction', 'Interaction', (54, 65))	('blocking', 'Var', (36, 44))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('growth', 'CPA', (81, 87))	('Grb2', 'Gene', '14784', (49, 53))
34533	25613377	The treatment of PanD24-transplanted animals with CD95-Fc resulted in decreased tumour growth strengthening the conclusions derived from murine tumour treatment.	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('CD95-Fc', 'Var', (50, 57))	('murine', 'Species', '10090', (137, 143))	('decreased tumour', 'Disease', 'MESH:D009369', (70, 86))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', (144, 150))	('tumour growth', 'Disease', (80, 93))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour growth', 'Disease', 'MESH:D006130', (80, 93))	('decreased tumour', 'Disease', (70, 86))
34534	25613377	Strikingly, the study objective of increasing the percentage of patients reaching the 6-month rate of progression-free survival by 100% in the CD95-Fc group was substantially exceeded.	('patients', 'Species', '9606', (64, 72))	('CD95-Fc', 'Var', (143, 150))	('increasing', 'PosReg', (35, 45))
34541	25613377	Probe sets were preranked according to the differential expression between CD95 High (33% of samples with highest CD95 expression) and CD95 Low (33% of samples with lowest CD95 expression) tumour samples using empirical Bayes moderated t-statistics computed with the limma package from Bioconductor ('R package' UCR, Institute for integrative genome biology, Riverside, CA, USA).	('tumour', 'Disease', (189, 195))	('CD95', 'Var', (135, 139))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))
34557	25613377	Immunohistochemistry staining of paraffin-embedded pancreatic tumour sections was performed as described previously using the following antibodies: CD95 (alpha-APG101; Apogenix GmbH), CD95L (CD95L; ab15285; Abcam, Cambridge, UK).	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (51, 68))	('CD95L', 'Var', (184, 189))	('paraffin', 'Chemical', 'MESH:D010232', (33, 41))	('pancreatic tumour', 'Disease', 'MESH:D010190', (51, 68))	('pancreatic tumour', 'Disease', (51, 68))
34563	25024889	Lower IL-2 values (<7.97 pg/ml vs. >=7.97 pg/ml, P = 0.029) und CD4+ counts (<200 cells/mul vs. >=200 cells/mul, P < 0.001) correlated significantly with a shorter OS.	('CD4', 'Gene', '920', (64, 67))	('shorter OS', 'Disease', (156, 166))	('Lower', 'NegReg', (0, 5))	('CD4', 'Gene', (64, 67))	('IL-2 values', 'MPA', (6, 17))	('<200', 'Var', (77, 81))
34635	25024889	Since the positive role of IL-2 (Th1 immune response) against gliomagenesis is known, that is, IL-2 mediates the infiltration of immune cells into the tumor mass as well as activates the lytic process, several groups have tried to substitute IL-2 directly in the tumor bed in an animal glioma model.	('glioma', 'Disease', (286, 292))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('lytic process', 'CPA', (187, 200))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (151, 156))	('Th1', 'Gene', '51497', (33, 36))	('activates', 'PosReg', (173, 182))	('glioma', 'Disease', 'MESH:D005910', (286, 292))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('tumor', 'Disease', (263, 268))	('IL-2', 'Var', (95, 99))	('Th1', 'Gene', (33, 36))	('glioma', 'Disease', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
34640	25024889	IL-2 fused to the human antibody fragment F16) showed a significantly longer survival compared with TMZ monotherapy.	('IL-2', 'Gene', (0, 4))	('survival', 'CPA', (77, 85))	('human', 'Species', '9606', (18, 23))	('fused', 'Var', (5, 10))	('longer', 'PosReg', (70, 76))	('TMZ', 'Chemical', 'MESH:D000077204', (100, 103))
34642	25024889	Furthermore, IL-2 substitution or activation in the tumor site may also have some therapeutic consequence.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('IL-2', 'Gene', (13, 17))	('tumor', 'Disease', (52, 57))	('substitution', 'Var', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
34727	23956932	Stereotactic dentatectomies, putamenotomies, and posterior rhizotomies in other cerebral palsied children and adults had similar but not as pronounced improvements in their involuntary movements, as observed in the first boy.	('involuntary movements', 'Phenotype', 'HP:0004305', (173, 194))	('men', 'Species', '9606', (189, 192))	('children', 'Species', '9606', (97, 105))	('cerebral palsied', 'Phenotype', 'HP:0100021', (80, 96))	('involuntary movements', 'Disease', 'MESH:D004409', (173, 194))	('putamenotomies', 'Var', (29, 43))	('men', 'Species', '9606', (33, 36))	('involuntary movements', 'Disease', (173, 194))	('improvements', 'PosReg', (151, 163))	('boy', 'Species', '9606', (221, 224))	('men', 'Species', '9606', (158, 161))	('involuntary movement', 'Phenotype', 'HP:0004305', (173, 193))
34771	32997991	However, the role of the two major PI3K isoforms, p110alpha and p110beta, in PTEN-deficient gliomagenesis remains unknown.	('PTEN-deficient gliomagenesis', 'Disease', (77, 105))	('p110alpha', 'Var', (50, 59))	('p110beta', 'Var', (64, 72))	('PTEN-deficient gliomagenesis', 'Disease', 'MESH:D006223', (77, 105))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
34772	32997991	We show that PTEN-deficient GBM largely depends on p110alpha for proliferation and p110beta for migration.	('migration', 'CPA', (96, 105))	('p110alpha', 'Var', (51, 60))	('PTEN-deficient GBM', 'Disease', 'MESH:D006223', (13, 31))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('p110beta', 'Var', (83, 91))	('PTEN-deficient GBM', 'Disease', (13, 31))
34773	32997991	Genetic ablation of either isoform delays tumor progression in mice, but only ablating both isoforms completely blocks GBM driven by the concurrent ablation of Pten and p53.	('blocks', 'NegReg', (112, 118))	('Pten', 'Gene', '19211', (160, 164))	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('p53', 'Gene', (169, 172))	('mice', 'Species', '10090', (63, 67))	('delays tumor', 'Disease', 'MESH:D009369', (35, 47))	('delays tumor', 'Disease', (35, 47))	('GBM', 'CPA', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ablation', 'Var', (148, 156))	('Pten', 'Gene', (160, 164))
34775	32997991	BKM120 extends the survival of mice bearing intracranial tumors in which p110beta, but not p110alpha, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110beta effectively.	('extends', 'PosReg', (7, 14))	('survival', 'CPA', (19, 27))	('intracranial tumors', 'Disease', 'MESH:D001932', (44, 63))	('BKM120', 'Var', (0, 6))	('ablated', 'NegReg', (123, 130))	('glioma', 'Disease', (152, 158))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('intracranial tumors', 'Disease', (44, 63))	('mice', 'Species', '10090', (31, 35))	('BKM120', 'Chemical', 'MESH:C571178', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('Pten', 'Gene', (138, 142))	('Pten', 'Gene', '19211', (138, 142))
34776	32997991	show that p110alpha and p110beta isoforms of PI3K play overlapping and divergent roles in PTEN-deficient glioblastomas, suggesting the importance of blocking both PI3K isoforms to effectively treat PTEN-deficient glioblastomas.	('PTEN-deficient glioblastomas', 'Disease', (90, 118))	('PTEN-deficient glioblastomas', 'Disease', 'MESH:D006223', (90, 118))	('glioblastomas', 'Phenotype', 'HP:0012174', (213, 226))	('PTEN-deficient glioblastomas', 'Disease', (198, 226))	('PTEN-deficient glioblastomas', 'Disease', 'MESH:D006223', (198, 226))	('glioblastomas', 'Phenotype', 'HP:0012174', (105, 118))	('p110alpha', 'Var', (10, 19))
34779	32997991	The loss of PTEN (phosphatase and tensin homolog) through genetic or epigenetic alterations happens frequently in GBM and is associated with therapeutic resistance.	('epigenetic alterations', 'Var', (69, 91))	('phosphatase and tensin homolog', 'Gene', '19211', (18, 48))	('genetic', 'Var', (58, 65))	('therapeutic resistance', 'CPA', (141, 163))	('GBM', 'Disease', (114, 117))	('PTEN', 'Gene', (12, 16))	('associated with', 'Reg', (125, 140))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('loss', 'NegReg', (4, 8))
34782	32997991	Among them, class IA PI3Ks are clearly involved in cancer.	('involved', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PI3Ks', 'Var', (21, 26))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
34786	32997991	There are three p110 catalytic isoforms, p110alpha, p110beta, and p110delta, encoded by PIK3CA, PIK3CB, and PIK3CD, respectively.	('PIK3CD', 'Gene', '18707', (108, 114))	('PIK3CB', 'Gene', '74769', (96, 102))	('PIK3CA', 'Gene', '18706', (88, 94))	('p110 catalytic isoforms, p110alpha', 'Gene', '18706', (16, 50))	('PIK3CB', 'Gene', (96, 102))	('p110delta', 'Gene', (66, 75))	('PIK3CA', 'Gene', (88, 94))	('p110beta', 'Var', (52, 60))	('PIK3CD', 'Gene', (108, 114))	('p110delta', 'Gene', '18707', (66, 75))
34787	32997991	The p110alpha and p110beta isoforms are expressed ubiquitously, whereas p110delta is mainly expressed in leukocytes.	('p110beta', 'Var', (18, 26))	('p110alpha', 'Var', (4, 13))	('p110delta', 'Gene', '18707', (72, 81))	('p110delta', 'Gene', (72, 81))
34789	32997991	While p110alpha is activated by receptor tyrosine kinase (RTK) signaling, p110beta mediates both RTK and G protein-coupled receptors (GPCR) signaling.	('RTK', 'Gene', '22174', (97, 100))	('p110beta', 'Var', (74, 82))	('RTK', 'Gene', (97, 100))	('G protein-coupled receptors', 'MPA', (105, 132))	('receptor tyrosine kinase', 'Gene', (32, 56))	('RTK', 'Gene', '22174', (58, 61))	('RTK', 'Gene', (58, 61))	('receptor tyrosine kinase', 'Gene', '22174', (32, 56))	('p110alpha', 'Var', (6, 15))
34791	32997991	Broadly speaking, most tumors driven by RTK or Ras depend on p110alpha, while tumors driven by PTEN loss depend on p110beta.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('PTEN loss depend', 'Disease', (95, 111))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('RTK', 'Gene', '22174', (40, 43))	('p110alpha', 'Var', (61, 70))	('RTK', 'Gene', (40, 43))	('depend', 'Reg', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PTEN loss depend', 'Disease', 'MESH:D006223', (95, 111))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
34794	32997991	It has been shown that concurrent deletion of Pten and Trp53 (p53) in the brains of mice resulted in high-grade gliomas that recapitulate the pathology and biology of human GBM.	('Pten', 'Gene', (46, 50))	('Pten', 'Gene', '19211', (46, 50))	('Trp53', 'Gene', (55, 60))	('resulted in', 'Reg', (89, 100))	('GBM', 'Phenotype', 'HP:0012174', (173, 176))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('gliomas', 'Disease', (112, 119))	('deletion', 'Var', (34, 42))	('Trp53', 'Gene', '22059', (55, 60))	('human', 'Species', '9606', (167, 172))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('mice', 'Species', '10090', (84, 88))
34795	32997991	To examine the specific roles of p110alpha and p110beta in a murine GBM model driven by the loss of Pten and p53, we generated compound mouse strains with floxed alleles of Pten and p53 along with floxed alleles of Pik3ca (encoding p110alpha) and/or Pik3cb (encoding p110beta) as the following: p53f/f;Ptenf/f (PP), p53f/f;Ptenf/f;Pik3caf/f (PPA), p53f/f;Ptenf/f;Pik3cbf/f (PPB), and p53f/f;Ptenf/f;Pik3caf/f;Pik3cbf/f (PPAB).	('Pten', 'Gene', '19211', (355, 359))	('Pik3ca', 'Gene', '18706', (399, 405))	('Pten', 'Gene', (173, 177))	('Pten', 'Gene', '19211', (173, 177))	('PPA', 'Gene', (342, 345))	('Pik3ca', 'Gene', (331, 337))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('Pik3ca', 'Gene', '18706', (215, 221))	('murine', 'Species', '10090', (61, 67))	('PPA', 'Gene', (420, 423))	('Pten', 'Gene', (391, 395))	('Pten', 'Gene', '19211', (323, 327))	('Pten', 'Gene', '19211', (391, 395))	('PPAB', 'Chemical', '-', (420, 424))	('Pik3cb', 'Gene', '74769', (363, 369))	('PPB', 'Chemical', '-', (374, 377))	('Pik3ca', 'Gene', (399, 405))	('Pik3cb', 'Gene', (363, 369))	('PPA', 'Gene', '18619', (342, 345))	('Pik3cb', 'Gene', '74769', (250, 256))	('Pik3cb', 'Gene', (250, 256))	('PPA', 'Gene', '18619', (420, 423))	('Pten', 'Gene', (302, 306))	('Pten', 'Gene', '19211', (302, 306))	('Pik3cb', 'Gene', '74769', (409, 415))	('Pik3ca', 'Gene', '18706', (331, 337))	('Pik3ca', 'Gene', (215, 221))	('p53f/f', 'Var', (316, 322))	('Pik3cb', 'Gene', (409, 415))	('Pten', 'Gene', (100, 104))	('Pten', 'Gene', '19211', (100, 104))	('Pten', 'Gene', (323, 327))	('mouse', 'Species', '10090', (136, 141))	('Pten', 'Gene', (355, 359))
34798	32997991	Ablation of either p110alpha or p110beta alone delayed the development of brain tumors (PPA or PPB tumor).	('delayed', 'NegReg', (47, 54))	('PPA', 'Gene', '18619', (88, 91))	('brain tumors', 'Disease', 'MESH:D001932', (74, 86))	('brain tumors', 'Phenotype', 'HP:0030692', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PPB tumor', 'Disease', (95, 104))	('brain tumor', 'Phenotype', 'HP:0030692', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('p110alpha', 'Var', (19, 28))	('brain tumors', 'Disease', (74, 86))	('PPA', 'Gene', (88, 91))	('PPB tumor', 'Disease', 'MESH:C537516', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('p110beta', 'Var', (32, 40))
34800	32997991	However, ablation of both p110alpha and p110beta completely blocked glioma formation in PPAB mice (Figure 1B).	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('p110beta', 'Var', (40, 48))	('blocked', 'NegReg', (60, 67))	('p110alpha', 'Var', (26, 35))	('mice', 'Species', '10090', (93, 97))	('glioma', 'Disease', (68, 74))	('PPAB', 'Chemical', '-', (88, 92))
34801	32997991	These data suggest that, while either PI3K isoform can support the development of PP GBM, blockade of both isoforms is required to block the gliomagenesis driven by the concurrent loss of Pten and p53 in mice.	('GBM', 'Phenotype', 'HP:0012174', (85, 88))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('Pten', 'Gene', (188, 192))	('loss', 'Var', (180, 184))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('Pten', 'Gene', '19211', (188, 192))	('p53', 'Gene', (197, 200))	('mice', 'Species', '10090', (204, 208))	('glioma', 'Disease', (141, 147))
34803	32997991	PPA and PPB tumor cells have absent p110alpha or p110beta protein, respectively (Figure 1C).	('PPB tumor', 'Disease', (8, 17))	('PPB tumor', 'Disease', 'MESH:C537516', (8, 17))	('PPA', 'Gene', '18619', (0, 3))	('absent', 'NegReg', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('p110beta', 'Var', (49, 57))	('p110alpha', 'Var', (36, 45))	('PPA', 'Gene', (0, 3))
34804	32997991	However, the phosphorylation levels of Akt and S6RP, two well-characterized downstream signaling molecules, were not significantly altered by ablation of either isoform alone (Figure 1C), suggesting that ablating either isoform alone is not sufficient to block PI3K signaling in PP GBM cells.	('Akt', 'Gene', '11651', (39, 42))	('S6RP', 'Protein', (47, 51))	('Akt', 'Gene', (39, 42))	('GBM', 'Phenotype', 'HP:0012174', (282, 285))	('ablating', 'Var', (204, 212))
34807	32997991	This inducible knockout approach allowed us to delete Pten, p53, p110alpha, or p110beta upon 4-OHT treatment (Figure S1A).	('Pten', 'Gene', (54, 58))	('Pten', 'Gene', '19211', (54, 58))	('p53', 'Var', (60, 63))	('p110beta', 'Var', (79, 87))	('4-OHT', 'Chemical', 'MESH:C032278', (93, 98))	('p110alpha', 'Var', (65, 74))
34808	32997991	Notably, the phosphorylation levels of Akt and S6RP were significantly reduced only by ablating both isoforms (Figure S1A).	('Akt', 'Gene', '11651', (39, 42))	('S6RP', 'Protein', (47, 51))	('ablating', 'Var', (87, 95))	('reduced', 'NegReg', (71, 78))	('phosphorylation levels', 'MPA', (13, 35))	('Akt', 'Gene', (39, 42))
34809	32997991	Consistent with our observation in PPA and PPB tumor cells above, ablation of either isoform alone underwent little change in the phosphorylation levels of Akt or S6RP (Figure S1A).	('PPA', 'Gene', (35, 38))	('Akt', 'Gene', '11651', (156, 159))	('ablation', 'Var', (66, 74))	('PPB tumor', 'Disease', (43, 52))	('S6RP', 'Protein', (163, 167))	('Akt', 'Gene', (156, 159))	('phosphorylation levels', 'MPA', (130, 152))	('PPB tumor', 'Disease', 'MESH:C537516', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('PPA', 'Gene', '18619', (35, 38))
34812	32997991	Notably, while all of the PP and PPA tumors were highly diffusive, some of the PPB tumors displayed defined borders with neighboring tissues (Figure 1A, H&E), suggesting that the loss of p110beta rendered tumors less invasive.	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('PPA', 'Gene', (33, 36))	('the', 'Var', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors less invasive', 'Disease', (205, 225))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (37, 43))	('PPB tumors', 'Disease', (79, 89))	('tumors', 'Disease', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PPA', 'Gene', '18619', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('PPB tumors', 'Disease', 'MESH:C537516', (79, 89))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('H&E', 'Gene', '15139', (153, 156))	('H&E', 'Gene', (153, 156))	('tumors', 'Disease', (83, 89))	('tumors less invasive', 'Disease', 'MESH:D009361', (205, 225))
34815	32997991	It has been shown that p110beta interacts with Rac1/Cdc42 through its RBD domain.	('p110beta', 'Var', (23, 31))	('Rac1', 'Gene', '19353', (47, 51))	('interacts', 'Interaction', (32, 41))	('Cdc42', 'Gene', (52, 57))	('Rac1', 'Gene', (47, 51))	('Cdc42', 'Gene', '12540', (52, 57))
34816	32997991	Ectopic expression of wild-type (WT) p110beta restored migration in PPB tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('p110beta', 'Var', (37, 45))	('migration', 'CPA', (55, 64))	('PPB tumor', 'Disease', (68, 77))	('PPB tumor', 'Disease', 'MESH:C537516', (68, 77))	('restored', 'PosReg', (46, 54))
34817	32997991	However, a p110beta mutant that is unable to bind Rac1/Cdc42 had a statistically significant but partially restorative effect on the migration of PPB tumor cells (Figures 1E and S1B), suggesting that the interaction of p110beta with Rac1 plays a role in the migration and invasion of PP tumors.	('interaction', 'Interaction', (204, 215))	('migration', 'CPA', (133, 142))	('role', 'Reg', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PPB tumor', 'Disease', (146, 155))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('p110beta', 'Var', (219, 227))	('invasion', 'CPA', (272, 280))	('Cdc42', 'Gene', '12540', (55, 60))	('restorative', 'NegReg', (107, 118))	('Rac1', 'Gene', (50, 54))	('migration', 'CPA', (258, 267))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('Rac1', 'Gene', (233, 237))	('p110beta', 'Var', (11, 19))	('PPB tumor', 'Disease', 'MESH:C537516', (146, 155))	('Rac1', 'Gene', '19353', (50, 54))	('Cdc42', 'Gene', (55, 60))	('Rac1', 'Gene', '19353', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
34818	32997991	Furthermore, AZD6482 (also known as KIN193, p110beta-selective inhibitor) and GDC0941 (pan-PI3K inhibitor), but not BYL719 (p110alpha-selective inhibitor) (Table S1), significantly reduced the cell migration of PP cells in a transwell assay (Figure 1F).	('reduced', 'NegReg', (181, 188))	('AZD6482', 'Var', (13, 20))	('AZD6482', 'Chemical', 'MESH:C578518', (13, 20))	('cell migration of PP cells in a transwell assay', 'CPA', (193, 240))	('GDC0941', 'Chemical', 'MESH:C532162', (78, 85))
34820	32997991	Notably, both PDCLs have p53 mutations concurrent with PTEN deficiency.	('p53', 'Gene', (25, 28))	('PTEN deficiency', 'Disease', (55, 70))	('mutations', 'Var', (29, 38))	('PTEN deficiency', 'Disease', 'MESH:D006223', (55, 70))
34821	32997991	We also observed that AZD6482 and GDC0941, but not BYL719, significantly reduced the cell migration of BT179 and BT224 cells (Figure 1G), suggesting that p110beta also contributes to the migration of patient-derived GBM cells, which is consistent with the data from our murine PP GBM model.	('cell migration', 'CPA', (85, 99))	('GDC0941', 'Var', (34, 41))	('GBM', 'Phenotype', 'HP:0012174', (280, 283))	('GDC0941', 'Chemical', 'MESH:C532162', (34, 41))	('AZD6482', 'Var', (22, 29))	('contributes', 'Reg', (168, 179))	('AZD6482', 'Chemical', 'MESH:C578518', (22, 29))	('reduced', 'NegReg', (73, 80))	('migration', 'CPA', (187, 196))	('murine', 'Species', '10090', (270, 276))	('GBM', 'Phenotype', 'HP:0012174', (216, 219))	('p110beta', 'Var', (154, 162))	('patient', 'Species', '9606', (200, 207))
34822	32997991	We next used PI3K inhibitors to explore the specific roles of p110alpha and p110beta in a panel of primary mouse GBM cells lines derived from PP, PPA, and PPB tumors ex vivo.	('GBM', 'Phenotype', 'HP:0012174', (113, 116))	('PPB tumors', 'Disease', (155, 165))	('p110alpha', 'Var', (62, 71))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PPA', 'Gene', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('PPB tumors', 'Disease', 'MESH:C537516', (155, 165))	('PPA', 'Gene', '18619', (146, 149))	('p110beta', 'Var', (76, 84))
34823	32997991	While GDC0941 reduced phosphorylation levels of both Akt and S6RP in tumor cells, neither BYL719 nor AZD6482 significantly reduced the phosphorylation levels of Akt and S6RP in PP glioma cells (Figure 2A, left panel).	('GDC0941', 'Chemical', 'MESH:C532162', (6, 13))	('phosphorylation levels', 'MPA', (22, 44))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('S6RP', 'Protein', (61, 65))	('Akt', 'Gene', (53, 56))	('GDC0941', 'Var', (6, 13))	('AZD6482', 'Var', (101, 108))	('BYL719', 'Var', (90, 96))	('Akt', 'Gene', '11651', (53, 56))	('Akt', 'Gene', (161, 164))	('phosphorylation levels', 'MPA', (135, 157))	('glioma', 'Disease', (180, 186))	('reduced', 'NegReg', (14, 21))	('AZD6482', 'Chemical', 'MESH:C578518', (101, 108))	('tumor', 'Disease', (69, 74))	('Akt', 'Gene', '11651', (161, 164))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('reduced', 'NegReg', (123, 130))
34824	32997991	We further showed that AZD6482 inhibited the pAkt and p6RP in PPA tumors where p110alpha is ablated, and vice versa, BYL719 inhibited the pAkt and p6RP in PPB tumors where p110beta is ablated (Figure 2A, center and right panels).	('PPB tumors', 'Disease', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Akt', 'Gene', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', (159, 165))	('PPB tumors', 'Disease', 'MESH:C537516', (155, 165))	('inhibited', 'NegReg', (124, 133))	('PPA', 'Gene', (62, 65))	('Akt', 'Gene', '11651', (46, 49))	('AZD6482', 'Var', (23, 30))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('ablated', 'Var', (92, 99))	('AZD6482', 'Chemical', 'MESH:C578518', (23, 30))	('PPA', 'Gene', '18619', (62, 65))	('Akt', 'Gene', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Akt', 'Gene', '11651', (139, 142))	('tumors', 'Disease', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('inhibited', 'NegReg', (31, 40))	('BYL719', 'Var', (117, 123))	('p110alpha', 'Var', (79, 88))
34827	32997991	We assessed PIP3 levels in PP cells upon treatment with BYL719, AZD6482, or GDC0941.	('PIP3', 'Chemical', '-', (12, 16))	('BYL719', 'Var', (56, 62))	('assessed', 'Reg', (3, 11))	('AZD6482', 'Var', (64, 71))	('GDC0941', 'Var', (76, 83))	('AZD6482', 'Chemical', 'MESH:C578518', (64, 71))	('GDC0941', 'Chemical', 'MESH:C532162', (76, 83))	('PIP3 levels', 'MPA', (12, 23))
34828	32997991	GDC0941 significantly reduced the PIP3 level in PP tumor cells, as expected.	('GDC0941', 'Var', (0, 7))	('GDC0941', 'Chemical', 'MESH:C532162', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PIP3 level', 'MPA', (34, 44))	('tumor', 'Disease', (51, 56))	('PIP3', 'Chemical', '-', (34, 38))	('reduced', 'NegReg', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
34829	32997991	BYL719 or AZD6482 also significantly reduced the PIP3 levels in PP cells, despite few changes in the pAkt and pS6PR levels in these cells (Figure S2A).	('Akt', 'Gene', (102, 105))	('Akt', 'Gene', '11651', (102, 105))	('PIP3 levels', 'MPA', (49, 60))	('PIP3', 'Chemical', '-', (49, 53))	('reduced', 'NegReg', (37, 44))	('AZD6482', 'Var', (10, 17))	('AZD6482', 'Chemical', 'MESH:C578518', (10, 17))	('BYL719', 'Var', (0, 6))
34831	32997991	To further assess the roles of PI3K isoforms in established PP GBM, we used a CRISPR system to knock out Pik3ca or Pik3cb in PP tumor cells to generate isogenic cell lines lacking either p110alpha or p110beta, called PP-sgGFP, PP-alphaKO, and PP-betaKO (Figure S2B).	('p110beta', 'Var', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Pik3cb', 'Gene', '74769', (115, 121))	('Pik3ca', 'Gene', (105, 111))	('knock', 'Var', (95, 100))	('Pik3ca', 'Gene', '18706', (105, 111))	('p110alpha', 'Var', (187, 196))	('Pik3cb', 'Gene', (115, 121))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
34833	32997991	Consistent with this result, BYL719, but not AZD6482, had a modest but statistically significant effect on the proliferation of PP-sgGFP cells (Figure 2B).	('proliferation', 'CPA', (111, 124))	('BYL719', 'Var', (29, 35))	('AZD6482', 'Chemical', 'MESH:C578518', (45, 52))
34834	32997991	Again, the pan-PI3K inhibitor GDC0941 most significantly suppressed the proliferation of all PP-sgGFP, PP-alphaKO, or PP-betaKO cells (Figure 2B).	('PP-betaKO', 'Var', (118, 127))	('proliferation', 'CPA', (72, 85))	('GDC0941', 'Var', (30, 37))	('GDC0941', 'Chemical', 'MESH:C532162', (30, 37))	('suppressed', 'NegReg', (57, 67))
34835	32997991	Notably, p110alpha may play a relatively more prominent role than p110beta in terms of tumor cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p110alpha', 'Var', (9, 18))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
34836	32997991	Treatment with BYL719 or AZD6482 alone had only marginal effects on p-Akt473 and p-S6RP levels in BT179 or BT224.	('p-S6RP levels', 'MPA', (81, 94))	('Akt', 'Gene', (70, 73))	('AZD6482', 'Var', (25, 32))	('Akt', 'Gene', '11651', (70, 73))	('AZD6482', 'Chemical', 'MESH:C578518', (25, 32))
34837	32997991	In contrast, GDC0941 significantly reduced p-Akt and p-S6RP levels (Figure 2C).	('GDC0941', 'Chemical', 'MESH:C532162', (13, 20))	('Akt', 'Gene', (45, 48))	('reduced', 'NegReg', (35, 42))	('Akt', 'Gene', '11651', (45, 48))	('p-S6RP levels', 'MPA', (53, 66))	('GDC0941', 'Var', (13, 20))
34838	32997991	Proliferation analyses of both PDCLs showed that they were more resistant to isoform-specific PI3K inhibitors than to the pan-PI3K inhibitor, suggesting that patient PTEN-null GBM cells can use either p110alpha or p110beta to maintain signaling and proliferation (Figure 2D).	('p110beta', 'Var', (214, 222))	('p110alpha', 'Var', (201, 210))	('patient', 'Species', '9606', (158, 165))	('maintain', 'PosReg', (226, 234))	('proliferation', 'CPA', (249, 262))	('signaling', 'MPA', (235, 244))	('GBM', 'Phenotype', 'HP:0012174', (176, 179))
34842	32997991	Both BYL719 and, to a lesser degree, AZD6482 inhibited tumor growth and reduced tumor weight, but combined treatment with BYL719 and AZD6482 was able to flatten the PP tumor growth curve (Figures 3A and 3B).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('reduced', 'NegReg', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor weight', 'Disease', 'MESH:D015431', (80, 92))	('AZD6482', 'Var', (133, 140))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (55, 60))	('AZD6482', 'Chemical', 'MESH:C578518', (37, 44))	('BYL719', 'Var', (122, 128))	('AZD6482', 'Chemical', 'MESH:C578518', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('inhibited', 'NegReg', (45, 54))	('tumor weight', 'Disease', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
34843	32997991	Western blot (WB) and IHC analyses of tumor tissues revealed that, whereas BYL719 and AZD6482 had a modest or little effect on reducing pAkt and pS6RP levels, the combined treatment of BYL719 and AZD6482 effectively blocked phosphorylation of both Akt and S6RP (Figures 3C and S3).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Akt', 'Gene', (248, 251))	('S6RP', 'Protein', (256, 260))	('Akt', 'Gene', '11651', (137, 140))	('AZD6482', 'Var', (196, 203))	('phosphorylation', 'MPA', (224, 239))	('blocked', 'NegReg', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Akt', 'Gene', (137, 140))	('AZD6482', 'Chemical', 'MESH:C578518', (196, 203))	('Akt', 'Gene', '11651', (248, 251))	('AZD6482', 'Chemical', 'MESH:C578518', (86, 93))	('BYL719', 'Var', (185, 191))
34845	32997991	BKM120 is currently the only pan-PI3K inhibitor with proven brain penetration and has been tested in the clinic for GBM patients.	('BKM120', 'Var', (0, 6))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('patients', 'Species', '9606', (120, 128))	('brain penetration', 'CPA', (60, 77))
34846	32997991	Treatment with BKM120 prolonged the median survival of PP-bearing mice slightly from 22 to 27 days (Figure 4A).	('mice', 'Species', '10090', (66, 70))	('median survival', 'CPA', (36, 51))	('BKM120', 'Var', (15, 21))	('prolonged', 'PosReg', (22, 31))	('BKM120', 'Chemical', 'MESH:C571178', (15, 21))
34847	32997991	WB and IHC analyses of tumors harvested from experimental mice showed that BKM120 modestly reduced phosphorylation of both Akt and S6RP (Figures 4B and 4C), suggesting that while BKM120 can cross the BBB, it cannot deeply suppress Akt-mammalian target of rapamycin (mTOR) signaling.	('Akt', 'Gene', '11651', (231, 234))	('mTOR', 'Gene', '2475', (266, 270))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('BBB', 'CPA', (200, 203))	('mammalian target of rapamycin', 'Gene', '2475', (235, 264))	('BKM120', 'Var', (179, 185))	('Akt', 'Gene', (123, 126))	('S6RP', 'Protein', (131, 135))	('mammalian target of rapamycin', 'Gene', (235, 264))	('tumors', 'Disease', (23, 29))	('Akt', 'Gene', '11651', (123, 126))	('mice', 'Species', '10090', (58, 62))	('BKM120', 'Chemical', 'MESH:C571178', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('phosphorylation', 'MPA', (99, 114))	('Akt', 'Gene', (231, 234))	('mTOR', 'Gene', (266, 270))	('BKM120', 'Chemical', 'MESH:C571178', (179, 185))	('reduced', 'NegReg', (91, 98))
34848	32997991	Our data are consistent with a recent clinical trial that showed that BKM120 does not effectively suppress S6RP phosphorylation despite adequate brain penetration and has limited efficacy in patients with GBM.	('patients', 'Species', '9606', (191, 199))	('BKM120', 'Var', (70, 76))	('BKM120', 'Chemical', 'MESH:C571178', (70, 76))	('GBM', 'Phenotype', 'HP:0012174', (205, 208))	('S6RP', 'Protein', (107, 111))
34849	32997991	We hypothesized that the modest effect observed here and in clinical trials for BKM120 in GBM may be due to its relatively weak inhibition of p110beta (Table S1).	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('p110beta', 'Var', (142, 150))	('BKM120', 'Chemical', 'MESH:C571178', (80, 86))	('BKM120', 'Gene', (80, 86))
34850	32997991	To test this hypothesis genetically, we compared the efficacy of BKM120 on mice bearing PP, PPA, or PPB tumors.	('PPB tumors', 'Disease', (100, 110))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PPA', 'Gene', '18619', (92, 95))	('BKM120', 'Var', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('BKM120', 'Chemical', 'MESH:C571178', (65, 71))	('PPB tumors', 'Disease', 'MESH:C537516', (100, 110))	('PPA', 'Gene', (92, 95))
34851	32997991	As shown in Figure 4A, BKM120 failed to prolong the median survival of PPA-bearing mice (26 versus 24 days).	('PPA', 'Gene', '18619', (71, 74))	('BKM120', 'Chemical', 'MESH:C571178', (23, 29))	('mice', 'Species', '10090', (83, 87))	('PPA', 'Gene', (71, 74))	('BKM120', 'Var', (23, 29))
34852	32997991	In contrast, BKM120 significantly prolonged the median survival of PPB-bearing mice to a much greater extent (Figure 4A, 37 versus 61 days).	('prolonged', 'PosReg', (34, 43))	('median survival', 'CPA', (48, 63))	('BKM120', 'Chemical', 'MESH:C571178', (13, 19))	('mice', 'Species', '10090', (79, 83))	('PPB', 'Chemical', '-', (67, 70))	('BKM120', 'Var', (13, 19))
34853	32997991	Consistent with our earlier observations that p110beta contributes to GBM diffusive phenotype (Figures 1A and 1D), BKM120 treatment did not decrease the diffusive feature of PPA tumors (Figure S4).	('diffusive feature', 'MPA', (153, 170))	('tumors', 'Disease', (178, 184))	('PPA', 'Gene', '18619', (174, 177))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('GBM', 'MPA', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('BKM120', 'Chemical', 'MESH:C571178', (115, 121))	('PPA', 'Gene', (174, 177))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('p110beta', 'Var', (46, 54))
34855	32997991	Our data thus indicate that BKM120, although developed as a pan-PI3K inhibitor, has limited activity in our PP GBM due to the inadequate inhibition of p110beta activity.	('BKM120', 'Chemical', 'MESH:C571178', (28, 34))	('p110beta activity', 'MPA', (151, 168))	('inhibition', 'NegReg', (137, 147))	('activity', 'MPA', (92, 100))	('BKM120', 'Var', (28, 34))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
34859	32997991	Similar results were observed in patient-derived PTEN-deficient GBM cells with coexisting p53 mutations.	('p53', 'Gene', (90, 93))	('patient', 'Species', '9606', (33, 40))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('PTEN-deficient GBM', 'Disease', (49, 67))	('mutations', 'Var', (94, 103))	('PTEN-deficient GBM', 'Disease', 'MESH:D006223', (49, 67))
34860	32997991	Our data in GBM are in contrast to the selective activation of p110beta that we and others have previously observed in a variety of PTEN-null tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('PTEN-null tumors', 'Disease', 'MESH:D006223', (132, 148))	('p110beta', 'Var', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('PTEN-null tumors', 'Disease', (132, 148))
34861	32997991	Most tumors do not use both p110alpha and p110beta for survival.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('p110beta', 'Var', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('p110alpha', 'Var', (28, 37))
34862	32997991	Typically, p110alpha activity is required in tumors driven by hyperactive RTK signaling or by oncogenes such as KRas, while p110beta activity is required in tumors in which PTEN-loss is the driving event.	('p110alpha', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('hyperactive', 'PosReg', (62, 73))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('KRas', 'Gene', (112, 116))	('tumors', 'Disease', (45, 51))	('RTK', 'Gene', '22174', (74, 77))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('KRas', 'Gene', '16653', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('RTK', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
34863	32997991	Sometimes PI3K isoforms play spatially differential roles in tumorigenesis, such as in the skin epidermis under conditions of PTEN-loss; in this case, p110alpha is critical in suprabasal cells, whereas p110beta is important in basal cells.	('PTEN-loss', 'Gene', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('p110alpha', 'Var', (151, 160))
34864	32997991	The requirement for p110alpha in RTK and oncogene-driven tumors appears to arise from its higher catalytic specific activity compared to p110beta.	('catalytic specific activity', 'MPA', (97, 124))	('RTK', 'Gene', '22174', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('RTK', 'Gene', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('higher', 'PosReg', (90, 96))	('p110alpha', 'Var', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
34865	32997991	How p110beta is selectively activated in many types of Pten-null tumors cells remains unclear.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Disease', (65, 71))	('p110beta', 'Var', (4, 12))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Pten', 'Gene', (55, 59))	('Pten', 'Gene', '19211', (55, 59))
34869	32997991	It is also widely known that p110beta has significant functions that are independent of its kinase activity, whereas KO either p110alpha or p110beta or knockin kinase-dead p110alpha results in early embryonic lethality in mice.	('embryonic lethality', 'Disease', 'MESH:D020964', (199, 218))	('mice', 'Species', '10090', (222, 226))	('p110beta', 'Var', (29, 37))	('embryonic lethality', 'Disease', (199, 218))	('p110beta', 'Var', (140, 148))	('results in', 'Reg', (182, 192))	('p110alpha', 'Var', (127, 136))
34877	32997991	Thus, effective treatment of PTEN-deficient GBM using PI3K inhibitors will require the development of brain-penetrant inhibitors that target p110alpha and p110beta effectively.	('GBM', 'Phenotype', 'HP:0012174', (44, 47))	('p110alpha', 'Var', (141, 150))	('PTEN-deficient GBM', 'Disease', (29, 47))	('PTEN-deficient GBM', 'Disease', 'MESH:D006223', (29, 47))	('p110beta', 'Var', (155, 163))
34878	32997991	Our data suggest that p110alpha plays a relatively larger role in GBM proliferation, while p110beta plays a major role in tumor invasion.	('p110beta', 'Var', (91, 99))	('GBM proliferation', 'CPA', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('p110alpha', 'Var', (22, 31))	('tumor', 'Disease', (122, 127))
34879	32997991	Prior studies show that p110alpha interacts with RAS and p110beta interacts with Rac1, which is known to play a major role in tumor cell mobility and invasiveness.	('interacts', 'Reg', (66, 75))	('p110beta', 'Var', (57, 65))	('Rac1', 'Gene', '19353', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Rac1', 'Gene', (81, 85))	('RAS', 'Protein', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('interacts', 'Reg', (34, 43))	('p110alpha', 'Var', (24, 33))	('tumor', 'Disease', (126, 131))
34880	32997991	A recent report suggested that BKM120 blocks GBM cell migration in vitro, however, through its off-target effects to reduce focal adhesions and microtubule treadmilling, not through direct inhibition of PI3K activity.	('BKM120', 'Var', (31, 37))	('blocks', 'NegReg', (38, 44))	('microtubule', 'MPA', (144, 155))	('BKM120', 'Chemical', 'MESH:C571178', (31, 37))	('reduce', 'NegReg', (117, 123))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('focal adhesions', 'CPA', (124, 139))	('GBM cell migration', 'CPA', (45, 63))
34881	32997991	Under our ex vivo and in vivo conditions, BKM120 likely does not have off-target effects and did not block GBM cell invasion and migration.	('BKM120', 'Chemical', 'MESH:C571178', (42, 48))	('GBM cell invasion', 'CPA', (107, 124))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))	('BKM120', 'Var', (42, 48))
34882	32997991	P53f/f (NCI mouse repository), Ptenf/f (from Hong Wu group), Pik3caf/f and Pik3cbf/f mice were backcrossed to FVB strain background for 10 generations.	('Pten', 'Gene', '19211', (31, 35))	('mice', 'Species', '10090', (85, 89))	('Pik3cb', 'Gene', '74769', (75, 81))	('Pik3ca', 'Gene', (61, 67))	('Pik3ca', 'Gene', '18706', (61, 67))	('mouse', 'Species', '10090', (12, 17))	('P53f/f', 'Var', (0, 6))	('Pik3cb', 'Gene', (75, 81))	('Pten', 'Gene', (31, 35))
34894	32997991	pMD.G (1.4 mug), pMD.MLV (4 mug), and pMSCV-creERt2-puro (5.4 mug) (Addgene#22776) or pBabe-puro-p110beta WT or pBabe-puro-p110beta-S205D/K224A(p110beta-MT) plasmids (5.4 mug) were transfected in 80% confluent HEK293T cells on 10 cm dish by Superfect (QIAGEN) according to the manufacturer's protocol or 40 muL PEI (1 mg/ml).	('pMD', 'Disease', (0, 3))	('pMD', 'Disease', (17, 20))	('ERt2', 'Gene', '26417', (47, 51))	('ERt2', 'Gene', (47, 51))	('S205D', 'Var', (132, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (210, 217))	('S205D', 'SUBSTITUTION', 'None', (132, 137))	('pMD', 'Disease', 'None', (0, 3))	('pMD', 'Disease', 'None', (17, 20))
34931	31427282	Recent phase 1 clinical trials demonstrate the safety of P-AscH- when administered with concurrent gemcitabine for stage IV pancreatic cancer, when combined with paclitaxel and carboplatin for ovarian cancer, as well when combined with radiation and gemcitabine for locally advanced pancreatic cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (193, 207))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (283, 300))	('paclitaxel', 'Chemical', 'MESH:D017239', (162, 172))	('pancreatic cancer', 'Disease', (124, 141))	('carboplatin', 'Chemical', 'MESH:D016190', (177, 188))	('ovarian cancer', 'Disease', (193, 207))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('pancreatic cancer', 'Disease', 'MESH:D010190', (283, 300))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('pancreatic cancer', 'Disease', (283, 300))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('P-AscH-', 'Var', (57, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (99, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('gemcitabine', 'Chemical', 'MESH:C056507', (250, 261))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('P-AscH-', 'Chemical', '-', (57, 64))
34932	31427282	In vitro and orthotopic animal models demonstrate P-AscH- selectively increases cancer cell oxidative stress, thereby sensitizing cancer cells to radiation and chemotherapy.	('oxidative stress', 'Phenotype', 'HP:0025464', (92, 108))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('sensitizing', 'Reg', (118, 129))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('increases', 'PosReg', (70, 79))	('P-AscH-', 'Var', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('P-AscH-', 'Chemical', '-', (50, 57))	('cancer', 'Disease', (80, 86))
34957	31427282	IDH1 testing for the R123H mutation was performed by PCR or next generation sequencing at the University of Iowa Diagnostic Laboratories.	('R123H', 'Var', (21, 26))	('R123H', 'Mutation', 'p.R123H', (21, 26))	('IDH1', 'Gene', (0, 4))	('P', 'Chemical', 'MESH:D010758', (53, 54))	('IDH1', 'Gene', '3417', (0, 4))
34958	31427282	The R123H mutation is the most common IDH1 mutation (accounts for 90% of the known IDH1 mutations).	('IDH1', 'Gene', '3417', (38, 42))	('IDH1', 'Gene', '3417', (83, 87))	('R123H', 'Var', (4, 9))	('R123H', 'Mutation', 'p.R123H', (4, 9))	('IDH1', 'Gene', (38, 42))	('IDH1', 'Gene', (83, 87))
34983	31427282	Two subjects had identified IDH1 mutations.	('IDH1', 'Gene', '3417', (28, 32))	('mutations', 'Var', (33, 42))	('IDH1', 'Gene', (28, 32))
35010	31427282	Historical data demonstrate patients without MGMT promoter methylation have a worse prognostic outcome relative to those with a methylated MGMT promoter.	('MGMT', 'Gene', (45, 49))	('MGMT', 'Gene', (139, 143))	('MGMT', 'Gene', '4255', (139, 143))	('methylation', 'Var', (59, 70))	('patients', 'Species', '9606', (28, 36))	('MGMT', 'Gene', '4255', (45, 49))
35016	31427282	Data suggest P-AscH- is safe when combined with RT and TMZ, with minimal toxicity relative to standard RT/TMZ therapy.	('TMZ', 'Chemical', 'MESH:D000077204', (55, 58))	('P-AscH-', 'Chemical', '-', (13, 20))	('toxicity', 'Disease', 'MESH:D064420', (73, 81))	('toxicity', 'Disease', (73, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (106, 109))	('P-AscH-', 'Var', (13, 20))
35017	31427282	While not powered to detect changes in effect size, data suggest P-AscH- may enhance RT/TMZ effectiveness in GBM patients, improving both PFS and OS, especially in subjects with undetectable MGMT promoter methylation and IDH wild type status.	('IDH', 'Gene', '3417', (221, 224))	('PFS', 'Disease', (138, 141))	('MGMT', 'Gene', '4255', (191, 195))	('MGMT', 'Gene', (191, 195))	('patients', 'Species', '9606', (113, 121))	('P-AscH-', 'Chemical', '-', (65, 72))	('TMZ', 'Chemical', 'MESH:D000077204', (88, 91))	('RT/TMZ effectiveness', 'MPA', (85, 105))	('P', 'Chemical', 'MESH:D010758', (138, 139))	('IDH', 'Gene', (221, 224))	('improving', 'PosReg', (123, 132))	('P', 'Chemical', 'MESH:D010758', (65, 66))	('enhance', 'PosReg', (77, 84))	('P-AscH-', 'Var', (65, 72))
35018	31427282	Several additional early phase clinical trials have found P-AscH- to be safe when combined with chemotherapy and may reduce cancer therapy associated normal tissue injury.	('cancer', 'Disease', (124, 130))	('P-AscH-', 'Chemical', '-', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('reduce', 'NegReg', (117, 123))	('P-AscH-', 'Var', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
35019	31427282	In stage III or IV ovarian cancer, pharmacological ascorbate combined with conventional carboplatin and paclitaxel demonstrated reduced incidence of gastrointestinal and hematopoietic toxicity while trending toward improved overall survival and time to disease progression.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('overall', 'MPA', (224, 231))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('ascorbate', 'Chemical', 'MESH:D001205', (51, 60))	('reduced', 'NegReg', (128, 135))	('gastrointestinal and hematopoietic toxicity', 'Disease', 'MESH:D005767', (149, 192))	('pharmacological', 'Var', (35, 50))	('improved', 'PosReg', (215, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('IV ovarian cancer', 'Disease', 'MESH:D009085', (16, 33))	('IV ovarian cancer', 'Disease', (16, 33))	('carboplatin', 'Chemical', 'MESH:D016190', (88, 99))
35021	31427282	In locally advanced pancreatic cancer, pharmacological ascorbate combined with radiation therapy and gemcitabine showed an increase in progression free survival and a trend towards an increase in overall survival.	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ascorbate', 'Chemical', 'MESH:D001205', (55, 64))	('increase', 'PosReg', (184, 192))	('gemcitabine', 'Chemical', 'MESH:C056507', (101, 112))	('increase', 'PosReg', (123, 131))	('pharmacological ascorbate', 'Var', (39, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('progression free survival', 'CPA', (135, 160))	('overall', 'MPA', (196, 203))	('pancreatic cancer', 'Disease', (20, 37))
35022	31427282	To our knowledge, this clinical trial was the first to combine P-AscH- with RT and TMZ for a primary brain tumor.	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('brain tumor', 'Phenotype', 'HP:0030692', (101, 112))	('P-AscH-', 'Var', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('P-AscH-', 'Chemical', '-', (63, 70))	('brain tumor', 'Disease', (101, 112))	('brain tumor', 'Disease', 'MESH:D001932', (101, 112))
35023	31427282	Compared to RT/TMZ alone for GBM therapy, P-AscH- did not appear to increase hematologic toxicity but instead may provide protective effect.	('P-AscH-', 'Var', (42, 49))	('hematologic toxicity', 'Disease', (77, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (15, 18))	('P-AscH-', 'Chemical', '-', (42, 49))	('hematologic toxicity', 'Disease', 'MESH:D006402', (77, 97))	('protective effect', 'CPA', (122, 139))
35028	31427282	These initial data suggest P-AscH- may increase RT and TMZ therapeutic tolerability, increasing a subject's quality of life and decreasing therapeutic toxicity.	('P-AscH-', 'Var', (27, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (55, 58))	('toxicity', 'Disease', 'MESH:D064420', (151, 159))	('toxicity', 'Disease', (151, 159))	('increase RT', 'Phenotype', 'HP:0008151', (39, 50))	('increasing', 'PosReg', (85, 95))	('P-AscH-', 'Chemical', '-', (27, 34))	('increase', 'PosReg', (39, 47))	('decreasing', 'NegReg', (128, 138))	('quality of life', 'MPA', (108, 123))
35039	31427282	Data support pharmacological ascorbate is safe and well-tolerated when combined with radiation and temozolomide and may improve therapeutic outcome.	('improve', 'PosReg', (120, 127))	('pharmacological', 'Var', (13, 28))	('ascorbate', 'Chemical', 'MESH:D001205', (29, 38))	('therapeutic', 'MPA', (128, 139))	('temozolomide', 'Chemical', 'MESH:D000077204', (99, 111))
35180	29625055	In the LGG marker paper, analysis of OS showed that patients diagnosed with an IDH1 and IDH2 (two very similar genes, hereafter referred to collectively as IDH) mutation with or without 1p/19q codeletion had substantially longer OS than did patients who had wild-type IDH, proving that IDH-1p/19q status represents a more robust survival predictor than LGG histologic subtype.	('IDH-1p', 'Gene', (286, 292))	('IDH', 'Gene', (88, 91))	('IDH1', 'Gene', (79, 83))	('IDH', 'Gene', (79, 82))	('mutation', 'Var', (161, 169))	('IDH', 'Gene', (286, 289))	('IDH', 'Gene', '3417', (88, 91))	('patients', 'Species', '9606', (52, 60))	('IDH1', 'Gene', '3417', (79, 83))	('IDH', 'Gene', (268, 271))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (156, 159))	('OS', 'Chemical', '-', (229, 231))	('OS', 'Chemical', '-', (37, 39))	('IDH', 'Gene', '3417', (286, 289))	('patients', 'Species', '9606', (241, 249))	('longer', 'PosReg', (222, 228))	('IDH2', 'Gene', (88, 92))	('IDH-1p', 'Gene', '3417', (286, 292))	('IDH2', 'Gene', '3418', (88, 92))	('IDH', 'Gene', '3417', (268, 271))	('IDH', 'Gene', '3417', (156, 159))
35358	28076333	Finally, analysis of tumor protein lysates on antibody microarrays demonstrated an increase in pro-inflammatory cytokines, such as CXCL10, and a decrease in angiogenic proteins in debulking + anti-CD47 vs non-debulking + IgG tumors.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('increase', 'PosReg', (83, 91))	('debulking + anti-CD47', 'Var', (180, 201))	('tumors', 'Disease', (225, 231))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('rat', 'Species', '10116', (74, 77))	('tumor', 'Disease', (225, 230))	('pro-inflammatory cytokines', 'MPA', (95, 121))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('decrease', 'NegReg', (145, 153))	('angiogenic proteins', 'MPA', (157, 176))	('CXCL10', 'Gene', '3627', (131, 137))	('CXCL10', 'Gene', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
35359	28076333	The results indicated that surgical resection combined with anti-CD47 blocking immunotherapy promoted an inflammatory response and prolonged survival in animals, and is therefore an attractive strategy for clinical translation.	('anti-CD47', 'Var', (60, 69))	('inflammatory response', 'CPA', (105, 126))	('prolonged', 'PosReg', (131, 140))	('rat', 'Species', '10116', (195, 198))	('promoted', 'PosReg', (93, 101))	('survival', 'CPA', (141, 149))
35370	28076333	Studies performed with experimental models of solid tumors including GBM as well as some hematopoietic cancers have shown that blocking the interaction between CD47 and SIRPalpha with anti-CD47 monoclonal antibodies (mAbs) promotes phagocytosis in vitro and inhibits tumor growth in vivo.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('blocking', 'Var', (127, 135))	('SIRPalpha', 'Gene', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('interaction', 'Interaction', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('solid tumors', 'Disease', 'MESH:D009369', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('phagocytosis', 'CPA', (232, 244))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inhibits', 'NegReg', (258, 266))	('hematopoietic cancers', 'Disease', (89, 110))	('promotes', 'PosReg', (223, 231))	('CD47', 'Gene', (160, 164))	('solid tumors', 'Disease', (46, 58))	('tumor', 'Disease', (267, 272))	('anti-CD47', 'Gene', (184, 193))	('anti-CD47', 'Var', (184, 193))	('hematopoietic cancers', 'Disease', 'MESH:D019337', (89, 110))
35375	28076333	The results indicate that CD47 blocking immunotherapy might be a promising postsurgical treatment for GBM and that targeting CD47 has the potential to eliminate tumor cells driving recurrence in GBM.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('CD47', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CD47', 'Protein', (26, 30))	('targeting', 'Var', (115, 124))	('tumor', 'Disease', (161, 166))	('GBM', 'Disease', (102, 105))
35383	28076333	All rats survived to the end of the study with tumor debulking significantly prolonging overall survival time as assessed in survival curves (median survival, 68.5 vs 42.5 days, debulking and non-debulking survival times, respectively; Figure 1D).	('overall survival time', 'CPA', (88, 109))	('prolonging', 'PosReg', (77, 87))	('rats', 'Species', '10116', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('debulking', 'Var', (53, 62))	('tumor', 'Disease', (47, 52))
35397	28076333	Phagocytic indices indicated that P3 and P13 GBM cells incubated with anti-CD47 antibody were more efficiently phagocytosed by rat macrophages than P3 and P13 cells treated with control IgG antibody or PBS (P3: 32%, 12% and 8%; and P13: 82%, 42%, and 42%; CD47, IgG and PBS control, respectively; Figure 4B).	('P13', 'Gene', (232, 235))	('P13', 'Gene', '440926', (232, 235))	('phagocytosed', 'CPA', (111, 123))	('IgG antibody', 'Phenotype', 'HP:0003237', (186, 198))	('P13', 'Gene', (41, 44))	('P13', 'Gene', '440926', (41, 44))	('rat', 'Species', '10116', (127, 130))	('P13', 'Gene', (155, 158))	('anti-CD47', 'Var', (70, 79))	('P13', 'Gene', '440926', (155, 158))	('more', 'PosReg', (94, 98))
35398	28076333	Differences in uptake were statistically significant for anti-CD47 treated P3 and P13 cells relative to the PBS and IgG antibody controls (P = 0.00001 and 0.00008 for P3; P = 0.023 and = 0.015 for P13; PBS and IgG respectively).	('P13', 'Gene', (197, 200))	('anti-CD47', 'Var', (57, 66))	('P13', 'Gene', '440926', (197, 200))	('uptake', 'MPA', (15, 21))	('P13', 'Gene', (82, 85))	('P13', 'Gene', '440926', (82, 85))	('IgG antibody', 'Phenotype', 'HP:0003237', (116, 128))
35400	28076333	In order to determine whether anti-CD47 antibody was effective against tumor growth in a setting more similar to the clinic, treatment was initiated 4 weeks after implantation, a time point where tumor was clearly evident in rats by MRI (Figure 1B).	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('anti-CD47', 'Var', (30, 39))	('R', 'Gene', '287469', (234, 235))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('rats', 'Species', '10116', (225, 229))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
35402	28076333	Differences in tumor volumes evaluated by MRI scan were not evident in rats when treatment with anti-CD47 was initiated at 4 weeks after implantation relative to controls (Figure 5B).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('R', 'Gene', '287469', (43, 44))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('anti-CD47', 'Var', (96, 105))	('tumor', 'Disease', (15, 20))	('rats', 'Species', '10116', (71, 75))
35403	28076333	Treatment with anti-CD47 antibody thus did not inhibit tumor growth when injected at 4 weeks after implantation into solid tumors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('solid tumors', 'Disease', 'MESH:D009369', (117, 129))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('solid tumors', 'Disease', (117, 129))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('anti-CD47', 'Gene', (15, 24))	('anti-CD47', 'Var', (15, 24))
35406	28076333	Anti-CD47 mAb relative to IgG inhibited tumor growth in combination with resection, and differences in tumor volume compared to controls were statistically significant at weeks 7 (P = 0.0064), 8 (P = 0.0169) and 9 (P = 0.0062; Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Anti-CD47', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
35407	28076333	Importantly, the observed delays in tumor growth in resected animals treated with anti-CD47 mAb treatment were associated with a significantly improved outcome compared to resected animals treated with IgG control antibody (81.5 days vs 69.0 days, anti-CD47 vs IgG control; P = 0.0007).	('anti-CD47', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('delays', 'NegReg', (26, 32))
35422	28076333	Debulking xenografts treated with CD47 antibody were characterized by significantly higher expression of cytokines/chemokines and immune cell markers CINC-3, CD54, IL-1F3, CXCL10, CXCL9, and CCL5 relative to debulking tumors treated with IgG antibody therapy (P < 0.05; Figure 7A).	('expression', 'MPA', (91, 101))	('CD47 antibody', 'Var', (34, 47))	('IgG antibody', 'Phenotype', 'HP:0003237', (238, 250))	('CXCL9', 'Gene', (180, 185))	('CXCL10', 'Gene', (172, 178))	('CCL5', 'Gene', '6352', (191, 195))	('higher', 'PosReg', (84, 90))	('CXCL9', 'Gene', '4283', (180, 185))	('CINC-3', 'MPA', (150, 156))	('CD54', 'Gene', (158, 162))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('CD54', 'Gene', '3383', (158, 162))	('IL-1F3', 'Gene', '3557', (164, 170))	('CCL5', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cytokines/chemokines', 'MPA', (105, 125))	('tumors', 'Disease', (218, 224))	('IL-1F3', 'Gene', (164, 170))	('CXCL10', 'Gene', '3627', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
35423	28076333	Quantification of angiogenesis associated proteins revealed that AR, CXCL16, GDNF, GM-CSF, CCL3, PDGF-AA, PIGF, Serpin B5, TIMP4 Tsp2 and VEGF-C were downregulated while Serpin E1 was upregulated in debulking tumors treated with anti-CD47 compared to debulking tumors treated with IgG (P < 0.05; Figure 7B).	('PIGF', 'Gene', '5281', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('CXCL16', 'Gene', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('GDNF', 'Gene', (77, 81))	('Serpin E1', 'Gene', (170, 179))	('CCL3', 'Gene', (91, 95))	('anti-CD47', 'Var', (229, 238))	('GDNF', 'Gene', '2668', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('Tsp2', 'Gene', '7058', (129, 133))	('TIMP4', 'Gene', (123, 128))	('TIMP4', 'Gene', '7079', (123, 128))	('Serpin E1', 'Gene', '5054', (170, 179))	('PIGF', 'Gene', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('downregulated', 'NegReg', (150, 163))	('Serpin B5', 'Gene', '5268', (112, 121))	('VEGF-C', 'Gene', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('Tsp2', 'Gene', (129, 133))	('GM-CSF', 'Gene', (83, 89))	('VEGF-C', 'Gene', '7424', (138, 144))	('upregulated', 'PosReg', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('CCL3', 'Gene', '6348', (91, 95))	('Serpin B5', 'Gene', (112, 121))	('CXCL16', 'Gene', '58191', (69, 75))	('GM-CSF', 'Gene', '1437', (83, 89))	('R', 'Gene', '287469', (66, 67))
35428	28076333	The results demonstrated first that debulking enhanced survival in animals, and reflected the therapeutic benefit of surgical resection in patients.	('patients', 'Species', '9606', (139, 147))	('survival', 'CPA', (55, 63))	('rat', 'Species', '10116', (19, 22))	('enhanced', 'PosReg', (46, 54))	('debulking', 'Var', (36, 45))
35430	28076333	Second, anti-CD47 treatment enhanced antitumor activity but only in combination with surgery.	('anti-CD47', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('enhanced', 'PosReg', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
35432	28076333	A potential mechanism underlying therapeutic enhancement with anti-CD47 antibody may be the increased number/density of double positive pSTAT1-CD68 macrophages found in recurrent GBM tissue relative to non-resected xenografts.	('STAT1', 'Gene', (137, 142))	('STAT1', 'Gene', '6772', (137, 142))	('anti-CD47', 'Var', (62, 71))	('CD68', 'Gene', (143, 147))	('CD68', 'Gene', '968', (143, 147))	('enhancement', 'PosReg', (45, 56))
35444	28076333	CINC-3 is a strong chemotactic factor for neutrophils and was found to be downregulated in the debulking tumor + CD47 antibody group.	('CINC-3', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('downregulated', 'NegReg', (74, 87))	('debulking', 'Var', (95, 104))
35450	28076333	The result was consistent with a study showing that CD47 blockade leads to increased macrophage infiltration in tumors.	('macrophage infiltration', 'CPA', (85, 108))	('CD47', 'Protein', (52, 56))	('blockade', 'Var', (57, 65))	('increased macrophage infiltration', 'Phenotype', 'HP:0004311', (75, 108))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('rat', 'Species', '10116', (102, 105))	('increased', 'PosReg', (75, 84))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
35452	28076333	Thus, all together, these results provide a potential mechanism for the enhanced anti-tumor activity observed with blockade of CD47-SIRPa in the context of surgical debulking.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('SIRPa', 'Gene', '140885', (132, 137))	('SIRPa', 'Gene', (132, 137))	('enhanced', 'PosReg', (72, 80))	('blockade', 'Var', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
35453	28076333	Our observation that anti-CD47 therapy had no effect on the primary tumor mass in nude rats in the absence of debulking, corroborates previous results.	('tumor', 'Disease', (68, 73))	('rats', 'Species', '10116', (87, 91))	('anti-CD47', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('rat', 'Species', '10116', (128, 131))	('rat', 'Species', '10116', (87, 90))
35455	28076333	This result was surprising as our in vitro experiments had shown significant phagocytosis of tumor cells in the anti-CD47 group, but it was only smaller size after debulking in rats in the anti-CD47 group that was associated with significantly longer survival compared to controls.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('anti-CD47', 'Var', (112, 121))	('tumor', 'Disease', (93, 98))	('longer', 'PosReg', (244, 250))	('phagocytosis', 'CPA', (77, 89))	('rats', 'Species', '10116', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
35456	28076333	The results indicate that anti-CD47 therapy effectively enhanced treatment of recurrent tumors in the context of postsurgical tumor resection and thus might potentially improve overall survival of patients with GBM.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('anti-CD47', 'Var', (26, 35))	('patients', 'Species', '9606', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('treatment', 'MPA', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('enhanced', 'PosReg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('improve', 'PosReg', (169, 176))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (126, 131))
35463	28076333	These results support the rationale for evaluating clinical efficacy of anti-CD47 therapy post-surgically in human patients with GBM.	('patients', 'Species', '9606', (115, 123))	('human', 'Species', '9606', (109, 114))	('rat', 'Species', '10116', (26, 29))	('anti-CD47', 'Var', (72, 81))	('GBM', 'Disease', (129, 132))
35494	28076333	Detection was performed using biotinylated secondary antibody conjugated to peroxidase (40 min incubation; anti-mouse, K4007; anti-rabbit, K4011; DAKO) and DAB+ as the substrate (3 min; K4007; DAKO) according to the manufacturer's instructions.	('K4007', 'Var', (186, 191))	('rat', 'Species', '10116', (173, 176))	('rabbit', 'Species', '9986', (131, 137))	('K4011', 'Var', (139, 144))	('DAB+', 'Chemical', 'MESH:C000469', (156, 160))	('mouse', 'Species', '10090', (112, 117))
35502	28076333	For flow cytometry, single cell suspensions were immediately fixed in 4% PFA for 10 min followed by a wash with PBS, 15 min blocking in 0.5% BSA, and incubation with anti-CD47 or isotype control antibody for 20 min at room temperature.	('PFA', 'Chemical', 'MESH:C003043', (73, 76))	('pen', 'Gene', '27344', (35, 38))	('rat', 'Species', '10116', (228, 231))	('anti-CD47', 'Var', (166, 175))	('pen', 'Gene', (35, 38))
35582	26835125	IONP-HA-GEM-CTX-Cy5.5 had the highest accumulation in the liver at 3 h but was eliminated more than 50% at 48 h. The spleen also showed NP signal at 3 h with a slight increase at 48 h. The kidney had the second strong signal at 3 h among all organs with moderate decrease at 48 h. Based on these information, it can be expected that IONP-HA-GEM-CTX-Cy5.5 mainly degraded in liver and excreted through renal system.	('IONP-HA-GEM-CTX-Cy5', 'Chemical', '-', (333, 352))	('IONP-HA-GEM-CTX-Cy5', 'Chemical', '-', (0, 19))	('IONP-HA-GEM-CTX-Cy5.5', 'Var', (333, 354))	('excreted', 'MPA', (384, 392))	('degraded', 'NegReg', (362, 370))
35589	26835125	This result and the biodistribution result shown in Figure 3b suggest that IONP-HA-GEM-CTX-Cy5.5 was able to pass the BBB in live mice and accumulate in brains, although only a small amount of NPs were observed, because these mice did not bear brain tumours.	('brain tumours', 'Disease', 'MESH:D001932', (244, 257))	('mice', 'Species', '10090', (130, 134))	('brain tumours', 'Phenotype', 'HP:0030692', (244, 257))	('mice', 'Species', '10090', (226, 230))	('brain tumours', 'Disease', (244, 257))	('tumours', 'Phenotype', 'HP:0002664', (250, 257))	('accumulate', 'PosReg', (139, 149))	('brain tumour', 'Phenotype', 'HP:0030692', (244, 256))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('IONP-HA-GEM-CTX-Cy5', 'Chemical', '-', (75, 94))	('IONP-HA-GEM-CTX-Cy5.5', 'Var', (75, 96))
35592	26835125	Significantly, IONP-HA-GEM-CTX effectively entered and killed GBM cells, had prolonged blood circulation, and was excreted from renal system.	('prolonged blood circulation', 'Phenotype', 'HP:0011028', (77, 104))	('IONP-HA-GEM-CTX', 'Chemical', '-', (15, 30))	('GBM cells', 'CPA', (62, 71))	('blood circulation', 'CPA', (87, 104))	('prolonged', 'PosReg', (77, 86))	('IONP-HA-GEM-CTX', 'Var', (15, 30))
35594	26835125	Our experimental results suggest that IONP-HA-GEM-CTX has the potential to improve in vivo performance of GEM.	('IONP-HA-GEM-CTX', 'Var', (38, 53))	('GEM', 'Chemical', 'MESH:C056507', (46, 49))	('IONP-HA-GEM-CTX', 'Chemical', '-', (38, 53))	('improve', 'PosReg', (75, 82))	('GEM', 'Chemical', 'MESH:C056507', (106, 109))
35628	23242736	Under GFP fluorescence, the U87-GFP-FLuc tumor was surgically excised using a combination of surgical dissection and aspiration, and images of GFP were continuously captured to assess accuracy of GFP-guided surgical resection (n=26).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('U87-GFP-FLuc', 'Var', (28, 40))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('aspiration', 'Phenotype', 'HP:0002835', (117, 127))
35695	23242736	In this study, we utilized U87-GFP-FLuc human GBM that allowed the generation of a solid tumor that was necessary for efficient surgical resection, and lead to residual post-operative tumor deposits that were vital for studying GBM recurrence.	('U87-GFP-FLuc', 'Var', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('human', 'Species', '9606', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor deposits', 'Disease', 'MESH:D000079822', (184, 198))	('tumor', 'Disease', (184, 189))	('tumor deposits', 'Disease', (184, 198))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
35696	23242736	Using this model, we observed recurrent U87-GFP-FLuc tumors showed a higher growth rate and Ki-67 staining.	('Ki-67', 'Gene', '17345', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('growth rate', 'CPA', (76, 87))	('U87-GFP-FLuc', 'Var', (40, 52))	('Ki-67', 'Gene', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('higher', 'PosReg', (69, 75))	('tumors', 'Disease', (53, 59))
35705	32488114	Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family.	('FOXM1', 'Gene', (96, 101))	('expression', 'MPA', (57, 67))	('Alterations', 'Var', (0, 11))	('FOXM1', 'Gene', '2305', (96, 101))	('decreased', 'NegReg', (47, 56))
35711	32488114	Recurrence occurs in part because glioblastoma uses sophisticated cellular mechanisms to repair DNA damage from double-stranded breaks caused by ionizing radiation, specifically homologous recombination and non-homologous end-joining.	('stranded breaks caused by ionizing radiation', 'Phenotype', 'HP:0010997', (119, 163))	('glioblastoma', 'Disease', (34, 46))	('homologous recombination', 'Var', (178, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('non-homologous end-joining', 'Var', (207, 233))
35718	32488114	Splicing alterations are a common feature across cancer types and affect all hallmarks of cancer.	('affect', 'Reg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Splicing alterations', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (49, 55))
35738	32488114	In agreement, E2F1, E2F2, E2F8, and FOXM1 displayed a significant decrease upon radiation.	('decrease', 'NegReg', (66, 74))	('E2F2', 'Gene', '1870', (20, 24))	('FOXM1', 'Gene', (36, 41))	('E2F1', 'Var', (14, 18))	('FOXM1', 'Gene', '2305', (36, 41))	('E2F2', 'Gene', (20, 24))	('E2F8', 'Gene', (26, 30))	('E2F8', 'Gene', '79733', (26, 30))
35742	32488114	We corroborated the changes in expression of these transcription factors and some of their potential targets by qRT-PCR in U343 cells and also observed similar changes in the glioblastoma line A172 and the glioma stem cell line 3565 (Supplementary Fig.	('U343', 'CellLine', 'CVCL:S471', (123, 127))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('glioblastoma', 'Disease', (175, 187))	('glioblastoma', 'Disease', 'MESH:D005909', (175, 187))	('expression', 'MPA', (31, 41))	('qRT-PCR', 'Var', (112, 119))	('changes', 'Reg', (20, 27))	('glioma', 'Disease', (206, 212))
35759	32488114	Alternative splicing impacts genes implicated in all hallmarks of cancer and is an important component of changes in expression triggered by ionizing radiation.	('genes', 'Protein', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('impacts', 'Reg', (21, 28))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Alternative splicing', 'Var', (0, 20))	('cancer', 'Disease', (66, 72))
35778	32488114	Alterations in E2F genes can induce cancer in mice.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('E2F genes', 'Gene', (15, 24))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (36, 42))	('induce', 'Reg', (29, 35))	('mice', 'Species', '10090', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
35779	32488114	Specifically, we found that three E2F members showed decreased expression upon radiation: E2F1, E2F2, and E2F8, all of which have been previously implicated in glioblastoma development.	('glioblastoma', 'Disease', (160, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('E2F8', 'Gene', '79733', (106, 110))	('E2F2', 'Gene', '1870', (96, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('expression', 'MPA', (63, 73))	('E2F2', 'Gene', (96, 100))	('decreased', 'NegReg', (53, 62))	('E2F1', 'Var', (90, 94))	('E2F8', 'Gene', (106, 110))
35783	32488114	Several tumor suppressor miRNAs (let7b, miR-125b, miR-218, and miR-138) decrease the proliferation and growth of glioblastoma cells by targeting E2F2.	('glioblastoma', 'Disease', (113, 125))	('E2F2', 'Gene', (145, 149))	('miR-125b', 'Var', (40, 48))	('growth', 'CPA', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('let7b', 'Gene', '406884', (33, 38))	('E2F2', 'Gene', '1870', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('let7b', 'Gene', (33, 38))	('tumor', 'Disease', (8, 13))	('decrease', 'NegReg', (72, 80))	('miR-138', 'Var', (63, 70))	('targeting', 'Reg', (135, 144))	('proliferation', 'CPA', (85, 98))	('miR-218', 'Var', (50, 57))
35789	32488114	Additionally, FOXM1- and E2F2-mediated cell cycle transitions are implicated in the malignant progression of IDH1 mutant glioma.	('E2F2', 'Gene', '1870', (25, 29))	('FOXM1', 'Gene', (14, 19))	('IDH1', 'Gene', (109, 113))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('mutant', 'Var', (114, 120))	('glioma', 'Disease', (121, 127))	('cell cycle transitions', 'CPA', (39, 61))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('IDH1', 'Gene', '3417', (109, 113))	('E2F2', 'Gene', (25, 29))	('FOXM1', 'Gene', '2305', (14, 19))	('implicated', 'Reg', (66, 76))
35790	32488114	E2F and FOXM1 targeting could be considered as an option to increase radio-sensitivity.	('E2F', 'Var', (0, 3))	('FOXM1', 'Gene', (8, 13))	('radio-sensitivity', 'MPA', (69, 86))	('FOXM1', 'Gene', '2305', (8, 13))	('increase', 'PosReg', (60, 68))
35794	32488114	Many regulators of RNA processing are implicated in glioblastoma development, and splicing alterations affect all hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('splicing alterations', 'Var', (82, 102))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('cancer', 'Disease', (127, 133))	('implicated', 'Reg', (38, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('affect', 'Reg', (103, 109))
35798	32488114	Notch activation has been linked to radio-resistance in glioblastoma, and Notch targeting improves the results of radiation treatment.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('improves', 'PosReg', (90, 98))	('Notch targeting', 'Var', (74, 89))	('glioblastoma', 'Disease', (56, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('results', 'CPA', (103, 110))
35806	32488114	The depletion of RRM2B resulted in ADR-induced apoptosis, growth inhibition, and enhanced sensitivity to chemo- and radiotherapy.	('enhanced', 'PosReg', (81, 89))	('apoptosis', 'CPA', (47, 56))	('depletion', 'Var', (4, 13))	('RRM2B', 'Gene', (17, 22))	('growth inhibition', 'CPA', (58, 75))	('RRM2B', 'Gene', '50484', (17, 22))
35808	32488114	The combination of radiation therapy and IDO1 inhibition enhanced therapeutic response.	('IDO1', 'Gene', (41, 45))	('inhibition', 'Var', (46, 56))	('therapeutic response', 'CPA', (66, 86))	('IDO1', 'Gene', '3620', (41, 45))	('enhanced', 'PosReg', (57, 65))
35867	32065482	The risk score for each patient was calculated as follows: risk score = (0.1052 x expression level of DIRAS3) + (0.2152 x expression level of LGALS8) + (-0.3603 x expression level of MAPK8) + (-0.2851 x expression level of STAM).	('STAM', 'Gene', '8027', (223, 227))	('expression', 'MPA', (122, 132))	('DIRAS3', 'Gene', '9077', (102, 108))	('STAM', 'Gene', (223, 227))	('MAPK8', 'Gene', '5599', (183, 188))	('MAPK8', 'Gene', (183, 188))	('patient', 'Species', '9606', (24, 31))	('0.1052', 'Var', (73, 79))	('LGALS8', 'Gene', '3964', (142, 148))	('LGALS8', 'Gene', (142, 148))	('DIRAS3', 'Gene', (102, 108))
35871	32065482	As shown in the ROC curves, the area under curves (AUCs) of the risk signature for predicting the 1-, 3- and 5-year survival were 0.644 (Figure 2C), 0.727 (Figure 2D) and 0.877 (Figure 2E), respectively, which were larger than those of IDH1, MGMT promoter and G-CIMP status.	('0.727', 'Var', (149, 154))	('MGMT', 'Gene', '4255', (242, 246))	('IDH1', 'Gene', (236, 240))	('0.877', 'Var', (171, 176))	('MGMT', 'Gene', (242, 246))	('G-CIMP', 'Chemical', '-', (260, 266))	('IDH1', 'Gene', '3417', (236, 240))
35879	32065482	As shown in Figure 4A, high-risk group inclined to contain more elder patients, whereas samples with IDH1 mutant were all in low-risk group.	('IDH1', 'Gene', (101, 105))	('patients', 'Species', '9606', (70, 78))	('mutant', 'Var', (106, 112))	('IDH1', 'Gene', '3417', (101, 105))
35935	31541799	For initial selection, we used two patient-derived cell lines characterized by different GBM subtypes as a complex target to generate a panel of aptamers able to distinguish stem-like cells from adherent, differentiated counterparts.	('GBM', 'Phenotype', 'HP:0012174', (89, 92))	('patient', 'Species', '9606', (35, 42))	('aptamers', 'Var', (145, 153))	('GBM', 'Disease', (89, 92))	('GBM', 'Disease', 'MESH:D005909', (89, 92))
35943	31541799	Importantly, A40s was still able to bind to the GSC 1, 83, 74, and 163 cell lines (Figure 4B), but no binding to GSC 83, 30p, and 61 cells grown in adherent, differentiated conditions was observed, either with qRT-PCR or fluorescence assay (for the latter assay, A40s and negative control aptamer were labeled with Alexa488) (Figures 4C and 4D).	('A40s', 'Var', (263, 267))	('A40s', 'Var', (13, 17))	('Alexa488', 'Chemical', 'MESH:C417561', (315, 323))
35945	31541799	The signals for A40s and CD133 were co-localized, proving specific recognition of GSCs in GBM tissues (Figure 5B).	('CD133', 'Gene', (25, 30))	('CD133', 'Gene', '8842', (25, 30))	('GBM', 'Disease', (90, 93))	('A40s', 'Var', (16, 20))	('GBM', 'Disease', 'MESH:D005909', (90, 93))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))
35948	31541799	To this end, as previously described, we used sticky-end annealing to generate a molecular duplex chimera (termed A40s-miR-34c) (Figure 6D), consisting of a microRNA cargo and A40s as a carrier.	('miR-34c', 'Gene', '407042', (119, 126))	('miR-34c', 'Gene', (119, 126))	('A40s', 'Var', (176, 180))
35956	31541799	Interestingly, we found that, similar to 40L, A40s discriminated between GSCs and differentiated glioma cells.	('discriminated', 'Reg', (51, 64))	('A40s', 'Var', (46, 50))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('GSCs', 'Disease', (73, 77))
35963	31541799	In fact, we demonstrate that A40s and CD133 co-localize in sections from human brain tumor, indicating that the A40s signal localizes specifically to human brain cancer stem cells.	('human', 'Species', '9606', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('A40s', 'Var', (112, 116))	('cancer', 'Disease', (162, 168))	('brain tumor', 'Phenotype', 'HP:0030692', (79, 90))	('human', 'Species', '9606', (73, 78))	('brain tumor', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('brain tumor', 'Disease', 'MESH:D001932', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('CD133', 'Gene', (38, 43))	('CD133', 'Gene', '8842', (38, 43))	('brain cancer', 'Phenotype', 'HP:0030692', (156, 168))
35990	31541799	Primary antibodies used were as follows: anti-beta3-tubulin, anti-Sox2, anti-GFAP, anti-Nanog, and anti-beta-actin (Sigma-Aldrich).	('beta-actin', 'Gene', (104, 114))	('Sox2', 'Gene', '6657', (66, 70))	('Sox2', 'Gene', (66, 70))	('GFAP', 'Gene', (77, 81))	('tub', 'Gene', '7275', (52, 55))	('GFAP', 'Gene', '2670', (77, 81))	('tub', 'Gene', (52, 55))	('beta-actin', 'Gene', '728378', (104, 114))	('anti-Nanog', 'Var', (83, 93))
35999	31541799	For the A40s-34c chimera, the negative control was made from the unannealed single portions of the chimera (miR-34c guide strand, miR-34c passenger strand, and sticky and not sticky A40s).	('miR-34c', 'Gene', '407042', (130, 137))	('miR-34c', 'Gene', (130, 137))	('A40s-34c', 'Var', (8, 16))	('miR-34c', 'Gene', '407042', (108, 115))	('miR-34c', 'Gene', (108, 115))
36026	23429418	In order to investigate whether brazilin treatments affected cell viability, U87 cells were treated with various concentrations (0-40 muM) of brazilin for 24 h. As shown in Figure 2A, treatments with brazilin induced cell death in U87 cells.	('brazilin', 'Chemical', 'MESH:C044362', (142, 150))	('brazilin', 'Chemical', 'MESH:C044362', (32, 40))	('U87', 'Gene', (77, 80))	('brazilin', 'Chemical', 'MESH:C044362', (200, 208))	('U87', 'Gene', (231, 234))	('U87', 'Gene', '641648', (231, 234))	('cell death', 'CPA', (217, 227))	('U87', 'Gene', '641648', (77, 80))	('treatments', 'Var', (184, 194))
36045	23429418	Glioblastomas usually survive when there exist defects occurring in the expression and function of elements of the apoptotic machinery.	('expression', 'MPA', (72, 82))	('Glioblastomas', 'Disease', (0, 13))	('Glioblastomas', 'Disease', 'MESH:D005909', (0, 13))	('function', 'MPA', (87, 95))	('defects', 'Var', (47, 54))	('Glioblastomas', 'Phenotype', 'HP:0012174', (0, 13))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))
36116	30410731	The role primary cilia play during GBM pathogenesis may be dual, as there is evidence that the presence or loss of cilia, or associated signaling pathways, can promote tumor growth.	('promote', 'PosReg', (160, 167))	('tumor', 'Disease', (168, 173))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('presence', 'Var', (95, 103))	('loss of cilia', 'Disease', (107, 120))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('loss of cilia', 'Disease', 'MESH:C536287', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
36117	30410731	Mutations in the SHH signaling pathway, which primary cilia are known to transduce, can promote tumor growth in a fraction of GBMs.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', (96, 101))	('GBM', 'Phenotype', 'HP:0012174', (126, 129))	('SHH', 'Gene', '6469', (17, 20))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('SHH', 'Gene', (17, 20))
36120	30410731	Disrupting KIF3A and IFT88 in an SHH-responsive GBM cell line slowed tumor progression, whereas disrupting KIF3A in other SHH non-responsive cell lines either accelerated or had no effect on tumor growth.	('KIF3A', 'Gene', (11, 16))	('SHH', 'Gene', '6469', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('IFT88', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SHH', 'Gene', (122, 125))	('KIF3A', 'Gene', '11127', (107, 112))	('Disrupting', 'Var', (0, 10))	('SHH', 'Gene', (33, 36))	('KIF3A', 'Gene', '11127', (11, 16))	('disrupting', 'Var', (96, 106))	('slowed', 'NegReg', (62, 68))	('IFT88', 'Gene', '8100', (21, 26))	('tumor', 'Disease', (191, 196))	('KIF3A', 'Gene', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (69, 74))	('SHH', 'Gene', '6469', (122, 125))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('accelerated', 'PosReg', (159, 170))
36121	30410731	Moreover, CRISPR/Cas9 ablation of KIF3A and PCM1, another ciliogenesis gene, enhanced the sensitivity of GBM cells to the standard-of-care chemotherapeutic agent temozolomide (TMZ).	('enhanced', 'PosReg', (77, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (176, 179))	('PCM1', 'Gene', (44, 48))	('ablation', 'Var', (22, 30))	('sensitivity', 'MPA', (90, 101))	('temozolomide', 'Chemical', 'MESH:D000077204', (162, 174))	('PCM1', 'Gene', '5108', (44, 48))	('KIF3A', 'Gene', (34, 39))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))	('KIF3A', 'Gene', '11127', (34, 39))
36138	30410731	After FAC-sorting and expanding the GFP+ clones, we identified several cell lines that displayed Arl13b:GFP+ cilia in all gliomaspheres, under fluorescence and without the need for immunostaining (Fig.	('Arl13b', 'Gene', (97, 103))	('FAC', 'Gene', '2176', (6, 9))	('glioma', 'Disease', (122, 128))	('FAC', 'Gene', (6, 9))	('GFP+', 'Var', (104, 108))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
36140	30410731	We found that virtually all aaTub+ cilia were also GFP+ (Fig.	('GFP+', 'Var', (51, 55))	('aaTub', 'Gene', '10376', (28, 33))	('aaTub', 'Gene', (28, 33))
36148	30410731	Across all parental cell lines, we observed puncta that were adjacent to the tips of Arl13b+/aaTub+ cilia and, although Arl13b:GFP+ or Arl13b+, were aaTub- (Fig.	('aaTub', 'Gene', '10376', (149, 154))	('Arl13b:GFP+', 'Var', (120, 131))	('aaTub', 'Gene', '10376', (93, 98))	('aaTub', 'Gene', (93, 98))	('Arl13b+', 'Var', (135, 142))	('aaTub', 'Gene', (149, 154))
36154	30410731	These data support the possibility that ciliary tip excisions in GBM cells may utilize an F-actin-dependent mechanism similar to the one described in non-cancerous cells.	('F-actin-dependent', 'MPA', (90, 107))	('non-cancer', 'Disease', (150, 160))	('excisions', 'Var', (52, 61))	('non-cancer', 'Disease', 'MESH:D009369', (150, 160))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
36165	30410731	A recent study found that Arl13b directly binds to and stabilizes SMO and that higher levels of Arl13b prevent the degradation of SMO and accelerate tumor growth.	('binds', 'Interaction', (42, 47))	('SMO', 'Gene', '6608', (66, 69))	('SMO', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('stabilizes', 'MPA', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('degradation', 'MPA', (115, 126))	('tumor', 'Disease', (149, 154))	('prevent', 'NegReg', (103, 110))	('accelerate', 'PosReg', (138, 148))	('Arl13b', 'Var', (96, 102))	('SMO', 'Gene', '6608', (130, 133))	('SMO', 'Gene', (130, 133))
36177	30410731	However, those studies found that the fragment tips contained both Arl13b and aaTub, whereas we and others have found that the Arl13b+ vesicles are weak or negative for aaTub.	('Arl13b', 'Var', (67, 73))	('aaTub', 'Gene', '10376', (78, 83))	('aaTub', 'Gene', (78, 83))	('contained', 'Reg', (52, 61))	('aaTub', 'Gene', '10376', (169, 174))	('aaTub', 'Gene', (169, 174))
36180	30410731	We did observe cilia that appeared to be in the process of budding were extending from cells lacking Ki67, which suggests that this phenomenon might occur in quiescent glioma cells, similarly to non-cancerous cells.	('cilia', 'CPA', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('non-cancer', 'Disease', (195, 205))	('non-cancer', 'Disease', 'MESH:D009369', (195, 205))	('Ki67', 'Var', (101, 105))	('glioma', 'Disease', (168, 174))
36198	30410731	Overexpressing Arl13b in GBM cells also led to some intriguing changes in the SHH signaling pathway and cell proliferation.	('SHH', 'Gene', '6469', (78, 81))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('cell proliferation', 'CPA', (104, 122))	('Arl13b', 'Gene', (15, 21))	('Overexpressing', 'Var', (0, 14))	('changes', 'Reg', (63, 70))	('SHH', 'Gene', (78, 81))
36199	30410731	Most Arl13b:GFP+ L0 clones displayed SMO in their cilia as well as increased cell proliferation, two features that we previously found to only occur after SHH exposure in the WT parental cell line.	('SHH', 'Gene', '6469', (155, 158))	('cilia', 'CPA', (50, 55))	('SHH', 'Gene', (155, 158))	('GFP+ L0', 'Var', (12, 19))	('SMO', 'Gene', '6608', (37, 40))	('increased', 'PosReg', (67, 76))	('Arl13b', 'Gene', (5, 11))	('SMO', 'Gene', (37, 40))	('cell proliferation', 'CPA', (77, 95))
36200	30410731	The enrichment of SMO in the cilia of Arl13b:GFP+ clones may have been due to increased Arl13b binding, which prevents SMO degradation.	('GFP+', 'Var', (45, 49))	('SMO', 'Gene', '6608', (18, 21))	('SMO', 'Gene', (18, 21))	('increased', 'PosReg', (78, 87))	('SMO', 'Gene', '6608', (119, 122))	('SMO', 'Gene', (119, 122))	('Arl13b', 'Protein', (88, 94))	('binding', 'Interaction', (95, 102))	('prevents', 'NegReg', (110, 118))
36204	30410731	However, the loss of Arl13b has also been shown to lead to increased SMO levels in the primary cilia of non-cancer cells, to ultrastructural defects in the cilium, and to aberrant polarity and proliferation of neural stem cells in the developing brain.	('Arl13b', 'Gene', (21, 27))	('SMO', 'Gene', '6608', (69, 72))	('non-cancer', 'Disease', 'MESH:D009369', (104, 114))	('SMO', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('loss', 'Var', (13, 17))	('proliferation', 'CPA', (193, 206))	('aberrant polarity', 'CPA', (171, 188))	('increased', 'PosReg', (59, 68))	('defects', 'NegReg', (141, 148))	('non-cancer', 'Disease', (104, 114))
36206	30410731	Dysregulated levels of Arl13b in glioma cells may have significant consequences on the SHH signaling pathway and tumor cell proliferation.	('tumor', 'Disease', (113, 118))	('glioma', 'Disease', (33, 39))	('consequences', 'Reg', (67, 79))	('SHH', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('Arl13b', 'Gene', (23, 29))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('SHH', 'Gene', '6469', (87, 90))
36207	30410731	A recent study has shown that the disruption of Arl13b inhibits cilia-dependent oncogenic Shh overactivation in medulloblastoma.	('medulloblastoma', 'Phenotype', 'HP:0002885', (112, 127))	('medulloblastoma', 'Disease', 'MESH:D008527', (112, 127))	('inhibits', 'NegReg', (55, 63))	('Shh', 'Gene', '6469', (90, 93))	('disruption', 'Var', (34, 44))	('medulloblastoma', 'Disease', (112, 127))	('Arl13b', 'Gene', (48, 54))	('Shh', 'Gene', (90, 93))
36214	30410731	DMEM/F12 medium, B27 (cat # 17504-044), EGF (cat # PHG0311), bFGF (cat # PHG0026), and antibiotics (cat# 15240-062) were obtained from Gibco (Life Technologies, CA).	('B27', 'Gene', (17, 20))	('EGF', 'Gene', (40, 43))	('DMEM', 'Chemical', '-', (0, 4))	('B27', 'Gene', '56246', (17, 20))	('bFGF', 'Gene', (61, 65))	('cat # 17504-044', 'Var', (22, 37))	('EGF', 'Gene', '1950', (40, 43))	('cat# 15240-062', 'Var', (100, 114))	('F12 medium', 'Chemical', '-', (5, 15))	('cat # PHG0311', 'Var', (45, 58))	('bFGF', 'Gene', '2247', (61, 65))
36227	30410731	Primary antibodies used for immunocytochemistry (ICC) or immunohistochemistry (IHC) included mouse anti-acetylated alpha-tubulin [1:3000 (ICC/IHC); Sigma (cat # T6793; lot # 088K4829)], mouse anti-Arl13b [1:1000 (ICC); clone N295B/66; NeuroMab], rabbit anti-Arl13b [1:3000 (IHC); Proteintech (cat # 17711-1-AP; lot # 00017960)], rabbit anti-Ki67 [1:200 (ICC); Vector (cat # VP-RM04; lot # V0523)], rabbit anti-SMO [1:1000 (ICC); Abcam (cat #ab38686; lot #GR198520-1)], and rabbit anti-PCM1 [1:1000 (ICC/IHC); Bethyl Laboratories (cat # A301-150A; lot # A301-150A-1)].	('mouse', 'Species', '10090', (93, 98))	('PCM1', 'Gene', '5108', (485, 489))	('N295B', 'Var', (225, 230))	('N295B', 'SUBSTITUTION', 'None', (225, 230))	('PCM1', 'Gene', (485, 489))	('alpha-tubulin', 'Gene', (115, 128))	('rabbit', 'Species', '9986', (246, 252))	('rabbit', 'Species', '9986', (473, 479))	('mouse', 'Species', '10090', (186, 191))	('SMO', 'Gene', (410, 413))	('rabbit', 'Species', '9986', (329, 335))	('alpha-tubulin', 'Gene', '10376', (115, 128))	('SMO', 'Gene', '6608', (410, 413))	('rabbit', 'Species', '9986', (398, 404))
36230	30410731	To label F-actin, Alexa Fluor 488 (cat # A12379; lot # 44507A) and/or Alexa Fluor 568 (cat # A12380; lot # 41C1-1)-conjugated phalloidin (1:100; Invitrogen) were used during the secondary antibody step.	('cat # A12380;', 'Var', (87, 100))	('Alexa Fluor 488', 'Chemical', '-', (18, 33))	('phalloidin', 'Chemical', 'MESH:D010590', (126, 136))	('cat # A12379', 'Var', (35, 47))	('Alexa Fluor 568', 'Chemical', '-', (70, 85))
36283	29343677	The univariate PFS analysis showed that complete surgical resection (P < 0.0001), age below 65 years (P = 0.002), frontal location (P = 0.0001), pre-operative KPS > 70) (P = 0.004) and XRT plus concomitant and adjuvant TMZ (P = 0.0001) were significant predictors of lengthier PFS.	('KPS > 70', 'Var', (159, 167))	('TMZ', 'Chemical', 'MESH:D000077204', (219, 222))	('lengthier PFS', 'Disease', (267, 280))	('XRT', 'Chemical', '-', (185, 188))
36294	29343677	Pre-operative KPS was associated with better OS only at univariate Cox regression.	('KPS', 'Var', (14, 17))	('OS', 'Chemical', '-', (45, 47))	('Cox', 'Gene', '1351', (67, 70))	('Cox', 'Gene', (67, 70))
36295	29343677	This issue may be explained by the fact that in our series nearly every patient had a KPS > 70 (102 patients out of 139) with subsequent reduction of statistical significance.	('reduction', 'NegReg', (137, 146))	('patient', 'Species', '9606', (72, 79))	('patient', 'Species', '9606', (100, 107))	('KPS', 'Var', (86, 89))	('patients', 'Species', '9606', (100, 108))
36326	29209782	The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression.	('manipulation', 'Var', (76, 88))	('tumor', 'Disease', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('men', 'Species', '9606', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cancer', 'Disease', (49, 55))
36329	29209782	These immunotherapeutics encompass antibody-drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells.	('modified', 'Var', (85, 93))	('chimeric antigen receptor', 'Gene', '9970', (94, 119))	('chimeric antigen receptor', 'Gene', (94, 119))
36344	29209782	Classical gliomas often present with epidermal growth factor receptor (EGFR) mutations, amplification of chromosome 7, and have genetic signatures most indicative of astrocytic origin.	('Classical gliomas', 'Disease', (0, 17))	('gliomas', 'Phenotype', 'HP:0009733', (10, 17))	('amplification', 'Var', (88, 101))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('present', 'Reg', (24, 31))	('EGFR', 'Gene', '1956', (71, 75))	('mutations', 'Var', (77, 86))	('epidermal growth factor receptor', 'Gene', (37, 69))	('EGFR', 'Gene', (71, 75))	('Classical gliomas', 'Disease', 'MESH:D005910', (0, 17))
36345	29209782	Proneural tumors commonly have isocitrate dehydrogenase 1 (IDH1) and platelet derived growth factor receptor A (PDGFRA) mutations and express genes indicative of oligodendroglial origin.	('PDGFRA', 'Gene', (112, 118))	('IDH1', 'Gene', '3417', (59, 63))	('express', 'Reg', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mutations', 'Var', (120, 129))	('PDGFRA', 'Gene', '5156', (112, 118))	('isocitrate dehydrogenase 1', 'Gene', (31, 57))	('IDH1', 'Gene', (59, 63))	('isocitrate dehydrogenase 1', 'Gene', '3417', (31, 57))
36419	29209782	For example, exploiting the fact that glioma stem cells upregulate the poliovirus receptor, CD155, a genetically engineered poliovirus, PVSRIPO, was designed to efficiently and specifically target cancer cells, thus causing immunogenic cell death, leading to the release of tumor-derived debris and viral antigen, which, in turn, is taken up by DCs and presented to T cells to initiate an anti-tumoral immune response to both the viral and tumoral antigens.	('tumor', 'Disease', (394, 399))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('glioma', 'Phenotype', 'HP:0009733', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('tumor', 'Disease', (274, 279))	('poliovirus', 'Species', '138950', (71, 81))	('tumor', 'Disease', (440, 445))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumoral', 'Disease', (394, 401))	('tumoral', 'Disease', 'MESH:D009369', (394, 401))	('tumor', 'Disease', 'MESH:D009369', (440, 445))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('cancer', 'Disease', (197, 203))	('poliovirus', 'Species', '138950', (124, 134))	('CD155', 'Var', (92, 97))	('tumoral', 'Disease', (440, 447))	('tumoral', 'Disease', 'MESH:D009369', (440, 447))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('glioma', 'Disease', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('causing', 'Reg', (216, 223))	('release', 'MPA', (263, 270))	('glioma', 'Disease', 'MESH:D005910', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('upregulate', 'PosReg', (56, 66))
36421	29209782	In the case of most genetic therapies, glioma-derived cells selectively receive a viral thymidine kinase (TK) gene and patients are administered either ganciclovir (GCV) or valacyclovir, irreparably damaging the DNA of the cells expressing the viral TK, leading to cell death, and hopefully eliciting a T-cell mediated immune response.	('glioma', 'Disease', (39, 45))	('ganciclovir', 'Chemical', 'MESH:D015774', (152, 163))	('patients', 'Species', '9606', (119, 127))	('gene', 'Var', (110, 114))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('DNA', 'MPA', (212, 215))	('cell death', 'CPA', (265, 275))	('leading to', 'Reg', (254, 264))	('eliciting', 'Reg', (291, 300))	('TK', 'Gene', (106, 108))	('GCV', 'Chemical', 'MESH:D015774', (165, 168))	('damaging', 'Reg', (199, 207))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('valacyclovir', 'Chemical', 'MESH:D000077483', (173, 185))
36424	29209782	Aside from these few examples, genetically modified HSV, reovirus, Newcastle disease virus, other adenoviral vectors, and measles are currently being evaluated in clinical trials for glioma therapy as well.	('measles', 'Species', '11234', (122, 129))	('glioma', 'Disease', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('genetically', 'Var', (31, 42))	('reovirus', 'Species', '10891', (57, 65))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('Newcastle disease virus', 'Species', '11176', (67, 90))
36433	29209782	In addition to preventing the activation of checkpoint blockade to promote CTL functionality, depleting T regulatory cells (Tregs) to reduce immunosuppression from the tumor microenvironment is touted as another potential therapeutic angle.	('tumor', 'Disease', (168, 173))	('men', 'Species', '9606', (186, 189))	('depleting', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('immunosuppression', 'MPA', (141, 158))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('promote', 'PosReg', (67, 74))
36443	29209782	As a proof of principle, treatment with pembroluzimab, a PD-1 blocking antibody, was reported to cause massive lymphocytic infiltration of tumor tissue and radiographic tumor reduction in the case of a patient with a hyper-mutated GBM.	('lymphocytic infiltration of tumor', 'Disease', (111, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('lymphocytic infiltration of tumor', 'Disease', 'MESH:D017254', (111, 144))	('pembroluzimab', 'Var', (40, 53))	('patient', 'Species', '9606', (202, 209))	('pembroluzimab', 'Chemical', '-', (40, 53))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('reduction', 'NegReg', (175, 184))	('tumor', 'Disease', (169, 174))	('men', 'Species', '9606', (30, 33))
36444	29209782	A phase II clinical trial evaluating the efficacy of durvalumab which targets PD-L1 in recurrent GBM is ongoing and may benefit patients with a select immune signature in their tumors (NCT02336165).	('benefit', 'PosReg', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('durvalumab', 'Chemical', 'MESH:C000613593', (53, 63))	('PD-L1', 'Gene', (78, 83))	('GBM', 'Disease', (97, 100))	('NCT02336165', 'Var', (185, 196))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('patients', 'Species', '9606', (128, 136))
36456	29209782	Other groups have shown that pharmacological depletion of GAMs from tumors, in a similar fashion, helps to slow tumor progression.	('tumor', 'Disease', (68, 73))	('pharmacological', 'Var', (29, 44))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('GAM', 'Chemical', '-', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (112, 117))	('slow', 'NegReg', (107, 111))
36458	29209782	PLX3397 is a CSF1R and c-Kit inhibitor, which selectively kills CSF1R-expressing macrophages and microglia.	('c-Kit', 'Gene', (23, 28))	('c-Kit', 'Gene', '3815', (23, 28))	('microglia', 'CPA', (97, 106))	('kills', 'NegReg', (58, 63))	('PLX3397', 'Chemical', 'MESH:C000600259', (0, 7))	('PLX3397', 'Var', (0, 7))
36459	29209782	It was shown that mice given oral PLX3397 exhibited less GAM infiltrate in tumors and less invasive tumors, overall.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('PLX3397', 'Var', (34, 41))	('GAM', 'Chemical', '-', (57, 60))	('GAM infiltrate in', 'CPA', (57, 74))	('mice', 'Species', '10090', (18, 22))	('tumors', 'Disease', (100, 106))	('invasive tumors', 'Disease', (91, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('invasive tumors', 'Disease', 'MESH:D009369', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PLX3397', 'Chemical', 'MESH:C000600259', (34, 41))	('tumors', 'Disease', (75, 81))	('less', 'NegReg', (52, 56))	('less', 'NegReg', (86, 90))
36471	29209782	showed that the administration of a bispecific antibody against Ang-2 and VEGF was able to promote an anti-tumorigenic polarization of GAMs in both a syngeneic orthotopic and a xenograft murine glioma model.	('murine', 'Species', '10090', (187, 193))	('promote', 'PosReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('glioma', 'Disease', (194, 200))	('Ang-2', 'Gene', (64, 69))	('tumor', 'Disease', (107, 112))	('VEGF', 'Gene', (74, 78))	('bispecific antibody', 'Var', (36, 55))	('Ang-2', 'Gene', '11731', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('GAM', 'Chemical', '-', (135, 138))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))
36478	29209782	It can downregulate perforin, granzyme A/B, IFNgamma, and FasL expression by CTLs, which are all mediators of CTL-mediated cytotoxicity.	('cytotoxicity', 'Disease', (123, 135))	('granzyme A/B', 'Gene', '3001;3002', (30, 42))	('FasL', 'Gene', (58, 62))	('IFNgamma', 'Gene', (44, 52))	('FasL', 'Gene', '356', (58, 62))	('IFNgamma', 'Gene', '3458', (44, 52))	('perforin', 'Protein', (20, 28))	('downregulate', 'NegReg', (7, 19))	('cytotoxicity', 'Disease', 'MESH:D064420', (123, 135))	('CTLs', 'Var', (77, 81))	('granzyme A/B', 'Gene', (30, 42))
36487	29209782	CC122, for example works by causing the degradation of Ikaros and Aiolos in cells leading to enhancement in the transcription of IFN response elements which all serve to boost anti-tumoral immunity.	('men', 'Species', '9606', (100, 103))	('men', 'Species', '9606', (145, 148))	('boost', 'PosReg', (170, 175))	('enhancement', 'PosReg', (93, 104))	('CC122', 'Var', (0, 5))	('IFN', 'Gene', (129, 132))	('tumoral', 'Disease', (181, 188))	('tumoral', 'Disease', 'MESH:D009369', (181, 188))	('Ikaros', 'Gene', '10320', (55, 61))	('Ikaros', 'Gene', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('IFN', 'Gene', '3439', (129, 132))	('transcription', 'MPA', (112, 125))
36507	24351290	For example, common molecular alterations identified in low-grade oligodendrogliomas and astrocytomas are allelic loss of 1p and 19q and mutations in p53, respectively, whereas grade 3 and 4 astrocytomas typically are driven by alterations in phosphoinositide 3-kinase (PI3K), EGFR, VEGF, and PTEN signaling.	('VEGF', 'Gene', '7422', (283, 287))	('astrocytomas', 'Disease', (191, 203))	('PTEN', 'Gene', '5728', (293, 297))	('alterations', 'Reg', (228, 239))	('EGFR', 'Gene', '1956', (277, 281))	('astrocytomas', 'Disease', (89, 101))	('VEGF', 'Gene', (283, 287))	('p53', 'Gene', '7157', (150, 153))	('oligodendrogliomas', 'Disease', (66, 84))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('p53', 'Gene', (150, 153))	('astrocytomas', 'Disease', 'MESH:D001254', (191, 203))	('astrocytomas', 'Disease', 'MESH:D001254', (89, 101))	('loss', 'NegReg', (114, 118))	('EGFR', 'Gene', (277, 281))	('rat', 'Species', '10116', (232, 235))	('PTEN', 'Gene', (293, 297))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (66, 84))	('mutations', 'Var', (137, 146))	('rat', 'Species', '10116', (34, 37))
36508	24351290	More recently, mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) have been identified in low-grade glioma and secondary glioblastoma, which were then discovered to form the oncometabolite 2-hydroxyglutarate (2-HG) that demonstrated the capacity to regulate global epigenetic programs in these tumors.	('tumors', 'Disease', (311, 317))	('rat', 'Species', '10116', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (206, 224))	('mutations', 'Var', (15, 24))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('IDH1', 'Gene', (77, 81))	('glioblastoma', 'Disease', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('IDH1', 'Gene', '3417', (77, 81))	('rat', 'Species', '10116', (220, 223))	('rat', 'Species', '10116', (244, 247))	('glioma', 'Disease', (117, 123))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))
36520	24351290	GSH synthesis through cystine uptake has been previously described to play an important role in glioma cell survival during redox stress and hypoxia and modulating this metabolic pathway has demonstrated therapeutic potential.	('GSH', 'Chemical', 'MESH:D005978', (0, 3))	('modulating', 'Var', (153, 163))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('rat', 'Species', '10116', (198, 201))	('hypoxia', 'Disease', 'MESH:D000860', (141, 148))	('cystine', 'Chemical', 'MESH:D003553', (22, 29))	('hypoxia', 'Disease', (141, 148))	('glioma', 'Disease', (96, 102))
36532	24351290	Mass spectrometer conditions were selective reaction monitoring, negative ionization mode, and HESI source, and monitored transitions were CSA, m/z 152 >= 88; CSA-D4, m/z 156 >= 92.	('m/z 156 >= 92', 'Var', (167, 180))	('CSA-D4', 'Chemical', '-', (159, 165))	('CSA', 'Chemical', 'MESH:C013461', (139, 142))	('m/z 152 >= 88', 'Var', (144, 157))	('CSA', 'Chemical', 'MESH:C013461', (159, 162))
36582	24351290	On the basis of the initial observation of CSA attenuating cellular respiration, we sought to determine whether pretreating cells with CSA could modulate pyruvate-induced oxygen consumption.	('CSA', 'Var', (43, 46))	('oxygen', 'Chemical', 'MESH:D010100', (171, 177))	('cellular respiration', 'MPA', (59, 79))	('pyruvate', 'Chemical', 'MESH:D019289', (154, 162))	('modulate', 'Reg', (145, 153))	('CSA', 'Chemical', 'MESH:C013461', (135, 138))	('pyruvate-induced oxygen consumption', 'MPA', (154, 189))	('CSA', 'Chemical', 'MESH:C013461', (43, 46))	('attenuating', 'NegReg', (47, 58))	('rat', 'Species', '10116', (73, 76))
36599	24351290	Dichloroacetate has been previously shown to inhibit PDH kinase (PDK), which is an endogenous inhibitor of PDH.	('PDH', 'Gene', '54704', (107, 110))	('Dichloroacetate', 'Var', (0, 15))	('PDH', 'Gene', (53, 56))	('Dichloroacetate', 'Chemical', 'MESH:D003999', (0, 15))	('PDH', 'Gene', '54704', (53, 56))	('PDH', 'Gene', (107, 110))	('inhibit', 'NegReg', (45, 52))
36604	24351290	Similar to the metabolism findings, pyruvate addition led to an expected increase in oxidative phosphorylation, resulting in a decrease in mitochondrial membrane potential.	('pyruvate', 'Var', (36, 44))	('increase', 'PosReg', (73, 81))	('decrease', 'NegReg', (127, 135))	('mitochondrial membrane potential', 'MPA', (139, 171))	('oxidative phosphorylation', 'MPA', (85, 110))	('pyruvate', 'Chemical', 'MESH:D019289', (36, 44))
36606	24351290	We went on to determine the mechanism by which CSA inhibits cellular respiration in our described models.	('CSA', 'Var', (47, 50))	('inhibits', 'NegReg', (51, 59))	('rat', 'Species', '10116', (74, 77))	('CSA', 'Chemical', 'MESH:C013461', (47, 50))	('cellular respiration', 'MPA', (60, 80))
36613	24351290	S5D, the addition of pyruvate, but not glucose, had an expected increase in oxygen consumption in isolated mitochondria.	('oxygen consumption in isolated mitochondria', 'MPA', (76, 119))	('pyruvate', 'Chemical', 'MESH:D019289', (21, 29))	('oxygen', 'Chemical', 'MESH:D010100', (76, 82))	('glucose', 'Chemical', 'MESH:D005947', (39, 46))	('pyruvate', 'Var', (21, 29))	('increase', 'PosReg', (64, 72))
36628	24351290	4A, U251 shCDO cells had a significantly decreased growth when compared with shControl (P = 0.004), with Western blot analysis performed on excised tumors demonstrating a 67% and 91% decrease in CDO1 expression (Fig.	('shControl', 'Chemical', '-', (77, 86))	('U251', 'CellLine', 'CVCL:0021', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('rat', 'Species', '10116', (162, 165))	('decrease', 'NegReg', (183, 191))	('CDO1', 'Gene', (195, 199))	('decreased', 'NegReg', (41, 50))	('tumors', 'Disease', (148, 154))	('U251', 'Var', (4, 8))	('expression', 'MPA', (200, 210))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('growth', 'MPA', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('decreased growth', 'Phenotype', 'HP:0001510', (41, 57))
36629	24351290	U251 shCDO cells led to increased survival when compared with vector control (P = 0.01), with IHC performed on tumor sections confirming decreased CDO1 expression in these tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('U251', 'Var', (0, 4))	('tumors', 'Disease', (172, 178))	('CDO1', 'Gene', (147, 151))	('tumor', 'Disease', (172, 177))	('U251', 'CellLine', 'CVCL:0021', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('decreased', 'NegReg', (137, 146))	('expression', 'MPA', (152, 162))	('increased', 'PosReg', (24, 33))
36631	24351290	Of these, perhaps one of the most notable has been the identification of mutations in the metabolic enzyme IDH1 in low-grade glioma and secondary glioblastoma.	('glioma', 'Disease', (125, 131))	('IDH1', 'Gene', (107, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('IDH1', 'Gene', '3417', (107, 111))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('glioblastoma', 'Disease', (146, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))	('mutations', 'Var', (73, 82))
36632	24351290	This led to a series of contributions underscoring the elegant complexity of tumorigenesis, linking a genetic mutation with the formation of a neomorphic enzyme and novel oncometabolite, 2-HG, which in turn, orchestrates specific epigenetic programs defining a glioma subtype.	('glioma subtype', 'Disease', (261, 275))	('rat', 'Species', '10116', (215, 218))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('orchestrates', 'Reg', (208, 220))	('mutation', 'Var', (110, 118))	('tumor', 'Disease', (77, 82))	('glioma subtype', 'Disease', 'MESH:D005910', (261, 275))
36645	24351290	They went on to show cystine uptake was via the system xc- transporter, which mediates the exchange of extracellular cystine and intracellular glutamate, and blocking this exchange attenuated tumor growth in vivo.	('cystine', 'Chemical', 'MESH:D003553', (21, 28))	('tumor', 'Disease', (192, 197))	('glutamate', 'Chemical', 'MESH:D018698', (143, 152))	('blocking', 'Var', (158, 166))	('cystine', 'Chemical', 'MESH:D003553', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('attenuated', 'NegReg', (181, 191))
36653	24351290	Anso and colleagues identified the capacity of c-MYC to attenuate both baseline OCR and spare respiratory capacity in osteogenic sarcoma models and Sandulache and colleagues identified a diminished spare respiratory capacityinp53 mutated head and neck cancer models.	('osteogenic sarcoma', 'Disease', (118, 136))	('spare respiratory capacity', 'MPA', (88, 114))	('osteogenic sarcoma', 'Phenotype', 'HP:0002669', (118, 136))	('c-MYC', 'Gene', '4609', (47, 52))	('head and neck cancer', 'Phenotype', 'HP:0012288', (238, 258))	('rat', 'Species', '10116', (99, 102))	('rat', 'Species', '10116', (209, 212))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('neck cancer', 'Disease', 'MESH:D006258', (247, 258))	('neck cancer', 'Disease', (247, 258))	('c-MYC', 'Gene', (47, 52))	('p53', 'Gene', '7157', (226, 229))	('attenuate', 'NegReg', (56, 65))	('baseline OCR', 'MPA', (71, 83))	('p53', 'Gene', (226, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('diminished', 'NegReg', (187, 197))	('osteogenic sarcoma', 'Disease', 'MESH:D012516', (118, 136))	('mutated', 'Var', (230, 237))
36661	24351290	Interestingly, two recent reports identified methylation and silencing of CDO1 as a common event in tumorigenesis, suggesting its role as a tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('CDO1', 'Gene', (74, 78))	('silencing', 'NegReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('methylation', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (140, 145))
36662	24351290	Specifically, Dietrich and colleagues identified CDO1 promoter methylation in breast cancer and demonstrated its capacity to serve as a predictive factor for distant metastases.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('rat', 'Species', '10116', (103, 106))	('metastases', 'Disease', (166, 176))	('CDO1', 'Gene', (49, 53))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('methylation', 'Var', (63, 74))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
36663	24351290	Using a microarray-based approach, Brait and colleagues identified CDO1 expression to be modulated in colorectal cancer cell lines by promoter methylation and following treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine.	('colorectal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('modulated', 'Reg', (89, 98))	('promoter methylation', 'Var', (134, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('CDO1', 'Gene', (67, 71))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (212, 234))
36664	24351290	A high frequency of CDO1 promoter methylation in colon cancer was then identified when compared with normal colon, and findings were extended to several other malignancies, including breast, esophagus, lung, bladder, and gastric cancer.	('lung', 'Disease', (202, 206))	('gastric cancer', 'Disease', (221, 235))	('methylation', 'Var', (34, 45))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('CDO1', 'Gene', (20, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('bladder', 'Disease', (208, 215))	('colon cancer', 'Phenotype', 'HP:0003003', (49, 61))	('malignancies', 'Disease', (159, 171))	('breast', 'Disease', (183, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (221, 235))	('esophagus', 'Disease', (191, 200))	('colon cancer', 'Disease', 'MESH:D015179', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('colon cancer', 'Disease', (49, 61))
36680	28129148	Compared to the most recently proposed multi-stage unsupervised feature learning system (PSDnSPM), Multi-Scale-CSCSPM consistently achieves better performance over two distinct tumor types, with significantly less number of filters (i.e., 300 vs. 1024 on GBM; and 600 vs. 1024 on KIRC).	('Multi-Scale-CSCSPM', 'Var', (99, 117))	('better', 'PosReg', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
36730	26539408	Abnormally large collagen deposition is the most well-documented ECM alteration in many tumor types, and collagen deposition has been causally linked to an increase in mammary tumor and metastasis incidence.	('linked', 'Reg', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('increase', 'PosReg', (156, 164))	('metastasis', 'CPA', (186, 196))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Abnormally', 'Var', (0, 10))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
36734	26539408	First, the production of the glycosaminoglycan HA has been demonstrated to induce EMT in both normal and transformed epithelial cells in vitro [reviewed in Ref.	('glycosaminoglycan', 'Protein', (29, 46))	('EMT', 'CPA', (82, 85))	('production', 'Var', (11, 21))	('induce', 'PosReg', (75, 81))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
36736	26539408	However, overproduction of HA is not in itself enough to create an invasive phenotype, on its own it actually decreases cell motility and tumorigenesis.	('cell motility', 'CPA', (120, 133))	('tumor', 'Disease', (138, 143))	('HA', 'Chemical', 'MESH:D006820', (27, 29))	('decreases', 'NegReg', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('overproduction', 'Var', (9, 23))
36737	26539408	However, if the general turnover of HA is increased due to high levels of both HA synthases and hyaluronidases, i.e., increased levels of LMW-HA, then this leads to an increase in cell motility in vitro.	('increase', 'PosReg', (168, 176))	('increased', 'PosReg', (42, 51))	('levels', 'MPA', (128, 134))	('LMW-HA', 'Var', (138, 144))	('HA', 'Chemical', 'MESH:D006820', (79, 81))	('increased', 'PosReg', (118, 127))	('HA', 'Chemical', 'MESH:D006820', (142, 144))	('cell motility in vitro', 'CPA', (180, 202))	('HA', 'Chemical', 'MESH:D006820', (36, 38))
36747	26539408	Furthermore, LMW-HA is also angiogenic, so the production of LMW-HA fragments in the tumor microenvironment can thus compromise the tumor vessel integrity and promote angiogenesis, making it easier for cancer cells to intravasate and continue the metastatic process.	('tumor', 'Disease', (85, 90))	('metastatic process', 'CPA', (247, 265))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('HA', 'Chemical', 'MESH:D006820', (17, 19))	('HA', 'Chemical', 'MESH:D006820', (65, 67))	('fragments', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('easier', 'PosReg', (191, 197))	('angiogenesis', 'CPA', (167, 179))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('compromise', 'NegReg', (117, 127))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', (202, 208))	('LMW-HA', 'Gene', (61, 67))	('promote', 'PosReg', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
36750	26539408	Recently, it has been reported that inhibition of collagen synthesis in human MDA-MB231 breast cancer xenografts leads to a decrease in local invasion into the surrounding adipose tissue and to a decrease in metastasis to both the draining lymph nodes and lungs.	('inhibition', 'Var', (36, 46))	('decrease', 'NegReg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('local invasion into the surrounding adipose tissue', 'CPA', (136, 186))	('collagen synthesis', 'MPA', (50, 68))	('human', 'Species', '9606', (72, 77))	('MDA-MB231 breast cancer', 'Disease', 'MESH:D001943', (78, 101))	('metastasis to', 'CPA', (208, 221))	('decrease', 'NegReg', (124, 132))	('MDA-MB231 breast cancer', 'Disease', (78, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
36764	26539408	A further mediator of cell motility is tenascin C. By binding to either integrin alphavbeta1 or alphavbeta6, recombinant tenascin C induced a change in the morphology of the breast cancer cell line MCF-7 to a more mesenchymal phenotype (Figure 2).	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('morphology', 'CPA', (156, 166))	('change', 'Reg', (142, 148))	('alphavbeta6', 'Var', (96, 107))	('more mesenchymal phenotype', 'CPA', (209, 235))	('MCF-7', 'CellLine', 'CVCL:0031', (198, 203))	('binding', 'Interaction', (54, 61))
36765	26539408	were able to diminish the invasive potential of a metastatic breast cancer cell line by knocking down tenascin C expression.	('expression', 'MPA', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('diminish', 'NegReg', (13, 21))	('knocking', 'Var', (88, 96))	('tenascin', 'Protein', (102, 110))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
36786	26539408	The importance of cancer cell interaction with HA on endothelial cells in the process of extravasation is backed by a recent in vivo study, which showed that knockdown of the HA receptor CD44 in MDA-MB-231 breast cancer cells drastically decreased the number of experimental metastases in an intracardiac dissemination model.	('metastases', 'Disease', (275, 285))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('CD44', 'Gene', (187, 191))	('HA', 'Chemical', 'MESH:D006820', (175, 177))	('metastases', 'Disease', 'MESH:D009362', (275, 285))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('breast cancer', 'Disease', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('knockdown', 'Var', (158, 167))	('cancer', 'Disease', (213, 219))	('decreased', 'NegReg', (238, 247))	('CD44', 'Gene', '960', (187, 191))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('HA', 'Chemical', 'MESH:D006820', (47, 49))
36789	26539408	recently showed that the levels of circulating LMW-HA in the blood is an important factor for melanoma cell adhesion to endothelial cells.	('HA', 'Chemical', 'MESH:D006820', (51, 53))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('adhesion', 'CPA', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('LMW-HA', 'Var', (47, 53))
36791	26539408	Strikingly, elevated LMW-HA in serum also prevented spontaneous lung and lymph node metastasis of orthotopically implanted human MDA-MB-231 and mouse 4T1 breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('mouse', 'Species', '10090', (144, 149))	('LMW-HA', 'Var', (21, 27))	('HA', 'Chemical', 'MESH:D006820', (25, 27))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('prevented', 'NegReg', (42, 51))
36793	26539408	Blocking HARE or saturating it with HA can prevent direct binding of cancer cells to HARE+ cells through their HA-rich pericellular matrix and simultaneously the elevated blood levels of HA, created by lack of HARE-mediated clearance, might also saturate CD44 on the cancer cells, preventing them from utilizing this previously demonstrated important factor for extravasation.	('lack', 'NegReg', (202, 206))	('HARE', 'Gene', '55576', (210, 214))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('HARE', 'Gene', (85, 89))	('CD44', 'Gene', '960', (255, 259))	('HARE', 'Gene', (210, 214))	('HA', 'Chemical', 'MESH:D006820', (111, 113))	('CD44', 'Gene', (255, 259))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('extravasation', 'MPA', (362, 375))	('HA', 'Chemical', 'MESH:D006820', (85, 87))	('binding', 'Interaction', (58, 65))	('HARE', 'Gene', '55576', (9, 13))	('preventing', 'NegReg', (281, 291))	('blood levels', 'MPA', (171, 183))	('HA', 'Chemical', 'MESH:D006820', (187, 189))	('HA', 'Chemical', 'MESH:D006820', (36, 38))	('HARE', 'Gene', (9, 13))	('cancer', 'Disease', (267, 273))	('HA', 'Chemical', 'MESH:D006820', (210, 212))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', (69, 75))	('prevent', 'NegReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HA', 'Chemical', 'MESH:D006820', (9, 11))	('saturate', 'Var', (246, 254))	('HARE', 'Gene', '55576', (85, 89))
36797	26539408	Lysyl oxidase, LOXL2, or LOXL4 expression in the primary breast tumor leads to pre-metastatic deposition of collagen I in the lungs of mice (Figure 4), favoring the formation of metastases in the lungs.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('Lysyl oxidase', 'Gene', (0, 13))	('formation', 'CPA', (165, 174))	('LOXL4', 'Gene', '67573', (25, 30))	('breast tumor', 'Phenotype', 'HP:0100013', (57, 69))	('favoring', 'PosReg', (152, 160))	('LOXL2', 'Var', (15, 20))	('breast tumor', 'Disease', 'MESH:D001943', (57, 69))	('metastases', 'Disease', (178, 188))	('LOXL4', 'Gene', (25, 30))	('mice', 'Species', '10090', (135, 139))	('pre-metastatic', 'MPA', (79, 93))	('Lysyl oxidase', 'Gene', '16948', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('breast tumor', 'Disease', (57, 69))
36798	26539408	Furthermore, LOX-mediated cross-linking of collagen I increases the fibrotic response in lungs and livers of mice and helps form a favorable metastatic niche in these organs.	('LOX-mediated', 'Var', (13, 25))	('collagen I', 'Protein', (43, 53))	('increases', 'PosReg', (54, 63))	('fibrotic response', 'CPA', (68, 85))	('helps', 'PosReg', (118, 123))	('mice', 'Species', '10090', (109, 113))
36806	26539408	By combining the breast cancer model with periostin null mice, the authors could reveal that stromal periostin supports the survival and proliferation of cancer stem cells (CSCs, CD90+, and CD24+) through the activation of WNT signaling (Figure 4).	('CD24', 'Gene', '100133941', (190, 194))	('CD24', 'Gene', (190, 194))	('mice', 'Species', '10090', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('CD90+', 'Var', (179, 184))	('WNT signaling', 'Pathway', (223, 236))	('breast cancer', 'Disease', (17, 30))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('survival', 'CPA', (124, 132))	('supports', 'PosReg', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('proliferation', 'CPA', (137, 150))
36812	26539408	The tenascin C knockdown resulted in a 90% inhibition of lung colonization in either experimental or spontaneous lung metastases of these cells.	('knockdown', 'Var', (15, 24))	('inhibition', 'NegReg', (43, 53))	('lung colonization', 'CPA', (57, 74))	('lung metastases', 'Disease', (113, 128))	('lung metastases', 'Disease', 'MESH:D009362', (113, 128))	('tenascin C', 'Gene', (4, 14))
36814	26539408	used an inducible knockdown model narrowing down the time frame for the dependency on tumor-derived tenascin C. Interestingly, depriving the breast cancer cells of tenascin C only affected the outgrowth of metastases when they reached a certain size.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('metastases', 'Disease', 'MESH:D009362', (206, 216))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('depriving', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('metastases', 'Disease', (206, 216))	('affected', 'Reg', (180, 188))
36815	26539408	In pancreatic cancer, ectopic tenascin C expression in RIP-Taq2 mice significantly increased the establishment of micrometastases, whereas a tenascin C knockout reduced tumor cell engraftment in the lungs.	('reduced', 'NegReg', (161, 168))	('pancreatic cancer', 'Disease', (3, 20))	('increased', 'PosReg', (83, 92))	('ectopic', 'Var', (22, 29))	('RIP', 'Gene', '110628', (55, 58))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mice', 'Species', '10090', (64, 68))	('metastases', 'Disease', (119, 129))	('tenascin C', 'Gene', (30, 40))	('tumor', 'Disease', (169, 174))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('RIP', 'Gene', (55, 58))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
36819	26539408	Extravasated MDA-MB-231 cells with a knockdown of prolyl-4-hydroxylases, an enzyme essential for correct collagen biosynthesis, were able to survive but formed smaller lung metastases than their wild-type counterparts.	('smaller lung', 'Phenotype', 'HP:0002089', (160, 172))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (13, 23))	('knockdown', 'Var', (37, 46))	('prolyl-4-hydroxylases', 'Gene', (50, 71))	('lung metastases', 'Disease', 'MESH:D009362', (168, 183))	('smaller', 'NegReg', (160, 167))	('lung metastases', 'Disease', (168, 183))
36822	26539408	LOX-mediated cross-linking of collagen IV recruits CD11b+ BMDC to the metastatic niche in the lungs, and these CD11b+ cells further remodel the ECM into a favorable home for extravasating cancer cells, e.g., by laying down the proteoglycan versican (Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CD11b+', 'Var', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('remodel', 'Reg', (132, 139))
36823	26539408	Inhibiting versican production by CD11b+ BDMCs radically decreased the burden of lung metastases in a mouse model of spontaneous breast cancer, specifically preventing the progression from micrometastases to macrometastases.	('breast cancer', 'Disease', (129, 142))	('metastases', 'Disease', (86, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('metastases', 'Disease', (194, 204))	('metastases', 'Disease', 'MESH:D009362', (86, 96))	('Inhibiting', 'NegReg', (0, 10))	('mouse', 'Species', '10090', (102, 107))	('lung metastases', 'Disease', (81, 96))	('CD11b+ BDMCs', 'Var', (34, 46))	('metastases', 'Disease', 'MESH:D009362', (194, 204))	('lung metastases', 'Disease', 'MESH:D009362', (81, 96))	('metastases', 'Disease', (213, 223))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('preventing', 'NegReg', (157, 167))	('decreased', 'NegReg', (57, 66))	('metastases', 'Disease', 'MESH:D009362', (213, 223))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
36834	26539408	revealed an inverse time course of the role of tumor-endogenous and stromal tenascin C. While an induced knockdown of the protein diminished metastatic engraftment in the beginning, tumor cells induced myofibroblasts to produce tenascin C when the tumors reached a certain size, compensating the loss of the matricellular protein.	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', (182, 187))	('diminished', 'NegReg', (130, 140))	('knockdown', 'Var', (105, 114))	('tumors', 'Disease', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('metastatic engraftment', 'CPA', (141, 163))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
36837	26539408	Although having its main function in creating a metastatic niche and inducing WNT and NOTCH signaling pathways, tenascin C depletion did not correlate with a reduction of stem cell characteristics of the breast cancer cells in this study.	('inducing', 'Reg', (69, 77))	('reduction', 'NegReg', (158, 167))	('depletion', 'Var', (123, 132))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (204, 217))	('stem cell characteristics of', 'CPA', (171, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))
36851	26539408	Although hyaluronidase treatment of cancers produces LMW-HA fragments, which can increase angiogenesis and disrupt vessel integrity, PEGPH20 treatment of experimental pancreatic cancer in combination with chemotherapy increased overall survival and decreased the metastatic incidence.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('PEG', 'Gene', (133, 136))	('increase', 'PosReg', (81, 89))	('angiogenesis', 'CPA', (90, 102))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (167, 184))	('increased', 'PosReg', (218, 227))	('disrupt', 'NegReg', (107, 114))	('overall survival', 'CPA', (228, 244))	('LMW-HA', 'Var', (53, 59))	('metastatic incidence', 'CPA', (263, 283))	('vessel integrity', 'MPA', (115, 131))	('PEG', 'Gene', '5047', (133, 136))	('HA', 'Chemical', 'MESH:D006820', (57, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (167, 184))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('decreased', 'NegReg', (249, 258))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pancreatic cancer', 'Disease', (167, 184))
36852	26539408	It is conceivable that by stripping cancer cells of their pericellular matrix, the hyaluronidase treatment is sensitizing any extravasating cancer cells to immune cell lysis, in this way counteracting the effect of restoring tumor vessel function.	('extravasating', 'MPA', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('cancer', 'Disease', (36, 42))	('stripping', 'Var', (26, 35))	('cancer', 'Disease', (140, 146))	('tumor', 'Disease', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
36859	26539408	Several in vivo studies have reported promising inhibition of tumor growth and metastasis formation upon treatment with 4-MU [reviewed in Ref.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('4-MU', 'Chemical', 'MESH:D006923', (120, 124))	('tumor', 'Disease', (62, 67))	('4-MU [', 'Var', (120, 126))	('inhibition', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
36871	26539408	However, sHA fragments of a similar size correlate to increased lymphatic invasion and development of lymph node metastasis in colorectal cancer patients, suggesting that small sHA may promote tumor progression.	('patients', 'Species', '9606', (145, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('sHA', 'Chemical', '-', (177, 180))	('increased', 'PosReg', (54, 63))	('colorectal cancer', 'Disease', (127, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('sHA', 'Chemical', '-', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('promote', 'PosReg', (185, 192))	('development of lymph node metastasis', 'CPA', (87, 123))	('lymphatic invasion', 'CPA', (64, 82))	('small', 'Var', (171, 176))
36901	26539408	CP4H catalyzes the conversion of proline to hydroxyproline, facilitating the assembly of three procollagen proteins into a procollagen triple helix.	('assembly', 'MPA', (77, 85))	('hydroxyproline', 'Chemical', 'MESH:D006909', (44, 58))	('proline', 'Chemical', 'MESH:D011392', (51, 58))	('CP4H', 'Chemical', '-', (0, 4))	('CP4H', 'Var', (0, 4))	('proline', 'Chemical', 'MESH:D011392', (33, 40))
36902	26539408	Recent studies in preclinical breast cancer models have shown that inhibition of CP4H either completely prevents or dramatically decreases spontaneous metastasis to the lungs.	('inhibition', 'Var', (67, 77))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('spontaneous metastasis to the lungs', 'CPA', (139, 174))	('CP4H', 'Protein', (81, 85))	('CP4H', 'Chemical', '-', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('decreases', 'NegReg', (129, 138))
36908	26539408	In particular, combination treatment with gold-standard therapeutics seems to be a promising strategy, as targeting the macromolecules facilitates the delivery and efficacy of the standard treatment and inhibits protumorigenic signaling of the ECM itself.	('inhibits', 'NegReg', (203, 211))	('targeting', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('delivery', 'MPA', (151, 159))	('tumor', 'Disease', (215, 220))	('efficacy', 'MPA', (164, 172))	('facilitates', 'PosReg', (135, 146))	('mole', 'Phenotype', 'HP:0003764', (125, 129))
36929	32789014	Furthermore, CSCs generate cellular heterogeneity by installing a differentiation hierarchy leading to various distinct cell types present within the tumor.	('CSCs', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('installing', 'Reg', (53, 63))	('tumor', 'Disease', (150, 155))
36953	32789014	When the diameter of the tumor reached 3 mm, mice were infused with 13C5 glutamine (99% enrichment; Cambridge Isotope Laboratories, Andover, MA) through the jugular vein.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('13C', 'Chemical', 'MESH:C000615229', (68, 71))	('13C5 glutamine', 'Var', (68, 82))	('glutamine', 'Chemical', 'MESH:D005973', (73, 82))
36963	32789014	Fragment ions of m/z 258 (unenriched) and 263 (enriched) 13C5 glutamine were quantified for both standard and experimental samples.	('263', 'Var', (42, 45))	('13C5', 'Var', (57, 61))	('m/z 258', 'Var', (17, 24))	('13C', 'Chemical', 'MESH:C000615229', (57, 60))	('glutamine', 'Chemical', 'MESH:D005973', (62, 71))
36995	32789014	When the tumor reached 3 mm, the mice were infused with [U-13C]glutamine as a bolus over 1 min followed by a continuous 5-h infusion.	('[U-13C]glutamine', 'Var', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('[U-13C]glutamine', 'Chemical', '-', (56, 72))	('mice', 'Species', '10090', (33, 37))
37020	32789014	Given the energy-generating and biosynthetic roles that glutamine plays in growing cells, inhibition of glutaminolysis might have the potential to effectively target cancer cells.	('glutamine', 'Chemical', 'MESH:D005973', (56, 65))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('inhibition', 'Var', (90, 100))
37038	32789014	Other studies have shown that IDH1 mutation or the sole presence of cystine directly impacts glutamine dependency in different environmental contexts.	('glutamine', 'Chemical', 'MESH:D005973', (93, 102))	('impacts', 'Reg', (85, 92))	('glutamine dependency', 'MPA', (93, 113))	('IDH1', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))	('IDH1', 'Gene', '15926', (30, 34))	('cystine', 'Chemical', 'MESH:D003553', (68, 75))
37046	32789014	Importantly, targeting glutamine metabolism in our GBM models reduces tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reduces', 'NegReg', (62, 69))	('tumor', 'Disease', (70, 75))	('glutamine', 'Chemical', 'MESH:D005973', (23, 32))	('glutamine metabolism', 'MPA', (23, 43))	('targeting', 'Var', (13, 22))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
37051	32789014	Further investigations must determine whether inhibition of glutamine metabolism impacts mesenchymal tumor cells' sensibility to radiation and TMZ chemotherapy.	('inhibition', 'Var', (46, 56))	('metabolism impacts mesenchymal tumor', 'Disease', (70, 106))	('sensibility to radiation', 'Phenotype', 'HP:0011133', (114, 138))	('metabolism impacts mesenchymal tumor', 'Disease', 'MESH:C535700', (70, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('glutamine', 'Protein', (60, 69))	('glutamine', 'Chemical', 'MESH:D005973', (60, 69))	('TMZ', 'Chemical', 'MESH:D000077204', (143, 146))	('sensibility', 'MPA', (114, 125))
37054	32789014	(R35 CA220449) to R.J.D, Exploratory/Development Grant from NINDS (R21NS099950) to W.-P.G., and "Ligue contre le cancer" and Region Pays de la Loire to C.P.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('R35 CA220449', 'Var', (1, 13))	('R21NS099950', 'Var', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
37062	32547705	Further, osimertinib inhibited D317's growth in vitro and in both heterotopic and orthotopic xenograft models.	('osimertinib', 'Chemical', 'MESH:C000596361', (9, 20))	('inhibited', 'NegReg', (21, 30))	('D317', 'Var', (31, 35))	('growth', 'MPA', (38, 44))
37068	32547705	At least four major molecular forms have been identified: 1) wild-type EGFR with gene amplification; 2) EGFR with a large deletion in the extracellular domain (EGFRvIII); 3) EGFR with kinase domain duplication (EGFR-KDD); and 4) EGFR fused with SEPT-14 (EGFR-SEPT14).	('SEPT-14', 'Gene', (245, 252))	('SEPT14', 'Gene', (259, 265))	('SEPT14', 'Gene', '74222', (259, 265))	('SEPT-14', 'Gene', '74222', (245, 252))	('deletion', 'Var', (122, 130))
37080	32547705	Because EGFRvIII has a deletion in its ligand-binding domain, its tyrosine kinase domain is constitutively active.	('tyrosine', 'Chemical', 'MESH:D014443', (66, 74))	('EGFRvIII', 'Gene', (8, 16))	('deletion', 'Var', (23, 31))	('tyrosine kinase domain', 'MPA', (66, 88))	('ligand-binding domain', 'MPA', (39, 60))
37081	32547705	To detect the constitutive activity of EGFRvIII tyrosine kinase, we used western blotting with an antibody specific for EGFR tyrosine kinase phosphorylated at Y1068.	('tyrosine', 'Chemical', 'MESH:D014443', (48, 56))	('tyrosine', 'Chemical', 'MESH:D014443', (125, 133))	('Y1068', 'Chemical', '-', (159, 164))	('Y1068', 'Var', (159, 164))	('EGFR', 'Gene', (120, 124))
37083	32547705	The highest tyrosine kinase activity is seen in D317 and D10-0171, followed by D09-0155 and D10-0279.	('D317', 'Var', (48, 52))	('tyrosine kinase activity', 'MPA', (12, 36))	('D09-0155', 'Var', (79, 87))	('D10-0279', 'Var', (92, 100))	('tyrosine', 'Chemical', 'MESH:D014443', (12, 20))	('D10-0171', 'Var', (57, 65))
37086	32547705	The expression of EGFRvIII was highest in D317 (Ct = 17.00) and lowest in HK412 (Ct = 36.72), explaining the differences in constitutive tyrosine kinase activities shown in Figure 1B.	('lowest', 'NegReg', (64, 70))	('constitutive', 'MPA', (124, 136))	('expression', 'MPA', (4, 14))	('highest', 'Reg', (31, 38))	('HK412', 'Chemical', '-', (74, 79))	('tyrosine', 'Chemical', 'MESH:D014443', (137, 145))	('EGFRvIII', 'Gene', (18, 26))	('D317', 'Var', (42, 46))
37089	32547705	As shown in Figure 2A, osimertinib potently inhibits the EGFRvIII's tyrosine phosphorylation at Y1068 with an IC50 of around 50 nM.	('tyrosine phosphorylation', 'MPA', (68, 92))	('Y1068', 'Chemical', '-', (96, 101))	('osimertinib', 'Chemical', 'MESH:C000596361', (23, 34))	('tyrosine', 'Chemical', 'MESH:D014443', (68, 76))	('Y1068', 'Var', (96, 101))	('inhibits', 'NegReg', (44, 52))
37095	32547705	In the case of EGFR, phosphorylation of the receptor at both Y1068 and Y1173 (rows 98 and 99, Supplementary Table 1) is blocked by osimertinib; the levels of total EGFR (row 97, Supplementary Table 1) are not affected by osimertinib.	('Y1068', 'Chemical', '-', (61, 66))	('Y1068', 'Var', (61, 66))	('osimertinib', 'Chemical', 'MESH:C000596361', (131, 142))	('phosphorylation', 'MPA', (21, 36))	('osimertinib', 'Chemical', 'MESH:C000596361', (221, 232))	('blocked', 'NegReg', (120, 127))	('Y1173', 'Var', (71, 76))
37109	32547705	EGFRvIII tyrosine kinase in D10-0171, like that in D317, is inhibited by osimertinib with high potency (IC50 <100 nM) (data not shown).	('osimertinib', 'Chemical', 'MESH:C000596361', (73, 84))	('tyrosine', 'Chemical', 'MESH:D014443', (9, 17))	('inhibited', 'NegReg', (60, 69))	('tyrosine kinase', 'Enzyme', (9, 24))	('D10-0171', 'Var', (28, 36))
37110	32547705	Further, osimertinib inhibited the growth of D10-0171 in a subcutaneous model but the effect was modest (T/C of 0.1669).	('osimertinib', 'Chemical', 'MESH:C000596361', (9, 20))	('D10-0171', 'Var', (45, 53))	('growth', 'MPA', (35, 41))	('inhibited', 'NegReg', (21, 30))
37135	32547705	Four EGFRvIII+ GSCs (D317, D10-0171, D09-0155, and D10-0279) were isolated from EGFRvIII-expressing patient-derived xenografts (PDXs) developed at the Duke Brain Tumor Center and characterized.	('D317', 'Var', (21, 25))	('GSCs', 'Chemical', '-', (15, 19))	('Tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Duke Brain Tumor', 'Disease', 'MESH:D001932', (151, 167))	('Brain Tumor', 'Phenotype', 'HP:0030692', (156, 167))	('patient', 'Species', '9606', (100, 107))	('D10-0171', 'Var', (27, 35))	('PD', 'Disease', 'MESH:D010300', (128, 130))	('D10-0279', 'Var', (51, 59))	('Duke Brain Tumor', 'Disease', (151, 167))	('D09-0155', 'Var', (37, 45))
37148	32547705	The following assays, with their catalog numbers in parentheses, were used: GAPDH (Hs99999905), EGFR (Hs01076090_m1), EGFRvIII (custom synthesized, Cat #4441117, Assay ID: AJPACOW), DYRK1 (Hs00176369_m1), OSMR (Hs00384276_m1), MGMT (Hs01037698_m1), TFRC (Hs00951083_m1), SOX2 (Hs01053049_s1), CD133 (Hs01009257_m1), NESTIN (Hs04187831_g1), NANOG (Hs04399610_g1), MSI-1 (Hs01045894_m1), and OLIG2 (Hs00377820_m1).	('SOX2', 'Gene', '20674', (271, 275))	('GAPDH', 'Gene', (76, 81))	('MSI-1', 'Gene', (363, 368))	('TFRC', 'Gene', (249, 253))	('OSMR', 'Gene', '18414', (205, 209))	('Hs00951083_m1', 'Var', (255, 268))	('Hs04187831_g1', 'Var', (324, 337))	('SOX2', 'Gene', (271, 275))	('NANOG', 'Gene', '71950', (340, 345))	('OLIG2', 'Gene', (390, 395))	('TFRC', 'Gene', '22042', (249, 253))	('MGMT', 'Gene', (227, 231))	('MSI-1', 'Gene', '17690', (363, 368))	('MGMT', 'Gene', '17314', (227, 231))	('Hs00176369_m1', 'Var', (189, 202))	('GAPDH', 'Gene', '14433', (76, 81))	('OLIG2', 'Gene', '50913', (390, 395))	('Hs01053049_s1', 'Var', (277, 290))	('Hs00377820_m1', 'Var', (397, 410))	('Hs04399610_g1', 'Var', (347, 360))	('CD133', 'Gene', (293, 298))	('Hs00384276_m1', 'Var', (211, 224))	('Hs01009257_m1', 'Var', (300, 313))	('OSMR', 'Gene', (205, 209))	('NANOG', 'Gene', (340, 345))	('CD133', 'Gene', '19126', (293, 298))	('Hs01045894_m1', 'Var', (370, 383))	('Hs01037698_m1', 'Var', (233, 246))
37179	32455423	Those subjects with T < 365, Delta = 1 are removed so the total number of subjects is 286 with P(Y = 1) = 45%, P(Y = 0) = 55%.	('Delta = 1', 'Gene', (29, 38))	('T < 365', 'Var', (20, 27))	('Delta = 1', 'Gene', '28514', (29, 38))
37198	31590360	The cellular origin of GBMs has long been a point of contention, with debate centering on whether these tumors are the result of the dedifferentiation of mature cells or the accumulation of oncologic mutations in neural stem cells (NSCs).	('GBMs', 'Disease', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutations', 'Var', (200, 209))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('GBMs', 'Phenotype', 'HP:0012174', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', (104, 110))
37215	31590360	Taqman probes were as follows: CHRM1 Hs00265195_s1, CHRM2 Hs00265208_s1, CHRM3 Hx00265216_s1, CHRM4 Hs00265219_s1, CHRM5 Hs00255278_s1, CHRNA3 Hs01088199_m1, CHRNA4 Hs00181247_m1, CHRNA5 Hs00181248_m1, CHRNA7 Hs01063372_m1, CHRNB2 Hs00181267_m1, CHRNB3 Hs00181269_m1, CHRNB4 Hs00609520_m1, and IPO8 Hs00914057_m1.	('CHRNA5', 'Gene', (180, 186))	('CHRM5', 'Gene', (115, 120))	('CHRM3', 'Gene', '1131', (73, 78))	('CHRNA7', 'Gene', '1139', (202, 208))	('CHRNB4', 'Gene', '1143', (268, 274))	('CHRNA3', 'Gene', '1136', (136, 142))	('CHRM4', 'Gene', (94, 99))	('CHRNA4', 'Gene', (158, 164))	('IPO8', 'Gene', '10526', (294, 298))	('Hs00181269_m1', 'Var', (253, 266))	('CHRNB2', 'Gene', (224, 230))	('CHRNB2', 'Gene', '1141', (224, 230))	('CHRNB3', 'Gene', (246, 252))	('CHRNA3', 'Gene', (136, 142))	('CHRM2', 'Gene', '1129', (52, 57))	('CHRNB4', 'Gene', (268, 274))	('IPO8', 'Gene', (294, 298))	('CHRM5', 'Gene', '1133', (115, 120))	('CHRM4', 'Gene', '1132', (94, 99))	('Hs00181267_m1', 'Var', (231, 244))	('CHRM3', 'Gene', (73, 78))	('CHRNB3', 'Gene', '1142', (246, 252))	('CHRNA4', 'Gene', '1137', (158, 164))	('CHRM1', 'Gene', (31, 36))	('CHRNA7', 'Gene', (202, 208))	('CHRNA5', 'Gene', '1138', (180, 186))	('CHRM2', 'Gene', (52, 57))	('CHRM1', 'Gene', '1128', (31, 36))
37243	31590360	We first queried the dataset to determine the frequency of mutations in the muscarinic AChR (mAChR) genes: CHRM1-5; neuronal nicotinic AChR (nAChR) genes: CHRNA2-7, CHRNA9-10, and CHRNB1-4; and muscle nAChR genes: CHRNA1, CHRNB1, CHRND, CHRNE, and CHRNG.	('CHRNE', 'Gene', (237, 242))	('CHRNG', 'Gene', '1146', (248, 253))	('CHRNA9-10', 'CellLine', 'CVCL:R704', (165, 174))	('CHRM1', 'Gene', (107, 112))	('CHRNA2', 'Gene', (155, 161))	('CHRNB1', 'Gene', (180, 186))	('nAChR', 'Gene', '1137', (201, 206))	('CHRM1', 'Gene', '1128', (107, 112))	('nAChR', 'Gene', (201, 206))	('CHRNA1', 'Gene', (214, 220))	('CHRNA2', 'Gene', '1135', (155, 161))	('nAChR', 'Gene', '1137', (141, 146))	('mutations', 'Var', (59, 68))	('CHRND', 'Gene', '1144', (230, 235))	('nAChR', 'Gene', (141, 146))	('CHRNB1', 'Gene', '1140', (222, 228))	('CHRNE', 'Gene', '1145', (237, 242))	('CHRNA1', 'Gene', '1134', (214, 220))	('CHRNG', 'Gene', (248, 253))	('CHRND', 'Gene', (230, 235))	('CHRNB1', 'Gene', (222, 228))	('CHRNB1', 'Gene', '1140', (180, 186))
37255	31590360	We utilized confocal time-lapse Ca2+-imaging to investigate changes in [Ca2+]i following AChR modulation in the GBM cell and xenograft lines (Figure 2).	('[Ca2+]i', 'MPA', (71, 78))	('AChR', 'Gene', (89, 93))	('modulation', 'Var', (94, 104))	('[Ca2+]i', 'Chemical', 'MESH:D002118', (71, 78))	('Ca2+', 'Chemical', 'MESH:D002118', (72, 76))	('Ca2+', 'Chemical', 'MESH:D002118', (32, 36))
37384	31564969	The current report provides a brief overview of the role of the CD95/CD95L signaling pathway in cancer pathogenesis and discusses how asunercept was designed to bind and neutralize CD95L and disrupt signaling thereby potentially improving outcomes in glioblastoma and other malignancies.	('CD95', 'Gene', '355', (69, 73))	('CD95', 'Gene', (64, 68))	('outcomes', 'MPA', (239, 247))	('glioblastoma', 'Disease', (251, 263))	('glioblastoma', 'Phenotype', 'HP:0012174', (251, 263))	('bind', 'Interaction', (161, 165))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('signaling', 'MPA', (199, 208))	('CD95', 'Gene', (181, 185))	('CD95', 'Gene', (69, 73))	('disrupt', 'NegReg', (191, 198))	('CD95', 'Gene', '355', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('malignancies', 'Disease', 'MESH:D009369', (274, 286))	('neutralize', 'Var', (170, 180))	('malignancies', 'Disease', (274, 286))	('improving', 'PosReg', (229, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (251, 263))	('CD95', 'Gene', '355', (181, 185))
37400	31564969	Inhibition of CD95/CD95L interaction might, therefore, represent a potential therapeutic approach for cancer immunotherapy.	('CD95', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('CD95', 'Gene', (14, 18))	('CD95', 'Gene', '355', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Inhibition', 'Var', (0, 10))	('CD95', 'Gene', '355', (14, 18))
37402	31564969	A number of other cells in the TME, including the tumor endothelium, and cancer-associated fibroblasts can also express CD95L and therefore induce T-cell apoptosis or suppress its function, for example when induced by angiogenic growth factors.	('CD95L', 'Var', (120, 125))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('induce', 'PosReg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('T-cell apoptosis', 'CPA', (147, 163))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('function', 'MPA', (180, 188))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('suppress', 'NegReg', (167, 175))	('tumor', 'Disease', (50, 55))
37404	31564969	CD95 is required for CSC survival and stimulation of CD95 on multiple tumor cells has been shown to result in conversion from non-CSC to CSC, independent of its apoptosis-inducing function, suggesting that CD95 expression could be a reliable surface marker for targeted therapy.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD95', 'Gene', (53, 57))	('CD95', 'Gene', '355', (0, 4))	('tumor', 'Disease', (70, 75))	('CD95', 'Gene', (0, 4))	('CD95', 'Gene', (206, 210))	('CD95', 'Gene', '355', (53, 57))	('conversion', 'Disease', (110, 120))	('stimulation', 'Var', (38, 49))	('non-CSC', 'Disease', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CD95', 'Gene', '355', (206, 210))
37415	31564969	Stimulation of glioblastoma cell lines (both apoptosis-resistant and apoptosis-sensitive) with CD95L increased migration of cells in the apoptosis-resistant cell line, but not in the apoptosis-sensitive cell line, and could be prevented by blocking MMP activity.	('CD95L', 'Var', (95, 100))	('glioblastoma cell', 'Disease', (15, 32))	('increased', 'PosReg', (101, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (15, 27))	('migration of cells', 'CPA', (111, 129))	('glioblastoma cell', 'Disease', 'MESH:D005909', (15, 32))
37417	31564969	Together these results suggest that CD95L from both autocrine and paracrine sources can contribute to the invasive nature of glioblastoma cells, and that asunercept can reduce this invasiveness by neutralizing CD95L.	('neutralizing', 'Var', (197, 209))	('invasive nature', 'CPA', (106, 121))	('glioblastoma cell', 'Disease', (125, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('CD95L', 'MPA', (210, 215))	('CD95L', 'MPA', (36, 41))	('glioblastoma cell', 'Disease', 'MESH:D005909', (125, 142))	('reduce', 'NegReg', (169, 175))
37424	31564969	Interestingly, in the same research, asunercept labeled with 123I crossed the blood-brain barrier and enriched glioblastoma cells, suggesting a synergistic effect in combination with radiotherapy or chemotherapy.	('glioblastoma cell', 'Disease', (111, 128))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('123I', 'Var', (61, 65))	('123I', 'Chemical', 'MESH:C492712', (61, 65))	('glioblastoma cell', 'Disease', 'MESH:D005909', (111, 128))
37429	31564969	These studies suggested that patients displaying a low level of methylation responded best to asunercept therapy (hazard ratio 0.19, 95% CI 0.06-0.58).	('patients', 'Species', '9606', (29, 37))	('methylation', 'Var', (64, 75))	('asunercept', 'Protein', (94, 104))
37430	31564969	There was a significant survival benefit for patients with low methylation when treated with a combination of asunercept and radiotherapy vs radiotherapy alone (HR 0.34, p=0.024), suggesting differential CD95L promoter methylation may represent a potential biomarker to predict response to asunercept treatment.	('CD95L', 'Gene', (204, 209))	('patients', 'Species', '9606', (45, 53))	('methylation', 'Var', (63, 74))	('low methylation', 'Var', (59, 74))
37432	31564969	The CD95/CD95L signaling pathway and asunercept, as a selective CD95L inhibitor, offer broad potential applicability to a range of malignancies with aberrant CD95/CD95L signaling, beyond recurrent glioblastoma patients.	('malignancies', 'Disease', (131, 143))	('CD95', 'Gene', (163, 167))	('CD95', 'Gene', '355', (4, 8))	('CD95', 'Gene', (64, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('CD95', 'Gene', '355', (9, 13))	('CD95', 'Gene', '355', (163, 167))	('CD95', 'Gene', (158, 162))	('CD95', 'Gene', '355', (64, 68))	('CD95', 'Gene', (4, 8))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))	('patients', 'Species', '9606', (210, 218))	('aberrant', 'Var', (149, 157))	('glioblastoma', 'Disease', (197, 209))	('CD95', 'Gene', '355', (158, 162))	('glioblastoma', 'Disease', 'MESH:D005909', (197, 209))	('CD95', 'Gene', (9, 13))
37469	29156610	EGFR amplifications, CDKN2A/B homozygous deletions, and a CYB5R2 overexpression are more frequent in mfGB than in sGB.	('GB', 'Phenotype', 'HP:0012174', (115, 117))	('amplifications', 'Var', (5, 19))	('CYB5R2', 'Gene', '51700', (58, 64))	('EGFR', 'Gene', (0, 4))	('mfGB', 'Chemical', '-', (101, 105))	('CYB5R2', 'Gene', (58, 64))	('GB', 'Phenotype', 'HP:0012174', (103, 105))	('mfGB', 'Disease', (101, 105))	('CDKN2A', 'Gene', (21, 27))	('deletions', 'Var', (41, 50))	('frequent', 'Reg', (89, 97))	('CDKN2A', 'Gene', '1029', (21, 27))	('EGFR', 'Gene', '1956', (0, 4))
37470	29156610	Conversely, isocitrate dehydrogenase 1 (IDH1), ATP-dependent helicase (ATRX), or platelet-derived growth factor receptor A (PDGFRA) mutations are unusual in mfGB.	('mfGB', 'Gene', (157, 161))	('isocitrate dehydrogenase 1', 'Gene', '3417', (12, 38))	('isocitrate dehydrogenase 1', 'Gene', (12, 38))	('IDH1', 'Gene', (40, 44))	('AT', 'Disease', 'None', (71, 73))	('platelet-derived growth factor receptor A', 'Gene', (81, 122))	('mutations', 'Var', (132, 141))	('PDGFRA', 'Gene', '5156', (124, 130))	('PDGFRA', 'Gene', (124, 130))	('IDH1', 'Gene', '3417', (40, 44))	('AT', 'Disease', 'None', (47, 49))	('platelet-derived growth factor receptor A', 'Gene', '5156', (81, 122))	('mfGB', 'Chemical', '-', (157, 161))	('GB', 'Phenotype', 'HP:0012174', (159, 161))
37565	29156610	However, due to the inherent multifocal tumor distribution, partial or total resection as compared to biopsy only at the time of initial diagnosis was more frequent in sGB than in mfGB (81% vs. 56%).	('partial', 'Var', (60, 67))	('GB', 'Phenotype', 'HP:0012174', (182, 184))	('mfGB', 'Chemical', '-', (180, 184))	('multifocal tumor', 'Disease', 'None', (29, 45))	('multifocal tumor', 'Disease', (29, 45))	('GB', 'Phenotype', 'HP:0012174', (169, 171))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('sGB', 'Disease', (168, 171))
37579	29156610	ATRX ATP-Dependent Helicase  BEV Bevacizumab  BSC Best Supportive Care  CCNU Lomustine  CCNU/TMZ Lomustine/Temozolomide  CDKN2A/B Cyclin-Dependent Kinase Inhibitor 2A/B  CYB5R2 Cytochrome b5 Reductase 2  DNA Deoxyribonucleic Acid  EGFR Epidermal Growth Factor Receptor  F Female  GB Glioblastoma  Gd Gadolinium contrast enhancer  IDH1 Isocitrate Dehydrogenase 1  Iri Irinotecan  KPS Karnofsky Performance Score  M Male  meth.	('AT', 'Disease', 'None', (5, 7))	('Iri Irinotecan  KPS Karnofsky', 'Disease', 'MESH:D007499', (363, 392))	('GB', 'Phenotype', 'HP:0012174', (280, 282))	('Glioblastoma', 'Disease', 'MESH:D005909', (283, 295))	('Temozolomide', 'Chemical', 'MESH:D000077204', (107, 119))	('Glioblastoma', 'Phenotype', 'HP:0012174', (283, 295))	('CYB5R2', 'Gene', '51700', (170, 176))	('EGFR', 'Gene', (231, 235))	('BEV', 'Chemical', 'MESH:D000068258', (29, 32))	('IDH1', 'Gene', (330, 334))	('TMZ', 'Chemical', 'MESH:D000077204', (93, 96))	('CCNU', 'Chemical', '-', (88, 92))	('2A/B', 'SUBSTITUTION', 'None', (125, 129))	('2A/B', 'Var', (125, 129))	('CYB5R2', 'Gene', (170, 176))	('AT', 'Disease', 'None', (0, 2))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (335, 361))	('Glioblastoma', 'Disease', (283, 295))	('Iri Irinotecan  KPS Karnofsky', 'Disease', (363, 392))	('IDH1', 'Gene', '3417', (330, 334))	('CCNU', 'Chemical', '-', (72, 76))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (33, 44))	('2A/B', 'SUBSTITUTION', 'None', (164, 168))	('2A/B', 'Var', (164, 168))	('EGFR', 'Gene', '1956', (231, 235))	('Isocitrate Dehydrogenase 1', 'Gene', (335, 361))	('BSC', 'Chemical', '-', (46, 49))
37584	28574446	Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The "Rotation Model" The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility, and differentiation.	('motility', 'CPA', (219, 227))	('epidermal growth factor receptor', 'Gene', '1956', (99, 131))	('EGF Receptor', 'Gene', '1956', (18, 30))	('EGF Receptor', 'Gene', (18, 30))	('Mutations', 'Var', (63, 72))	('epidermal growth factor receptor', 'Gene', (99, 131))	('differentiation', 'CPA', (233, 248))
37585	28574446	The dysregulated activation of the receptor is often implicated in human cancers.	('cancers', 'Disease', (73, 80))	('implicated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('activation', 'PosReg', (17, 27))	('human', 'Species', '9606', (67, 72))	('dysregulated', 'Var', (4, 16))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
37589	28574446	The aberrant activation of EGFR is implicated in a variety of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('EGFR', 'Gene', (27, 31))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('aberrant', 'Var', (4, 12))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('implicated', 'Reg', (35, 45))
37598	28574446	Consistently, treatment of EGFR-expressing cells with inhibitors of protein tyrosine phosphatases induces EGFR phosphorylation at the same level as in cells stimulated with EGF.	('inhibitors', 'Var', (54, 64))	('EGFR phosphorylation', 'MPA', (106, 126))	('induces', 'Reg', (98, 105))	('tyrosine', 'Chemical', 'MESH:D014443', (76, 84))
37610	28574446	An "electrostatic hook", which consists of acidic side chains (D1003, E1004 and E1005; D979, E980, and E981 in mature EGFR) in the turn after the AP-2 helix, forms ion pairs with residues in the kinase domain (H773, H850, K852 and K846; H749, H826, K828, and K822 in mature EGFR).	('H850', 'Var', (216, 220))	('AP-2', 'Gene', '7020', (146, 150))	('K852', 'Var', (222, 226))	('K822', 'Var', (259, 263))	('E981', 'Var', (103, 107))	('H773', 'Var', (210, 214))	('E1005; D979', 'Var', (80, 91))	('AP-2', 'Gene', (146, 150))	('D1003', 'Var', (63, 68))	('forms', 'Reg', (158, 163))	('K828', 'Var', (249, 253))	('K846; H749', 'Var', (231, 241))	('E980', 'Var', (93, 97))	('H826', 'Var', (243, 247))	('E1004', 'Var', (70, 75))
37614	28574446	Breaking the disulfide bond between C582 and C591 (C558 and C567 in mature EGFR) of the "tethering arm" of Subdomain IV through a double alanine replacement entirely abrogates the negative cooperativity.	('alanine', 'Chemical', 'MESH:D000409', (137, 144))	('disulfide', 'Chemical', 'MESH:D004220', (13, 22))	('abrogates', 'NegReg', (166, 175))	('negative cooperativity', 'MPA', (180, 202))	('double alanine replacement', 'Var', (130, 156))	('disulfide bond', 'MPA', (13, 27))
37617	28574446	In this model, the phosphorylation of tyrosine residues in the C-terminal tail, proximal to the kinase domain, is facilitated by a continuous array of "activator" and "receiver" kinase domains of the receptor tetramers and oligomers.	('facilitated', 'PosReg', (114, 125))	('phosphorylation', 'MPA', (19, 34))	('tyrosine', 'Chemical', 'MESH:D014443', (38, 46))	('tyrosine residues', 'Var', (38, 55))
37619	28574446	The epidermal growth factor receptor plays crucial roles in cellular processes such as cell proliferation and differentiation, and its aberrant activation is implicated in a variety of human cancers.	('human', 'Species', '9606', (185, 190))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('epidermal growth factor receptor', 'Gene', (4, 36))	('cancers', 'Disease', (191, 198))	('differentiation', 'CPA', (110, 125))	('cell proliferation', 'CPA', (87, 105))	('implicated', 'Reg', (158, 168))	('activation', 'PosReg', (144, 154))	('epidermal growth factor receptor', 'Gene', '1956', (4, 36))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('aberrant', 'Var', (135, 143))
37621	28574446	Amplification of the EGFR gene is one way to overproduce EGFR, and has been observed in various cancers including breast carcinomas, non-small-cell lung cancer (NSCLC), and glioblastoma multiforme (GBM).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast carcinomas', 'Disease', 'MESH:D001943', (114, 131))	('breast carcinomas', 'Disease', (114, 131))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('glioblastoma multiforme', 'Disease', (173, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (133, 159))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (173, 196))	('EGFR', 'Gene', (57, 61))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('breast carcinomas', 'Phenotype', 'HP:0003002', (114, 131))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('overproduce', 'PosReg', (45, 56))	('NSCLC', 'Disease', (161, 166))	('observed', 'Reg', (76, 84))	('non-small-cell lung cancer', 'Disease', (133, 159))	('EGFR', 'Gene', (21, 25))	('Amplification', 'Var', (0, 13))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (133, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))
37622	28574446	It has been shown that wild-type and mutant p53 proteins directly activate EGFR transcription by specific binding to its promoter.	('proteins', 'Protein', (48, 56))	('binding', 'Interaction', (106, 113))	('transcription', 'MPA', (80, 93))	('activate', 'PosReg', (66, 74))	('mutant', 'Var', (37, 43))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('EGFR', 'Gene', (75, 79))
37628	28574446	Mutations in the EGFR gene that constitutively activate the receptor frequently occur in human cancers.	('human', 'Species', '9606', (89, 94))	('activate', 'PosReg', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Mutations', 'Var', (0, 9))	('occur', 'Reg', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('EGFR', 'Gene', (17, 21))
37629	28574446	In this review, we only discuss mutations that have been found in cancer patients and that constitutively activate the receptor.	('activate', 'PosReg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', (66, 72))
37632	28574446	Unlike ligand-activated wild-type EGFR, however, EGFRvIII also activates the c-Jun N-terminal kinase through PI3K, but cannot activate the signal transducers and activators of transcription 1 (STAT1) and STAT3.	('STAT3', 'Gene', '20848', (204, 209))	('c-Jun N-terminal kinase', 'MPA', (77, 100))	('STAT3', 'Gene', (204, 209))	('PI3K', 'Var', (109, 113))	('PI3', 'Species', '1196084', (109, 112))	('EGFRvIII', 'Var', (49, 57))	('activates', 'PosReg', (63, 72))
37636	28574446	Missense mutations (R108K, T263P, A289V and G598V; R84K, T239P, A265V, and G574V in mature EGFR) in the extracellular domain of EGFR were also found in GBM and glioblastoma cell lines, which conferred anchorage-independent growth and tumorigenicity upon NIH 3T3 cells.	('R108K', 'Var', (20, 25))	('tumor', 'Disease', (234, 239))	('G574V', 'Mutation', 'p.G574V', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('T263P', 'Mutation', 'rs1057519829', (27, 32))	('A289V', 'Mutation', 'rs149840192', (34, 39))	('A265V', 'Var', (64, 69))	('R108K', 'Mutation', 'rs1057519828', (20, 25))	('A289V', 'Var', (34, 39))	('G574V', 'Var', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('anchorage-independent growth', 'CPA', (201, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('R84K', 'Mutation', 'p.R84K', (51, 55))	('G598V; R84K', 'Var', (44, 55))	('T263P', 'Var', (27, 32))	('NIH 3T3', 'CellLine', 'CVCL:0594', (254, 261))	('glioblastoma', 'Disease', (160, 172))	('G598V', 'Mutation', 'rs139236063', (44, 49))	('T239P', 'Var', (57, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('A265V', 'Mutation', 'p.A265V', (64, 69))	('T239P', 'Mutation', 'p.T239P', (57, 62))
37637	28574446	R108K and A289V occur at the interface between Subdomains I and II, and T263P occurs in Subdomain II just before the "beta-hairpin" that contacts Subdomain IV in the inactive "tethered" structure (Figure 2a).	('R108K', 'Var', (0, 5))	('T263P', 'Mutation', 'rs1057519829', (72, 77))	('R108K', 'Mutation', 'rs1057519828', (0, 5))	('T263P', 'Var', (72, 77))	('A289V', 'Var', (10, 15))	('A289V', 'Mutation', 'rs149840192', (10, 15))
37638	28574446	Sequencing of EGFR in a large cohort of GBM patients has identified over 30 different missense mutations within the extracellular domain, including C620Y, C620W, C624F, C628Y, and C636Y (C596Y, C596W, C600F, C604Y, and C612Y in mature EGFR).	('C604Y', 'Var', (208, 213))	('C628Y', 'Var', (169, 174))	('C620Y', 'Mutation', 'rs150899403', (148, 153))	('C624F', 'Var', (162, 167))	('patients', 'Species', '9606', (44, 52))	('C620W', 'Var', (155, 160))	('C596W', 'SUBSTITUTION', 'None', (194, 199))	('C612Y', 'Mutation', 'p.C612Y', (219, 224))	('C596W', 'Var', (194, 199))	('C628Y', 'Mutation', 'p.C628Y', (169, 174))	('C600F', 'Var', (201, 206))	('C612Y', 'Var', (219, 224))	('C620Y', 'Var', (148, 153))	('C604Y', 'Mutation', 'p.C604Y', (208, 213))	('C636Y', 'Mutation', 'p.C636Y', (180, 185))	('C600F', 'Mutation', 'p.C600F', (201, 206))	('C624F', 'Mutation', 'rs28384376', (162, 167))	('C596Y', 'Mutation', 'p.C596Y', (187, 192))	('C620W', 'SUBSTITUTION', 'None', (155, 160))
37640	28574446	These Subdomain IV mutations leave an unpaired cysteine residue available for the formation of an intermolecular disulfide bond.	('mutations', 'Var', (19, 28))	('unpaired cysteine residue', 'MPA', (38, 63))	('cysteine', 'Chemical', 'MESH:D003545', (47, 55))	('leave', 'Reg', (29, 34))	('disulfide', 'Chemical', 'MESH:D004220', (113, 122))
37641	28574446	Unlike EGFRvIII, which spontaneously formed a disulfide-bridge between protomers, these mutants form interprotomer cysteine disulfide bridges upon ligand stimulation.	('disulfide', 'Chemical', 'MESH:D004220', (124, 133))	('form', 'Reg', (96, 100))	('disulfide', 'Chemical', 'MESH:D004220', (46, 55))	('cysteine disulfide', 'Chemical', 'MESH:D003553', (115, 133))	('interprotomer cysteine disulfide bridges', 'MPA', (101, 141))	('mutants', 'Var', (88, 95))
37642	28574446	Three of the four mutants (C620Y, C624F, and C628Y) exhibit elevated levels of basal-tyrosine phosphorylation, with C620Y having the highest level.	('C620Y', 'Var', (116, 121))	('C628Y', 'Var', (45, 50))	('C620Y', 'Mutation', 'rs150899403', (116, 121))	('C628Y', 'Mutation', 'p.C628Y', (45, 50))	('elevated', 'PosReg', (60, 68))	('C620Y', 'Mutation', 'rs150899403', (27, 32))	('C624F', 'Var', (34, 39))	('C620Y', 'Var', (27, 32))	('C624F', 'Mutation', 'rs28384376', (34, 39))	('tyrosine', 'Chemical', 'MESH:D014443', (85, 93))	('basal-tyrosine phosphorylation', 'MPA', (79, 109))
37643	28574446	In particular, cell lines expressing the C620Y or C624F mutant grew better in soft agar than the control cells expressing wild-type EGFR, suggesting that these mutations are oncogenic.	('better', 'PosReg', (68, 74))	('C624F', 'Var', (50, 55))	('agar', 'Chemical', 'MESH:D000362', (83, 87))	('C624F', 'Mutation', 'rs28384376', (50, 55))	('C620Y', 'Var', (41, 46))	('C620Y', 'Mutation', 'rs150899403', (41, 46))	('grew', 'CPA', (63, 67))
37644	28574446	An EGFR-ligand autocrine loop may initiate the activation of the mutant receptors, and may then induce disulfide bridge formation that in turn rotates the transmembrane domains to constitutively activate the mutant receptors.	('activation', 'MPA', (47, 57))	('disulfide', 'Chemical', 'MESH:D004220', (103, 112))	('rotates', 'Reg', (143, 150))	('induce', 'Reg', (96, 102))	('activate', 'PosReg', (195, 203))	('mutant', 'Var', (65, 71))	('mutant', 'Var', (208, 214))	('disulfide bridge formation', 'MPA', (103, 129))
37645	28574446	V689M and L703F (V665M and L679F in mature EGFR), found in NSCLC patients, constitutively activate the mutant EGFR in the absence of a bound ligand to the same level as the wild type stimulated with a ligand.	('EGFR', 'Protein', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('L679F', 'Mutation', 'p.L679F', (27, 32))	('mutant', 'Var', (103, 109))	('V689M', 'Var', (0, 5))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('V665M', 'Mutation', 'rs1436919825', (17, 22))	('activate', 'PosReg', (90, 98))	('patients', 'Species', '9606', (65, 73))	('L703F', 'Mutation', 'rs1273890779', (10, 15))	('L679F', 'Var', (27, 32))	('EGFR', 'Gene', (43, 47))	('NSCLC', 'Disease', (59, 64))	('V689M', 'Mutation', 'p.V689M', (0, 5))
37646	28574446	A possible structural basis for the EGFR activation by the V665M or L679F mutation is that the side chain of a methionine substituted V689 projects into a cavity on the surface of the C-lobe, while the V689 side chain does not fill this cavity.	('V665M', 'Var', (59, 64))	('EGFR', 'Gene', (36, 40))	('V689', 'Var', (134, 138))	('L679F', 'Var', (68, 73))	('V665M', 'Mutation', 'rs1436919825', (59, 64))	('activation', 'PosReg', (41, 51))	('methionine', 'Chemical', 'MESH:D008715', (111, 121))	('L679F', 'Mutation', 'p.L679F', (68, 73))
37648	28574446	The mutation of L703 to phenylalanine could improve the packing of the JM-B of the "receiver" kinase with the C-lobe of the "activator" kinase for stabilization of the active configuration.	('L703', 'Var', (16, 20))	('improve', 'PosReg', (44, 51))	('packing', 'MPA', (56, 63))	('L703 to phenylalanine', 'Mutation', 'rs1273890779', (16, 37))
37649	28574446	The G719S mutation (G695S in mature EGFR) also activates the kinase, presumably by the destabilization of the symmetric inactive configuration of the dimer.	('G695S', 'Mutation', 'p.G695S', (20, 25))	('destabilization', 'NegReg', (87, 102))	('G695S', 'Var', (20, 25))	('G719S', 'Var', (4, 9))	('activates', 'PosReg', (47, 56))	('symmetric inactive configuration of the dimer', 'MPA', (110, 155))	('G719S', 'Mutation', 'rs28929495', (4, 9))	('EGFR', 'Gene', (36, 40))
37650	28574446	G719 contributes to interactions that hold helix alphaC in the inactive conformation.	('helix alphaC', 'Protein', (43, 55))	('G719', 'Var', (0, 4))	('interactions', 'Interaction', (20, 32))	('G719', 'Chemical', '-', (0, 4))
37651	28574446	The G719S mutation may not be able to do this, and may allow the helix to adopt its active conformation in the asymmetric dimeric configuration.	('active conformation', 'MPA', (84, 103))	('adopt', 'Reg', (74, 79))	('helix', 'Protein', (65, 70))	('G719S', 'Var', (4, 9))	('allow', 'Reg', (55, 60))	('G719S', 'Mutation', 'rs28929495', (4, 9))
37652	28574446	Substitutions of G719 to alanine or cysteine also occur in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('alanine', 'Chemical', 'MESH:D000409', (25, 32))	('cysteine', 'MPA', (36, 44))	('G719', 'Var', (17, 21))	('G719', 'Chemical', '-', (17, 21))	('cysteine', 'Chemical', 'MESH:D003545', (36, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('alanine', 'MPA', (25, 32))	('occur', 'Reg', (50, 55))	('NSCLC', 'Disease', (59, 64))
37653	28574446	Deletion mutants in the intracellular domain have also been found in NSCLC, and various deletions within the range encompassing E746 to I759 (E722 to I735 in mature EGFR) have been identified.	('EGFR', 'Gene', (165, 169))	('NSCLC', 'Disease', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('E746', 'Var', (128, 132))	('Deletion', 'Var', (0, 8))
37655	28574446	Two other mutations are a deletion in which residues from L747 to P753 (L723-P729 in mature EGFR) are replaced with a single serine to give the  L747-P753insS mutant, and the mutant  S752-I759 ( S728-I735 in mature EGFR) in which residues 752-759 are deleted.	('L747-P753insS', 'Var', (145, 158))	('serine', 'Chemical', 'MESH:D012694', (125, 131))	('L747', 'Var', (58, 62))	('L747-P753insS', 'Mutation', 'p.747,753insS', (145, 158))
37656	28574446	When these mutant EGFR genes were expressed in the murine hematopoietic Ba/F3 cell line, they all showed significantly higher basal (ligand-independent) tyrosine phosphorylation levels than wild-type receptors.	('mutant', 'Var', (11, 17))	('higher', 'PosReg', (119, 125))	('tyrosine', 'Chemical', 'MESH:D014443', (153, 161))	('EGFR genes', 'Gene', (18, 28))	('Ba/F3', 'CellLine', 'CVCL:0161', (72, 77))	('murine', 'Species', '10090', (51, 57))
37657	28574446	The R776H mutation (R752H in mature EGFR) is associated with lung cancer where there is no smoking history, and is found both in normal and tumor tissues.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('R776H', 'Mutation', 'rs483352806', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('R776H', 'Var', (4, 9))	('R752H', 'Mutation', 'p.R752H', (20, 25))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('R752H', 'Var', (20, 25))	('tumor', 'Disease', (140, 145))
37658	28574446	The R776H mutant receptor preferentially adopts the "receiver" position when paired with wild-type EGFR, providing support for the "superacceptor" hypothesis.	('adopts', 'Reg', (41, 47))	('R776H', 'Mutation', 'rs483352806', (4, 9))	('R776H', 'Var', (4, 9))	('preferentially', 'PosReg', (26, 40))
37660	28574446	G735S, G796S, and E804G mutations (G711S, G772S, and E780G in mature EGFR) found in prostate cancer are oncogenic, causing increased cell growth, transformation, and invasion.	('G735S', 'Mutation', 'rs121913430', (0, 5))	('prostate cancer', 'Disease', (84, 99))	('E780G', 'Var', (53, 58))	('G735S', 'Var', (0, 5))	('E804G', 'Var', (18, 23))	('E804G', 'Mutation', 'p.E804G', (18, 23))	('G772S', 'Mutation', 'p.G772S', (42, 47))	('increased', 'PosReg', (123, 132))	('G796S', 'Var', (7, 12))	('G796S', 'Mutation', 'rs754426793', (7, 12))	('G772S', 'Var', (42, 47))	('cell growth', 'CPA', (133, 144))	('causing', 'Reg', (115, 122))	('invasion', 'CPA', (166, 174))	('G711S', 'Mutation', 'p.G711S', (35, 40))	('E780G', 'Mutation', 'p.E780G', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('transformation', 'CPA', (146, 160))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))
37661	28574446	All of these mutant receptors demonstrate the increased phosphorylation of four tyrosine residues (Y869, Y1016, Y1092, and Y1197; Y845, Y992, Y1068, and Y1173 in mature EGFR) compared to wild-type EGFR in the absence of the ligand, indicating that the mutants are constitutively active.	('Y845', 'Var', (130, 134))	('Y1197; Y845', 'Var', (123, 134))	('Y992', 'Var', (136, 140))	('increased', 'PosReg', (46, 55))	('tyrosine', 'Chemical', 'MESH:D014443', (80, 88))	('Y1016', 'Var', (105, 110))	('Y1173', 'Var', (153, 158))	('Y1092', 'Var', (112, 117))	('phosphorylation', 'MPA', (56, 71))	('Y1068', 'Var', (142, 147))	('Y869', 'Var', (99, 103))
37662	28574446	The G735S and G796S mutations were also found in thyroid cancer and squamous cell carcinoma of the head and neck, respectively.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('G735S', 'Var', (4, 9))	('G796S', 'Var', (14, 19))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (82, 112))	('found', 'Reg', (40, 45))	('G796S', 'Mutation', 'rs754426793', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('squamous cell carcinoma', 'Disease', (68, 91))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 91))	('G735S', 'Mutation', 'rs121913430', (4, 9))
37663	28574446	The G796S and E804G mutations may destabilize the inactive dimer to form an asymmetric active configuration.	('G796S', 'Var', (4, 9))	('G796S', 'Mutation', 'rs754426793', (4, 9))	('destabilize', 'NegReg', (34, 45))	('E804G', 'Var', (14, 19))	('E804G', 'Mutation', 'p.E804G', (14, 19))	('inactive dimer', 'Interaction', (50, 64))
37664	28574446	The kinase domain mutation L858R (L834R in mature EGFR) has been observed in 40-45% of mutations in NSCLC.	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('L834R', 'Mutation', 'p.L834R', (34, 39))	('L858R', 'Mutation', 'rs121434568', (27, 32))	('EGFR', 'Gene', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('mutations', 'Var', (87, 96))
37665	28574446	An asymmetric configuration of the kinase domain dimer is required for the ligand-independent activity of NSCLC-associated EGFR kinase mutants.	('EGFR', 'Gene', (123, 127))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('mutants', 'Var', (135, 142))	('NSCLC', 'Disease', (106, 111))
37666	28574446	Crystal structural analysis indicates that the L858R mutation is likely to shift the equilibrium of the kinase domain dimer toward an active configuration by preventing key hydrophobic interactions between L858 and other residues in the N-lobe that lock the regulatory helix alphaC in the inactive position.	('key hydrophobic interactions', 'MPA', (169, 197))	('shift', 'Reg', (75, 80))	('L858R', 'Mutation', 'rs121434568', (47, 52))	('equilibrium', 'MPA', (85, 96))	('L858', 'Gene', (206, 210))	('preventing', 'NegReg', (158, 168))	('L858R', 'Var', (47, 52))
37667	28574446	This occurs by suppressing intrinsic disorder within the kinase domain N-lobe to allow the mutant kinase domain to act as a "superacceptor" within asymmetric kinase dimers.	('intrinsic disorder', 'Disease', 'MESH:D020919', (27, 45))	('intrinsic disorder', 'Disease', (27, 45))	('mutant', 'Var', (91, 97))	('suppressing', 'NegReg', (15, 26))
37668	28574446	In this ligand-independent activation of EGFR due to L858R, "beta-hairpin" interaction of the extracellular Subdomain II plays a critical role.	('L858R', 'Var', (53, 58))	('EGFR', 'Gene', (41, 45))	('L858R', 'Mutation', 'rs121434568', (53, 58))	('activation', 'PosReg', (27, 37))
37669	28574446	Interestingly, live-cell FRET measurements reveal that the L858R kinase mutation alters the extracellular domain structure such that unliganded mutant EGFR adopts an extended (untethered) configuration.	('adopts', 'Reg', (156, 162))	('L858R', 'Var', (59, 64))	('EGFR', 'Gene', (151, 155))	('alters', 'Reg', (81, 87))	('L858R', 'Mutation', 'rs121434568', (59, 64))	('extracellular domain structure', 'MPA', (92, 122))
37670	28574446	The L861Q mutation (L837Q in mature EGFR) found in NSCLC is also in the A-loop of the kinase domain.	('L861Q', 'Var', (4, 9))	('L837Q', 'Mutation', 'p.L837Q', (20, 25))	('NSCLC', 'Disease', (51, 56))	('L861Q', 'Mutation', 'rs121913444', (4, 9))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', (36, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
37671	28574446	The L861Q mutation could also disrupt the autoinhibitory interaction between the A-loop and helix alphaC of EGFR by destabilizing the set of hydrophobic interactions.	('L861Q', 'Var', (4, 9))	('EGFR', 'Gene', (108, 112))	('destabilizing', 'NegReg', (116, 129))	('L861Q', 'Mutation', 'rs121913444', (4, 9))	('set of hydrophobic interactions', 'MPA', (134, 165))	('disrupt', 'NegReg', (30, 37))	('autoinhibitory interaction', 'MPA', (42, 68))
37675	28574446	Recent genomic studies in GBM and NSCLC patients have identified an additional class of oncogenic mutations caused by the deletion of C-terminal coding regions.	('caused by', 'Reg', (108, 117))	('NSCLC', 'Disease', (34, 39))	('patients', 'Species', '9606', (40, 48))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('C-terminal coding', 'Protein', (134, 151))	('mutations', 'Var', (98, 107))	('deletion', 'Var', (122, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('oncogenic', 'Disease', (88, 97))
37676	28574446	Among them, mutants with a deletion of exon 25 (from G983 to L1038; from G959 to L1014 in mature EGFR) or both exons 25 and 26 (from G983 to G1054; from G959 to G1030 in mature EGFR, which is equivalent to EGFRvIVb above) are constitutively phosphorylated, and cause phosphorylation of downstream STAT3 when expressed in NIH 3T3 cells in the absence of the ligand.	('phosphorylation', 'MPA', (267, 282))	('STAT3', 'Gene', '20848', (297, 302))	('NIH 3T3', 'CellLine', 'CVCL:0594', (321, 328))	('G959 to L1014', 'Var', (73, 86))	('STAT3', 'Gene', (297, 302))	('cause', 'Reg', (261, 266))	('deletion', 'Var', (27, 35))	('from G983 to G1054; from G959 to G1030', 'Var', (128, 166))
37677	28574446	Exon 25 encodes 56 amino-acid residues from G983 to L1038 (from G959 to L1014 in mature EGFR), and encompasses the AP-2 helix and the electrostatic hook, which are involved in the stabilization of the symmetric inactive configuration of the kinase dimer.	('L1014', 'Var', (72, 77))	('AP-2', 'Gene', '7020', (115, 119))	('G959', 'Var', (64, 68))	('L1038', 'Var', (52, 57))	('AP-2', 'Gene', (115, 119))	('G983', 'Var', (44, 48))
37688	28659794	Targeting a particular gene, gene product, or signaling pathway can only eliminate a specific group of cells from the tumor, other genetically distinct variants can easily escape from that treatment and start developing tumor at surrounding area or may metastasize to distant sites.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('start', 'PosReg', (203, 208))	('tumor', 'Disease', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('metastasize', 'CPA', (253, 264))	('tumor', 'Disease', (118, 123))	('variants', 'Var', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
37770	28659794	Moreover, there combinations were found to exhibit chemo-preventive effects and reduced chemotherapy-induced toxicities and side effects.	('side effects', 'CPA', (124, 136))	('toxicities', 'Disease', 'MESH:D064420', (109, 119))	('reduced', 'NegReg', (80, 87))	('chemo-preventive effects', 'CPA', (51, 75))	('toxicities', 'Disease', (109, 119))	('combinations', 'Var', (16, 28))
37794	28659794	Although, NF-kappaB-mediated gene transcription is required for normal cellular activities, most of the cancers are associated with aberrant NF-kappaB signaling that lead to the release of different inflammatory cytokines followed by activation of diverse arrays of tumorigenic signaling pathways (Karin,).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NF-kappaB', 'Gene', '4790', (10, 19))	('activation', 'PosReg', (234, 244))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('NF-kappaB', 'Gene', '4790', (141, 150))	('release', 'MPA', (178, 185))	('aberrant', 'Var', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('NF-kappaB', 'Gene', (10, 19))	('tumor', 'Disease', (266, 271))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('inflammatory cytokines', 'MPA', (199, 221))	('lead to', 'Reg', (166, 173))	('cancers', 'Disease', (104, 111))	('NF-kappaB', 'Gene', (141, 150))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('associated', 'Reg', (116, 126))
37798	28659794	The subsequent prevention of DC maturation leads to immune tolerance due to T cells deletion or their differentiation into regulatory or suppressor T cells.	('immune tolerance', 'CPA', (52, 68))	('rat', 'Species', '10116', (36, 39))	('deletion', 'Var', (84, 92))	('differentiation', 'CPA', (102, 117))
37801	28659794	Similar observations were stated by couple of other groups where TQ treatment resulted in decease phosphorylation and subsequent activation of STAT3 (Badr et al.,; Kundu et al.,).	('STAT3', 'Gene', (143, 148))	('decease', 'NegReg', (90, 97))	('TQ', 'Chemical', 'MESH:C003466', (65, 67))	('treatment', 'Var', (68, 77))	('activation', 'PosReg', (129, 139))	('STAT3', 'Gene', '6774', (143, 148))
37853	27698831	Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('TMZ', 'Var', (84, 87))	('U87MG', 'CellLine', 'CVCL:0022', (95, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (84, 87))	('glioblastoma', 'Disease', (101, 113))	('examined', 'Reg', (29, 37))
37858	27698831	In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay.	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('Annexin V', 'Gene', '308', (133, 142))	('apoptosis rate', 'CPA', (58, 72))	('TMZ', 'Var', (108, 111))	('increased', 'PosReg', (44, 53))	('glioblastoma', 'Disease', (76, 88))	('astemizole', 'Chemical', 'MESH:D016589', (33, 43))	('Annexin V', 'Gene', (133, 142))
37861	27698831	Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Eag1', 'Gene', (16, 20))	('glioma', 'Disease', (120, 126))	('improve', 'PosReg', (48, 55))	('silencing', 'Var', (6, 15))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
37873	27698831	However, TMZ is known to lead to an increase in p53 protein expression, which accounts for its antitumor effects.	('tumor', 'Disease', (99, 104))	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (48, 51))	('increase', 'PosReg', (36, 44))	('TMZ', 'Chemical', 'MESH:D000077204', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('TMZ', 'Var', (9, 12))
37878	27698831	Monoclonal antibodies against Eag1 also had the ability to control tumor development, and proved as effective as the standard agent, cyclophosphamide, in a mouse model of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('Monoclonal', 'Var', (0, 10))	('effective', 'MPA', (100, 109))	('breast cancer', 'Disease', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('control', 'PosReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Eag1', 'Gene', (30, 34))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (133, 149))	('tumor', 'Disease', (67, 72))	('mouse', 'Species', '10090', (156, 161))
37885	27698831	In addition, the study evaluated whether silencing Eag1 with shRNA would increase the cell damage caused by TMZ, the first-line therapeutic agent for glioblastoma.	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('silencing', 'Var', (41, 50))	('increase', 'PosReg', (73, 81))	('glioblastoma', 'Disease', (150, 162))	('glioblastoma', 'Disease', 'MESH:D005909', (150, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('shRNA', 'Gene', (61, 66))	('Eag1', 'Gene', (51, 55))	('cell damage', 'CPA', (86, 97))
37895	27698831	Following the experimental treatment, Lipofectamine 2000 and Opti-MEM (Invitrogen; Thermo Fisher Scientific, Inc.) were used to transfect pKv10.1-3 and pScramble, according to the manufacturer's instructions.	('Opti-MEM', 'Chemical', '-', (61, 69))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (38, 56))	('Kv10.1-3', 'Gene', (139, 147))	('Kv10.1-3', 'Gene', '3756;27133', (139, 147))	('transfect', 'Var', (128, 137))
37903	27698831	Among them, PAPOLA showed the lowest rate of Cq value variation (qPCR) in glioma cells with Eag1 silencing compared with controls (~2%), an experimental condition that also reduces cell viability.	('PAPOLA', 'Gene', '10914', (12, 18))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('lowest', 'NegReg', (30, 36))	('silencing', 'Var', (97, 106))	('Cq value variation', 'MPA', (45, 63))	('Eag1', 'Gene', (92, 96))	('PAPOLA', 'Gene', (12, 18))	('glioma', 'Disease', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
37918	27698831	TMZ caused a decrease in cell viability in all time periods examined (24, 48 and 72 h).	('TMZ', 'Var', (0, 3))	('decrease', 'NegReg', (13, 21))	('cell viability', 'CPA', (25, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
37920	27698831	At 125 microM, TMZ caused a slight but stable decrease in cell viability compared with the mock group (100%) to 91, 87 and 89% after 24, 48 and 72 h, respectively (Fig.	('TMZ', 'Var', (15, 18))	('cell viability', 'CPA', (58, 72))	('decrease', 'NegReg', (46, 54))	('TMZ', 'Chemical', 'MESH:D000077204', (15, 18))
37925	27698831	1A), with 250 microM TMZ decreasing cell viability to a value close to 50%.	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))	('decreasing', 'NegReg', (25, 35))	('TMZ', 'Var', (21, 24))	('cell viability', 'CPA', (36, 50))
37939	27698831	Eag1 CTCF values was significantly lower in the cell group treated with pKv10.1 3 and 250 microM TMZ in comparison with pKv10.1 3 alone (P=0.049; Fig.	('CTCF', 'Chemical', '-', (5, 9))	('TMZ', 'Chemical', 'MESH:D000077204', (97, 100))	('Eag1 CTCF values', 'MPA', (0, 16))	('lower', 'NegReg', (35, 40))	('pKv10.1 3 and', 'Var', (72, 85))
37946	27698831	Lipofectamine also caused a decrease in glioblastoma cell viability compared with the mock control that was more intense at 24 h (22%) than at 72 h (10%).	('glioblastoma cell viability', 'Disease', (40, 67))	('Lipofectamine', 'Var', (0, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('Lipofectamine', 'Chemical', 'MESH:C086724', (0, 13))	('decrease', 'NegReg', (28, 36))	('glioblastoma cell viability', 'Disease', 'MESH:D005909', (40, 67))
37962	27698831	Suppression of Eag1 increased the induction of apoptosis (Q4 and Q2) caused by TMZ (Fig.	('apoptosis', 'CPA', (47, 56))	('Eag1', 'Gene', (15, 19))	('TMZ', 'Var', (79, 82))	('Suppression', 'NegReg', (0, 11))	('TMZ', 'Chemical', 'MESH:D000077204', (79, 82))
37964	27698831	In addition, treating with TMZ and silencing Eag1 with pKv10.1-3 increased the rate of apoptosis triggered by TMZ alone by 3.6-fold (17 vs. 63%; P=0.011; Fig.	('increased', 'PosReg', (65, 74))	('silencing', 'Var', (35, 44))	('TMZ', 'Chemical', 'MESH:D000077204', (110, 113))	('Kv10.1-3', 'Gene', (56, 64))	('Kv10.1-3', 'Gene', '3756;27133', (56, 64))	('apoptosis', 'CPA', (87, 96))	('Eag1', 'Gene', (45, 49))	('TMZ', 'Chemical', 'MESH:D000077204', (27, 30))
37970	27698831	Furthermore, glioblastoma cells treated with pKv10.1 3 plus 250 microM TMZ showed lower adherence with round and floating shapes, in comparison with TMZ alone, as determined by visual inspection.	('adherence', 'CPA', (88, 97))	('TMZ', 'Chemical', 'MESH:D000077204', (149, 152))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('TMZ', 'Chemical', 'MESH:D000077204', (71, 74))	('pKv10.1 3 plus', 'Var', (45, 59))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('lower', 'NegReg', (82, 87))
37972	27698831	Thus, deregulated activity or expression of ion channels will favor the loss of normal control of cell division, a classic hallmark of cancer.	('activity', 'MPA', (18, 26))	('cancer', 'Disease', (135, 141))	('loss', 'NegReg', (72, 76))	('expression', 'MPA', (30, 40))	('favor', 'PosReg', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('deregulated', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
37995	27698831	Among the four siRNAs evaluated, Kv10.1-3 caused the greatest silencing effect on Eag1, targeting nucleotides 1793-1813 of Eag1 mRNA (; NM_172362).	('silencing', 'MPA', (62, 71))	('Eag1', 'Gene', (123, 127))	('Eag1', 'Gene', (82, 86))	('Kv10.1-3', 'Gene', (33, 41))	('Kv10.1-3', 'Gene', '3756;27133', (33, 41))	('nucleotides 1793-1813', 'Var', (98, 119))
38001	27698831	It was observed that Eag1 has a role in the cell damage caused by TMZ on glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('cell damage', 'CPA', (44, 55))	('TMZ', 'Var', (66, 69))	('glioblastoma', 'Disease', (73, 85))	('Eag1', 'Gene', (21, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (73, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (66, 69))
38010	27698831	A viral vector expressing shRNA to Eag1 reduced tumor growth and angiogenesis of osteosarcoma, and siRNAs to Eag1 sensitized ovarian cancer cells to cisplatin.	('ovarian cancer', 'Disease', (125, 139))	('osteosarcoma', 'Disease', (81, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Eag1', 'Gene', (35, 39))	('tumor', 'Disease', (48, 53))	('sensitized', 'Reg', (114, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('reduced', 'NegReg', (40, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('angiogenesis', 'CPA', (65, 77))	('siRNAs', 'Var', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))
38011	27698831	To the best of our knowledge, no previous study has examined whether Eag1 gene silencing is able to sensitize glioblastoma cells to TMZ.	('sensitize', 'Reg', (100, 109))	('TMZ', 'Chemical', 'MESH:D000077204', (132, 135))	('gene silencing', 'Var', (74, 88))	('glioblastoma', 'Disease', (110, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (110, 122))	('Eag1', 'Gene', (69, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))
38016	27621679	IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies.	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('glioblastomas', 'Disease', (95, 108))	('intrahepatic cholangiocarcinomas', 'Disease', (127, 159))	('chondrosarcomas', 'Disease', (110, 125))	('IDH1/2', 'Gene', (0, 6))	('hematologic malignancies', 'Disease', (165, 189))	('glioblastomas', 'Disease', 'MESH:D005909', (95, 108))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('hematologic malignancies', 'Disease', 'MESH:D019337', (165, 189))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (127, 159))	('gliomas', 'Disease', (73, 80))	('mutations', 'Var', (7, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (110, 124))	('glioblastomas', 'Phenotype', 'HP:0012174', (95, 108))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (110, 125))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (140, 158))	('chondrosarcomas', 'Disease', 'MESH:D002813', (110, 125))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
38017	27621679	Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG).	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (162, 182))	('D-2-hydroxyglutarate', 'MPA', (162, 182))	('gain-of-function', 'PosReg', (43, 59))	('IDH1/2', 'Gene', '3417;3418', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('accumulation', 'MPA', (94, 106))	('secretion', 'MPA', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('IDH1/2', 'Gene', (27, 33))	('point mutations', 'Var', (8, 23))	('cancer', 'Disease', (63, 69))
38018	27621679	Indeed, high levels of D-2HG inhibit alpha-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation.	('alpha-ketoglutarate-dependent dioxygenases', 'Enzyme', (37, 79))	('hypermethylation', 'MPA', (148, 164))	('DNA demethylases', 'Enzyme', (103, 119))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (37, 56))	('inhibit', 'NegReg', (29, 36))	('D-2HG', 'Var', (23, 28))	('histone', 'Enzyme', (91, 98))	('cell differentiation', 'CPA', (188, 208))	('block', 'NegReg', (179, 184))
38019	27621679	Furthermore, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('mutations', 'Var', (71, 80))	('IDH1/2', 'Gene', (64, 70))
38020	27621679	Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy.	('IDH1/2', 'Gene', '3417;3418', (89, 95))	('IDH1/2', 'Gene', (16, 22))	('patients', 'Species', '9606', (75, 83))	('IDH1/2', 'Gene', (89, 95))	('IDH1/2', 'Gene', '3417;3418', (16, 22))	('mutations', 'Var', (96, 105))
38022	27621679	Point mutations in IDH1/2 define distinct subsets of low-grade glioma and secondary glioblastoma (GBM), chondrosarcoma, intrahepatic cholangiocarcinomas, hematologic malignancies, as well as premalignant diseases and rare inherited metabolism disorders.	('chondrosarcoma', 'Disease', 'MESH:D002813', (104, 118))	('chondrosarcoma', 'Disease', (104, 118))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('intrahepatic cholangiocarcinomas', 'Disease', (120, 152))	('inherited metabolism disorders', 'Disease', 'MESH:D008661', (222, 252))	('glioblastoma', 'Disease', (84, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('inherited metabolism disorders', 'Disease', (222, 252))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (104, 118))	('hematologic malignancies', 'Disease', (154, 178))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (120, 152))	('Point mutations', 'Var', (0, 15))	('premalignant diseases', 'Disease', (191, 212))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('hematologic malignancies', 'Disease', 'MESH:D019337', (154, 178))	('IDH1/2', 'Gene', '3417;3418', (19, 25))	('glioma', 'Disease', (63, 69))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (133, 151))	('IDH1/2', 'Gene', (19, 25))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))
38023	27621679	Multiple preclinical models have provided evidence for the oncogenic potential of IDH1/2 mutations, which alter epigenetic regulation, cancer cell differentiation, and metabolism.	('cancer', 'Disease', (135, 141))	('IDH1/2', 'Gene', '3417;3418', (82, 88))	('epigenetic regulation', 'MPA', (112, 133))	('alter', 'Reg', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('IDH1/2', 'Gene', (82, 88))	('mutations', 'Var', (89, 98))	('metabolism', 'MPA', (168, 178))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
38024	27621679	Depending on the associated genomic aberrations and the cellular context, the oncogenic potential of IDH1/2 mutations ranges from an initiating event - promoting transformation - to a secondary oncogenic event conferring selective advantage to cancer cells.	('mutations', 'Var', (108, 117))	('IDH1/2', 'Gene', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('IDH1/2', 'Gene', '3417;3418', (101, 107))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
38025	27621679	In vitro and in vivo preclinical studies have demonstrated that inhibition of IDH1/2-mutant enzymes decreases intracellular D-2-hydroxyglutarate (D-2HG) levels, reverses epigenetic dysregulation, and releases the differentiation block.	('differentiation', 'MPA', (213, 228))	('reverses', 'NegReg', (161, 169))	('IDH1/2', 'Gene', '3417;3418', (78, 84))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (124, 144))	('IDH1/2', 'Gene', (78, 84))	('inhibition', 'Var', (64, 74))	('decreases', 'NegReg', (100, 109))	('enzymes', 'Gene', (92, 99))	('epigenetic dysregulation', 'MPA', (170, 194))	('releases', 'PosReg', (200, 208))
38035	27621679	IDH1/2 mutations are heterozygous, missense mutations, leading to the substitution of the amino acids arginine 132 in IDH1 and arginine 172 or 140 in IDH2 (Table 1).	('IDH1', 'Gene', '3417', (0, 4))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('IDH1', 'Gene', (118, 122))	('arginine', 'Chemical', 'MESH:D001120', (127, 135))	('arginine', 'Chemical', 'MESH:D001120', (102, 110))	('arginine 172 or 140', 'Var', (127, 146))	('IDH1', 'Gene', '3417', (118, 122))	('IDH2', 'Gene', (150, 154))	('IDH1', 'Gene', (0, 4))	('IDH1/2', 'Gene', (0, 6))	('IDH2', 'Gene', '3418', (150, 154))	('mutations', 'Var', (7, 16))
38036	27621679	Initial functional studies of IDH1/2-mutant cells revealed that IDH1/2 mutations decrease the ability of the mutant enzymes to convert isocitrate to alphaKG3 and that IDH1/2-mutant enzymes inhibit wild-type activity in a dominant-negative manner.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('convert isocitrate', 'MPA', (127, 145))	('IDH1/2', 'Gene', (167, 173))	('decrease', 'NegReg', (81, 89))	('IDH1/2', 'Gene', (30, 36))	('IDH1/2', 'Gene', (64, 70))	('isocitrate', 'Chemical', 'MESH:C034219', (135, 145))	('mutations', 'Var', (71, 80))	('IDH1/2', 'Gene', '3417;3418', (167, 173))	('IDH1/2', 'Gene', '3417;3418', (30, 36))
38038	27621679	IDH1/2 mutant enzymes produce high levels of D-2HG in cells (50- to 100-fold higher than in normal tissues).	('mutant', 'Var', (7, 13))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('enzymes', 'Enzyme', (14, 21))	('D-2HG', 'MPA', (45, 50))	('IDH1/2', 'Gene', (0, 6))
38039	27621679	IDH1/2 mutants exclusively produce D-2HG.	('mutants', 'Var', (7, 14))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('IDH1/2', 'Gene', (0, 6))	('D-2HG', 'MPA', (35, 40))	('produce', 'Reg', (27, 34))
38042	27621679	In vitro ectopic expression of IDH1/2 mutants produces high D-2HG levels that inhibit alphaKG-dependent dioxygenases, including histone demethylases Jumonji 2 (JMJD2) and Jmj C domain-containing histone demethylase-1 (JHDM1), and DNA demethylases ten-eleven translocation 2 (TET2) proteins, resulting in the impairment of key steps in histone and DNA demethylation.	('JMJD2', 'Gene', '9682', (160, 165))	('mutants', 'Var', (38, 45))	('IDH1/2', 'Gene', '3417;3418', (31, 37))	('TET2', 'Gene', '54790', (275, 279))	('inhibit', 'NegReg', (78, 85))	('key steps', 'MPA', (322, 331))	('Jmj C', 'Var', (171, 176))	('JMJD2', 'Gene', (160, 165))	('DNA demethylation', 'MPA', (347, 364))	('histone', 'MPA', (335, 342))	('impairment', 'NegReg', (308, 318))	('IDH1/2', 'Gene', (31, 37))	('TET2', 'Gene', (275, 279))	('alphaKG-dependent dioxygenases', 'Enzyme', (86, 116))
38043	27621679	The epigenetic deregulation induced by IDH1/2 mutant enzymes translates into histone and DNA hypermethylation in a passage-dependent manner.	('epigenetic deregulation', 'MPA', (4, 27))	('IDH1/2', 'Gene', (39, 45))	('DNA hypermethylation', 'MPA', (89, 109))	('mutant', 'Var', (46, 52))	('histone', 'MPA', (77, 84))	('enzymes', 'Enzyme', (53, 60))	('IDH1/2', 'Gene', '3417;3418', (39, 45))
38048	27621679	Consequently, as observed in TET2 mutants, increased expression of stem cell markers and impaired differentiation are seen in cells expressing IDH1/2 mutant enzymes.	('TET2', 'Gene', '54790', (29, 33))	('mutant enzymes', 'Var', (150, 164))	('IDH1/2', 'Gene', '3417;3418', (143, 149))	('TET2', 'Gene', (29, 33))	('increased', 'PosReg', (43, 52))	('IDH1/2', 'Gene', (143, 149))	('impaired', 'NegReg', (89, 97))	('differentiation', 'CPA', (98, 113))	('expression', 'MPA', (53, 63))
38049	27621679	Hypermethylation can also compromise the binding of methylation-sensitive insulator proteins, which may result in the loss of insulation between topological DNA domains and aberrant gene activation, as recently demonstrated in IDH1-mutant gliomasphere models.	('insulation', 'MPA', (126, 136))	('activation', 'PosReg', (187, 197))	('compromise', 'NegReg', (26, 36))	('Hypermethylation', 'Var', (0, 16))	('binding', 'Interaction', (41, 48))	('IDH1', 'Gene', '3417', (227, 231))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('loss', 'NegReg', (118, 122))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('gliomas', 'Disease', (239, 246))	('IDH1', 'Gene', (227, 231))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))
38052	27621679	Mutations in D2HGDH and IDH2 are the molecular basis of this metabolic disorder, with a tendency to a more severe clinical phenotype in IDH2-mutant patients.	('patients', 'Species', '9606', (148, 156))	('D2HGDH', 'Gene', (13, 19))	('IDH2', 'Gene', (136, 140))	('D2HGDH', 'Gene', '728294', (13, 19))	('basis', 'Reg', (47, 52))	('IDH2', 'Gene', (24, 28))	('Mutations', 'Var', (0, 9))	('IDH2', 'Gene', '3418', (136, 140))	('IDH2', 'Gene', '3418', (24, 28))	('metabolic disorder', 'Phenotype', 'HP:0001939', (61, 79))
38053	27621679	Interestingly, although D-2HG levels are excessively high in patients with D-2HGA, no cancers have been reported so far in this population, which suggests that D-2HG accumulation is not sufficient alone to induce cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('high', 'PosReg', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (61, 69))	('D-2HGA', 'Var', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('D-2HG', 'MPA', (24, 29))	('cancer', 'Disease', (213, 219))	('cancers', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Disease', (86, 92))
38054	27621679	Indeed, while expression of mutant IDH1/2 enzymes was associated with increased progenitor cell marker expression and impaired cell differentiation, such epigenetics effects were not sufficient alone to drive oncogenesis.	('impaired', 'NegReg', (118, 126))	('cell differentiation', 'CPA', (127, 147))	('mutant', 'Var', (28, 34))	('increased', 'PosReg', (70, 79))	('progenitor cell marker', 'CPA', (80, 102))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('enzymes', 'Gene', (42, 49))	('IDH1/2', 'Gene', (35, 41))
38056	27621679	For example, excess of succinate is observed in case of mutations affecting genes coding for succinate dehydrogenase.	('mutations', 'Var', (56, 65))	('succinate', 'Chemical', 'MESH:D019802', (93, 102))	('succinate', 'MPA', (23, 32))	('succinate', 'Chemical', 'MESH:D019802', (23, 32))	('excess', 'PosReg', (13, 19))
38057	27621679	Similar to IDH1/2 mutations, such alterations have been linked with DNA hypermethylation, decreased expression of key genes involved in neuroendocrine differentiation, and a block in cellular differentiation.	('IDH1/2', 'Gene', '3417;3418', (11, 17))	('DNA', 'MPA', (68, 71))	('decreased', 'NegReg', (90, 99))	('expression', 'MPA', (100, 110))	('cellular differentiation', 'CPA', (183, 207))	('IDH1/2', 'Gene', (11, 17))	('alterations', 'Var', (34, 45))	('block', 'NegReg', (174, 179))	('mutations', 'Var', (18, 27))
38058	27621679	Few investigations have questioned metabolic changes associated with IDH1/2 mutations.	('metabolic', 'MPA', (35, 44))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('mutations', 'Var', (76, 85))	('IDH1/2', 'Gene', (69, 75))
38059	27621679	Recent metabolic flux analyses have shown that IDH1 mutations render tumor cells more dependent on mitochondrial oxidative tricarboxylic acid metabolism and compromise the conversion of glutamine to citrate and fatty acids under hypoxia as compared to IDH1-wild type cells.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('hypoxia', 'Disease', (229, 236))	('hypoxia', 'Disease', 'MESH:D000860', (229, 236))	('glutamine', 'Chemical', 'MESH:D005973', (186, 195))	('tumor', 'Disease', (69, 74))	('IDH1', 'Gene', (47, 51))	('more', 'PosReg', (81, 85))	('IDH1', 'Gene', (252, 256))	('dependent', 'MPA', (86, 95))	('compromise', 'NegReg', (157, 167))	('fatty acids', 'Chemical', 'MESH:D005227', (211, 222))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (123, 141))	('IDH1', 'Gene', '3417', (252, 256))	('IDH1', 'Gene', '3417', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('citrate', 'Chemical', 'MESH:D019343', (199, 206))
38061	27621679	Of note, D-2HG inhibits both ATP synthase and mTOR signaling in glioma cells, resulting in growth arrest and cell death under conditions of glucose limitation.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('cell death', 'CPA', (109, 119))	('ATP', 'Enzyme', (29, 32))	('growth arrest', 'Disease', 'MESH:D006323', (91, 104))	('mTOR', 'Gene', '2475', (46, 50))	('growth arrest', 'Disease', (91, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (91, 104))	('mTOR', 'Gene', (46, 50))	('inhibits', 'NegReg', (15, 23))	('D-2HG', 'Var', (9, 14))	('glioma', 'Disease', (64, 70))	('glucose', 'Chemical', 'MESH:D005947', (140, 147))	('glucose limitation', 'Phenotype', 'HP:0040270', (140, 158))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
38063	27621679	Overall, IDH1/2 mutations are likely associated with wide metabolic reprogramming.	('IDH1/2', 'Gene', (9, 15))	('mutations', 'Var', (16, 25))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('associated', 'Reg', (37, 47))	('wide metabolic reprogramming', 'CPA', (53, 81))
38064	27621679	Further deciphering of alterations in cellular metabolism associated with IDH1/2 mutations should highlight novel opportunities for therapeutic intervention and drug development.	('cellular metabolism', 'MPA', (38, 57))	('IDH1/2', 'Gene', (74, 80))	('mutations', 'Var', (81, 90))	('alterations', 'Reg', (23, 34))	('IDH1/2', 'Gene', '3417;3418', (74, 80))
38065	27621679	First identified in colorectal cancer, IDH1/2 mutations affecting IDH1 (R132) or IDH2 (R140, R172) are found across a broad spectrum of cancer types (Table 1).	('IDH1/2', 'Gene', (39, 45))	('R140', 'Var', (87, 91))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('IDH1', 'Gene', '3417', (66, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('mutations', 'Var', (46, 55))	('IDH1', 'Gene', (39, 43))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('IDH1', 'Gene', '3417', (39, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('colorectal cancer', 'Disease', (20, 37))	('IDH2', 'Gene', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('IDH2', 'Gene', '3418', (81, 85))	('IDH1/2', 'Gene', '3417;3418', (39, 45))	('IDH1', 'Gene', (66, 70))
38066	27621679	IDH1 mutations were described in 2008, in exome-sequencing studies of GBM (WHO grade IV astrocytoma).	('mutations', 'Var', (5, 14))	('astrocytoma', 'Disease', 'MESH:D001254', (88, 99))	('IDH1', 'Gene', (0, 4))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('astrocytoma', 'Disease', (88, 99))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('IDH1', 'Gene', '3417', (0, 4))
38067	27621679	Subsequent studies have shown that IDH1/2 mutations occur in a mutually exclusive manner in ~80% of WHO grade II/III oligodendrogliomas, astrocytomas, and oligoastrocytomas and secondary GBM (ie, GBM that had progressed from lower grade gliomas).	('astrocytomas', 'Disease', (160, 172))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('III oligodendrogliomas', 'Disease', (113, 135))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('III oligodendrogliomas', 'Disease', 'MESH:D009837', (113, 135))	('GBM', 'Phenotype', 'HP:0012174', (196, 199))	('secondary GBM', 'Disease', (177, 190))	('gliomas', 'Phenotype', 'HP:0009733', (237, 244))	('GBM', 'Phenotype', 'HP:0012174', (187, 190))	('astrocytomas', 'Disease', 'MESH:D001254', (137, 149))	('astrocytoma', 'Phenotype', 'HP:0009592', (137, 148))	('astrocytomas', 'Disease', 'MESH:D001254', (160, 172))	('astrocytoma', 'Phenotype', 'HP:0009592', (160, 171))	('gliomas', 'Disease', (128, 135))	('oligoastrocytomas', 'Disease', (155, 172))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('oligoastrocytomas', 'Disease', 'MESH:D001254', (155, 172))	('gliomas', 'Disease', (237, 244))	('IDH1/2', 'Gene', (35, 41))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('astrocytomas', 'Disease', (137, 149))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('gliomas', 'Disease', 'MESH:D005910', (237, 244))	('mutations', 'Var', (42, 51))
38069	27621679	IDH1 R132H mutation represents 80% of all IDH mutations.	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', (0, 3))	('R132H mutation', 'Var', (5, 19))	('IDH', 'Gene', '3417', (42, 45))	('IDH', 'Gene', '3417', (0, 3))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
38070	27621679	Rarely, other mutations are found affecting either IDH1 at Arg132 (including R132S, R132C, R132G, and R132L substitutions) or IDH2 at Arg172 (R172K most frequently; Table 1).	('R132L', 'Mutation', 'rs121913500', (102, 107))	('IDH1', 'Gene', '3417', (51, 55))	('R132S', 'Mutation', 'rs121913499', (77, 82))	('R132G', 'Var', (91, 96))	('R172K', 'Mutation', 'rs121913503', (142, 147))	('IDH2', 'Gene', (126, 130))	('R132L', 'Var', (102, 107))	('Arg132', 'Chemical', '-', (59, 65))	('R132C', 'Var', (84, 89))	('IDH2', 'Gene', '3418', (126, 130))	('IDH1', 'Gene', (51, 55))	('Arg172', 'Chemical', '-', (134, 140))	('R132S', 'Var', (77, 82))	('R132C', 'Mutation', 'rs121913499', (84, 89))	('R132G', 'Mutation', 'rs121913499', (91, 96))
38071	27621679	IDH1 R132H mutation can be diagnosed by immunohistochemistry or sequencing, while other mutations can be identified only by sequencing.	('IDH1', 'Gene', (0, 4))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('R132H', 'Var', (5, 10))	('IDH1', 'Gene', '3417', (0, 4))
38075	27621679	Accordingly, the IDH1/2 mutation is often referred to as a "trunk" initiating event in the clonal evolutionary tree of IDH1/2-mutant gliomas.	('IDH1/2', 'Gene', '3417;3418', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('IDH1/2', 'Gene', (119, 125))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('IDH1/2', 'Gene', (17, 23))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('mutation', 'Var', (24, 32))	('gliomas', 'Disease', (133, 140))
38076	27621679	Secondary genetic alterations occurring during the evolution of IDH1/2-mutant gliomas are often referred as "lineage-defining events", as TP53 and ATRX mutations characterize tumors of astrocytic lineage, whereas hTERT promoter mutation and 1p/19q codeletion are associated with oligodendroglial tumors.	('IDH1/2', 'Gene', '3417;3418', (64, 70))	('tumors', 'Disease', (175, 181))	('mutations', 'Var', (152, 161))	('IDH1/2', 'Gene', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('hTERT promoter', 'Gene', (213, 227))	('oligodendroglial tumors', 'Disease', (279, 302))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('1p/19q codeletion', 'Var', (241, 258))	('ATRX', 'Gene', (147, 151))	('TP53', 'Gene', (138, 142))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('ATRX', 'Gene', '546', (147, 151))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (279, 302))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('TP53', 'Gene', '7157', (138, 142))	('gliomas', 'Disease', (78, 85))	('tumors', 'Disease', (296, 302))	('associated', 'Reg', (263, 273))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
38078	27621679	Importantly, IDH1/2 mutations have been associated with prognostic and predictive values as biomarkers in gliomas, and assessment of the IDH1/2 status is being implemented in routine clinical practice for patients with primary brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('IDH1/2', 'Gene', '3417;3418', (137, 143))	('primary brain tumors', 'Disease', 'MESH:D001932', (219, 239))	('primary brain tumors', 'Disease', (219, 239))	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('patients', 'Species', '9606', (205, 213))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('IDH1/2', 'Gene', (137, 143))	('IDH1/2', 'Gene', (13, 19))	('brain tumors', 'Phenotype', 'HP:0030692', (227, 239))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))	('brain tumor', 'Phenotype', 'HP:0030692', (227, 238))	('mutations', 'Var', (20, 29))	('associated', 'Reg', (40, 50))
38080	27621679	Recent studies have demonstrated that IDH1/2 mutations are associated with younger age, better prognosis, and better response to treatment.	('IDH1/2', 'Gene', (38, 44))	('mutations', 'Var', (45, 54))	('IDH1/2', 'Gene', '3417;3418', (38, 44))
38082	27621679	Among IDH1/2-mutant gliomas, patients with oligodendroglial tumors harboring 1p19q codeletion have the more favorable prognosis.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('patients', 'Species', '9606', (29, 37))	('1p19q codeletion', 'Var', (77, 93))	('IDH1/2', 'Gene', '3417;3418', (6, 12))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (43, 66))	('oligodendroglial tumors', 'Disease', (43, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('IDH1/2', 'Gene', (6, 12))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
38083	27621679	The mechanisms underlying the relative chemo- and radiosensitive phenotypes associated with IDH1/2 mutations are not fully understood.	('mutations', 'Var', (99, 108))	('IDH1/2', 'Gene', '3417;3418', (92, 98))	('IDH1/2', 'Gene', (92, 98))
38084	27621679	Epigenetic silencing of the methyl-guanine methyl transferase (MGMT) - which encodes a DNA repair protein that counteracts the cytotoxic effect of alkylating agents - promoter gene by methylation is frequently observed in IDH1/2-mutant tumors and is associated with a partial inability of the tumor to repair the alkylating agent-induced DNA damage.	('IDH1/2', 'Gene', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('inability of the tumor', 'Disease', 'MESH:D016388', (276, 298))	('inability of the tumor', 'Disease', (276, 298))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('IDH1/2', 'Gene', '3417;3418', (222, 228))	('observed', 'Reg', (210, 218))	('tumors', 'Disease', (236, 242))	('Epigenetic', 'MPA', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('methylation', 'Var', (184, 195))
38085	27621679	IDH1 (R132) or IDH2 (R140 and R172) mutations are found in myeloid malignancies, that is, myelodysplastic syndromes (MDS), AML, and myeloproliferative neoplasms, and also in angioimmunoblastic T-cell lymphoma (AITL).	('MDS', 'Disease', (117, 120))	('IDH2', 'Gene', (15, 19))	('angioimmunoblastic T-cell lymphoma', 'Disease', (174, 208))	('myeloproliferative neoplasms', 'Disease', (132, 160))	('IDH2', 'Gene', '3418', (15, 19))	('R140 and R172) mutations', 'Var', (21, 45))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (132, 160))	('IDH1', 'Gene', (0, 4))	('cell lymphoma', 'Phenotype', 'HP:0012191', (195, 208))	('lymphoma', 'Phenotype', 'HP:0002665', (200, 208))	('neoplasms', 'Phenotype', 'HP:0002664', (151, 160))	('found', 'Reg', (50, 55))	('angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (174, 208))	('myeloid malignancies', 'Disease', 'MESH:D009369', (59, 79))	('IDH1', 'Gene', '3417', (0, 4))	('MDS', 'Phenotype', 'HP:0002863', (117, 120))	('myeloid malignancies', 'Disease', (59, 79))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (90, 115))	('myelodysplastic syndromes', 'Disease', (90, 115))	('MDS', 'Disease', 'MESH:D009190', (117, 120))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (132, 160))	('mutations', 'Var', (36, 45))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (90, 115))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (193, 208))	('AML', 'Disease', (123, 126))
38086	27621679	In myeloid malignancies, they are considered as an initiating event in 19% of patients with IDH1 mutations and 34% of patients with IDH2 mutations.	('myeloid malignancies', 'Disease', (3, 23))	('mutations', 'Var', (97, 106))	('IDH2', 'Gene', '3418', (132, 136))	('IDH1', 'Gene', (92, 96))	('patients', 'Species', '9606', (78, 86))	('IDH1', 'Gene', '3417', (92, 96))	('myeloid malignancies', 'Disease', 'MESH:D009369', (3, 23))	('patients', 'Species', '9606', (118, 126))	('IDH2', 'Gene', (132, 136))
38087	27621679	However, IDH1 mutations are likely to be implicated in early stages of de novo AML as others are, that is, NPM1, DNMT3A, TET2, and ASXL1.	('AML', 'Disease', (79, 82))	('ASXL1', 'Gene', (131, 136))	('NPM1', 'Gene', '4869', (107, 111))	('IDH1', 'Gene', (9, 13))	('TET2', 'Gene', (121, 125))	('DNMT3A', 'Gene', (113, 119))	('DNMT3A', 'Gene', '1788', (113, 119))	('IDH1', 'Gene', '3417', (9, 13))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('implicated', 'Reg', (41, 51))	('TET2', 'Gene', '54790', (121, 125))	('mutations', 'Var', (14, 23))	('NPM1', 'Gene', (107, 111))	('ASXL1', 'Gene', '171023', (131, 136))
38088	27621679	In de novo AML, IDH1/2 mutations are associated with older age, normal karyotype, and NPM1 mutations.	('IDH1/2', 'Gene', (16, 22))	('NPM1', 'Gene', '4869', (86, 90))	('mutations', 'Var', (23, 32))	('mutations', 'Var', (91, 100))	('AML', 'Disease', 'MESH:D015470', (11, 14))	('associated', 'Reg', (37, 47))	('IDH1/2', 'Gene', '3417;3418', (16, 22))	('NPM1', 'Gene', (86, 90))	('AML', 'Disease', (11, 14))
38090	27621679	IDH1 mutations are found in 6%-16% of de novo AML and are associated with a poorer outcome in patients treated with intensive chemotherapy, even in patients with favorable prognosis as per European LeukemiaNet (ELN) classification.	('patients', 'Species', '9606', (148, 156))	('IDH1', 'Gene', '3417', (0, 4))	('associated', 'Reg', (58, 68))	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (5, 14))	('AML', 'Disease', (46, 49))	('LeukemiaNet', 'Disease', (198, 209))	('IDH1', 'Gene', (0, 4))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('LeukemiaNet', 'Disease', 'None', (198, 209))
38091	27621679	IDH2 mutations are found in 8%-19% of de novo AML.	('mutations', 'Var', (5, 14))	('AML', 'Disease', (46, 49))	('IDH2', 'Gene', (0, 4))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('IDH2', 'Gene', '3418', (0, 4))
38093	27621679	Depending on the mutational spectrum, IDH2 R140Q mutations confer favorable or no impact on overall survival.	('overall', 'MPA', (92, 99))	('R140Q', 'Mutation', 'rs121913502', (43, 48))	('IDH2', 'Gene', (38, 42))	('IDH2', 'Gene', '3418', (38, 42))	('R140Q mutations', 'Var', (43, 58))
38094	27621679	Conversely, patients with IDH2 R172K mutation have a worse prognosis, with lower complete remission rate, higher relapse rate, and lower overall survival.	('lower', 'NegReg', (75, 80))	('patients', 'Species', '9606', (12, 20))	('complete remission rate', 'CPA', (81, 104))	('IDH2', 'Gene', (26, 30))	('relapse', 'CPA', (113, 120))	('higher', 'PosReg', (106, 112))	('R172K', 'Mutation', 'rs121913503', (31, 36))	('IDH2', 'Gene', '3418', (26, 30))	('lower', 'NegReg', (131, 136))	('overall', 'MPA', (137, 144))	('R172K', 'Var', (31, 36))
38095	27621679	IDH1/2 mutations are found in 4% to 12% of MDS cases, with a higher incidence (up to 23%) in high-risk MDS.	('MDS', 'Phenotype', 'HP:0002863', (103, 106))	('MDS', 'Disease', 'MESH:D009190', (103, 106))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('MDS', 'Disease', (103, 106))	('MDS', 'Disease', (43, 46))	('MDS', 'Disease', 'MESH:D009190', (43, 46))	('MDS', 'Phenotype', 'HP:0002863', (43, 46))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
38096	27621679	IDH1/2 mutations are associated with an older age, DNMT3A, ASXL1, SRSF2 mutations, and higher rate of transformation to AML.	('SRSF2', 'Gene', '6427', (66, 71))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('transformation', 'MPA', (102, 116))	('associated', 'Reg', (21, 31))	('AML', 'Disease', 'MESH:D015470', (120, 123))	('ASXL1', 'Gene', '171023', (59, 64))	('SRSF2', 'Gene', (66, 71))	('DNMT3A', 'Gene', '1788', (51, 57))	('DNMT3A', 'Gene', (51, 57))	('AML', 'Disease', (120, 123))	('IDH1/2', 'Gene', (0, 6))	('ASXL1', 'Gene', (59, 64))	('mutations', 'Var', (7, 16))
38097	27621679	In myeloproliferative neoplasms, the incidence of IDH1/2 mutations range between 2% and 4%, rising up to 31% after transformation to AML.	('IDH1/2', 'Gene', (50, 56))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (3, 31))	('neoplasms', 'Phenotype', 'HP:0002664', (22, 31))	('AML', 'Disease', 'MESH:D015470', (133, 136))	('rising', 'PosReg', (92, 98))	('mutations', 'Var', (57, 66))	('myeloproliferative neoplasms', 'Disease', (3, 31))	('AML', 'Disease', (133, 136))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (3, 31))
38098	27621679	They are associated with older age and SRSF2 mutations.	('SRSF2', 'Gene', '6427', (39, 44))	('SRSF2', 'Gene', (39, 44))	('mutations', 'Var', (45, 54))	('associated', 'Reg', (9, 19))
38099	27621679	In patients with myelofibrosis, IDH1/2 mutations confer worse prognosis.	('myelofibrosis', 'Phenotype', 'HP:0011974', (17, 30))	('IDH1/2', 'Gene', (32, 38))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (3, 11))	('IDH1/2', 'Gene', '3417;3418', (32, 38))	('myelofibrosis', 'Disease', (17, 30))	('myelofibrosis', 'Disease', 'MESH:D055728', (17, 30))
38100	27621679	Besides myeloid neoplasms, IDH2 mutations (mostly R172K) are found in 20%-45% of patients with AITL although its prognostic value is not yet known.	('R172K', 'Mutation', 'rs121913503', (50, 55))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (8, 25))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('patients', 'Species', '9606', (81, 89))	('found', 'Reg', (61, 66))	('R172K', 'Var', (50, 55))	('myeloid neoplasms', 'Disease', (8, 25))	('IDH2', 'Gene', (27, 31))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (8, 25))	('IDH2', 'Gene', '3418', (27, 31))
38101	27621679	IDH1/2 mutations have been detected in enchondromas and chondrosarcomas but rarely found in other mesenchymal tumors such as osteosarcomas.	('mesenchymal tumors', 'Disease', (98, 116))	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (56, 71))	('enchondromas and chondrosarcomas', 'Disease', 'MESH:D002812', (39, 71))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('osteosarcomas', 'Disease', (125, 138))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (56, 70))	('osteosarcomas', 'Phenotype', 'HP:0002669', (125, 138))	('enchondromas', 'Phenotype', 'HP:0030038', (39, 51))	('IDH1/2', 'Gene', (0, 6))	('osteosarcomas', 'Disease', 'MESH:D012516', (125, 138))	('detected', 'Reg', (27, 35))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (98, 116))	('mutations', 'Var', (7, 16))
38102	27621679	IDH1 mutations are the most frequent (40%-52%), and IDH2 mutations are present in 6%-11% of the cases.	('IDH2', 'Gene', (52, 56))	('IDH2', 'Gene', '3418', (52, 56))	('mutations', 'Var', (5, 14))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
38103	27621679	IDH1/2 mutations occur in up to 25% of intrahepatic cholangiocarcinomas.	('IDH1/2', 'Gene', '3417;3418', (0, 6))	('occur', 'Reg', (17, 22))	('intrahepatic cholangiocarcinomas', 'Disease', (39, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (39, 71))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))	('IDH1/2', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
38104	27621679	Again, IDH1 mutations are the most frequent (11%-24%) and IDH2 mutations are seen in 2%-6% of the cases.	('IDH1', 'Gene', '3417', (7, 11))	('IDH2', 'Gene', '3418', (58, 62))	('mutations', 'Var', (12, 21))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', (7, 11))
38105	27621679	Finally, sporadic cases of IDH1/2 mutations have been reported in other types of solid cancers: thyroid cancer, melanoma, prostate carcinoma, lung cancer, breast adenocarcinoma, colorectal cancer, esophageal cancer, and bladder cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('solid cancers', 'Disease', (81, 94))	('colorectal cancer', 'Disease', (178, 195))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (155, 176))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('lung cancer', 'Disease', (142, 153))	('melanoma', 'Disease', (112, 120))	('esophageal cancer', 'Disease', (197, 214))	('prostate carcinoma', 'Disease', 'MESH:D011472', (122, 140))	('breast adenocarcinoma', 'Disease', (155, 176))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (122, 140))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (155, 176))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('thyroid cancer', 'Disease', (96, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('IDH1/2', 'Gene', '3417;3418', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('IDH1/2', 'Gene', (27, 33))	('prostate carcinoma', 'Disease', (122, 140))	('reported', 'Reg', (54, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (220, 234))	('bladder cancer', 'Disease', (220, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('thyroid cancer', 'Disease', 'MESH:D013964', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('bladder cancer', 'Phenotype', 'HP:0009725', (220, 234))	('solid cancers', 'Disease', 'MESH:D009369', (81, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('mutations', 'Var', (34, 43))	('thyroid cancer', 'Phenotype', 'HP:0002890', (96, 110))
38106	27621679	D-2HG released in the serum and/or urine by cancer cells harboring IDH1/2 mutations is a biomarker for IDH1/2 mutations, presumably reflecting the neomorphic enzymatic activity of the mutant enzymes.	('mutations', 'Var', (110, 119))	('IDH1/2', 'Gene', (67, 73))	('cancer', 'Disease', (44, 50))	('mutations', 'Var', (74, 83))	('IDH1/2', 'Gene', '3417;3418', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('D-2HG', 'MPA', (0, 5))	('IDH1/2', 'Gene', '3417;3418', (67, 73))	('IDH1/2', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
38108	27621679	At diagnosis, D-2HG is a strong predictive biomarker for the presence of IDH1/2 mutations in AML.	('IDH1/2', 'Gene', (73, 79))	('AML', 'Disease', (93, 96))	('mutations', 'Var', (80, 89))	('IDH1/2', 'Gene', '3417;3418', (73, 79))	('AML', 'Disease', 'MESH:D015470', (93, 96))
38109	27621679	High total 2HG concentration was highly predictive of the presence of an IDH1/2 mutation, although separation of the d- and l-enantiomers distinguished IDH1/2-mutant and -wild-type AML with greater specificity.	('IDH1/2', 'Gene', (73, 79))	('IDH1/2', 'Gene', (152, 158))	('predictive', 'Reg', (40, 50))	('2HG concentration', 'MPA', (11, 28))	('AML', 'Disease', 'MESH:D015470', (181, 184))	('IDH1/2', 'Gene', '3417;3418', (73, 79))	('IDH1/2', 'Gene', '3417;3418', (152, 158))	('mutation', 'Var', (80, 88))	('AML', 'Disease', (181, 184))
38110	27621679	Increased serum and/or urine D-2HG levels predict IDH1/2 mutation in AML and intrahepatic cholangiocarcinoma and may be used as predictive biomarker for tumor response/recurrence.	('intrahepatic cholangiocarcinoma', 'Disease', (77, 108))	('mutation', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('AML', 'Disease', (69, 72))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('IDH1/2', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('IDH1/2', 'Gene', '3417;3418', (50, 56))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))
38112	27621679	Failure to normalize D-2HG levels is associated with treatment failure, whereas elevated D-2HG levels at complete remission are associated with poorer outcome, suggesting that D-2HG is a biomarker predictive of clinical response to intensive chemotherapy in AML patients with IDH1/2 mutations.	('AML', 'Disease', (258, 261))	('IDH1/2', 'Gene', (276, 282))	('mutations', 'Var', (283, 292))	('D-2HG', 'MPA', (21, 26))	('IDH1/2', 'Gene', '3417;3418', (276, 282))	('AML', 'Disease', 'MESH:D015470', (258, 261))	('patients', 'Species', '9606', (262, 270))
38114	27621679	Nevertheless, recent studies suggested that the urinary levels of D-2HG may increase the sensitivity and specificity for IDH1/2 mutation detection in glioma patients.	('increase', 'PosReg', (76, 84))	('IDH1/2', 'Gene', '3417;3418', (121, 127))	('urinary', 'MPA', (48, 55))	('patients', 'Species', '9606', (157, 165))	('D-2HG', 'Var', (66, 71))	('glioma', 'Disease', (150, 156))	('IDH1/2', 'Gene', (121, 127))	('mutation', 'Var', (128, 136))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
38118	27621679	The discovery of IDH1/2 mutations has resulted in a number of novel therapeutic approaches (Table 2), which either restore normal IDH1/2 function or block production or downstream effects of D-2HG.	('IDH1/2', 'Gene', '3417;3418', (17, 23))	('resulted in', 'Reg', (38, 49))	('IDH1/2', 'Gene', (130, 136))	('block', 'NegReg', (149, 154))	('IDH1/2', 'Gene', (17, 23))	('production', 'MPA', (155, 165))	('restore', 'PosReg', (115, 122))	('mutations', 'Var', (24, 33))	('IDH1/2', 'Gene', '3417;3418', (130, 136))	('function', 'MPA', (137, 145))
38119	27621679	Hypomethylating agents (HMAs) may be of interest in the context of CpG island methylator phenotype induced by IDH1/2 mutations.	('IDH1/2', 'Gene', '3417;3418', (110, 116))	('mutations', 'Var', (117, 126))	('IDH1/2', 'Gene', (110, 116))
38122	27621679	These series suggested the lack of association between IDH1/2 mutations and efficacy of HMAs or showed a better response to DNMT inhibitors among patients with IDH1/2-mutant AML.	('IDH1/2', 'Gene', (160, 166))	('DNMT', 'Gene', (124, 128))	('HMAs', 'CPA', (88, 92))	('AML', 'Disease', 'MESH:D015470', (174, 177))	('DNMT', 'Gene', '1786', (124, 128))	('IDH1/2', 'Gene', '3417;3418', (55, 61))	('IDH1/2', 'Gene', '3417;3418', (160, 166))	('AML', 'Disease', (174, 177))	('patients', 'Species', '9606', (146, 154))	('mutations', 'Var', (62, 71))	('IDH1/2', 'Gene', (55, 61))
38125	27621679	Preclinical in vitro and in vivo studies have validated the proof of concept that targeted inhibition of IDH1/2 mutants resulted in normalization in a dose-dependent manner of 2-HG, reversal of histone and DNA hypermethylation, and release of cellular differentiation block.	('reversal', 'Reg', (182, 190))	('IDH1/2', 'Gene', (105, 111))	('2-HG', 'MPA', (176, 180))	('cellular differentiation block', 'CPA', (243, 273))	('inhibition', 'NegReg', (91, 101))	('mutants', 'Var', (112, 119))	('normalization', 'MPA', (132, 145))	('IDH1/2', 'Gene', '3417;3418', (105, 111))
38126	27621679	AGI-5198 and AGI-6780 are selective inhibitors of mutant IDH1 and IDH2 enzymes, respectively.	('IDH2', 'Gene', '3418', (66, 70))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (57, 61))	('mutant', 'Var', (50, 56))	('IDH2', 'Gene', (66, 70))
38127	27621679	They normalized 2HG, reversed histone and DNA hypermethylation, and induced differentiation of not only TF-1 erythroleukemia cells but also primary human AML cells harboring IDH1/2 mutations.	('IDH1/2', 'Gene', '3417;3418', (174, 180))	('AML', 'Disease', 'MESH:D015470', (154, 157))	('differentiation', 'CPA', (76, 91))	('reversed', 'NegReg', (21, 29))	('induced', 'Reg', (68, 75))	('erythroleukemia', 'Disease', (109, 124))	('IDH1/2', 'Gene', (174, 180))	('human', 'Species', '9606', (148, 153))	('AML', 'Disease', (154, 157))	('mutations', 'Var', (181, 190))	('histone', 'MPA', (30, 37))	('DNA hypermethylation', 'MPA', (42, 62))	('erythroleukemia', 'Disease', 'MESH:D004915', (109, 124))	('normalized 2HG', 'MPA', (5, 19))
38130	27621679	Together, these studies indicate that differentiation therapy may be achievable in cancers with IDH1/2 mutations, thereby supporting the initiation of clinical trials (Table 2).	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('mutations', 'Var', (103, 112))	('IDH1/2', 'Gene', '3417;3418', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IDH1/2', 'Gene', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
38132	27621679	Separate first-in-human, Phase I, dose-escalation studies of AG-120 and AG-221 are underway in patients with IDH1/2-mutated hematologic malignancies (NCT02074839 and NCT01915498).	('NCT02074839', 'Var', (150, 161))	('hematologic malignancies', 'Disease', (124, 148))	('IDH1/2', 'Gene', (109, 115))	('patients', 'Species', '9606', (95, 103))	('human', 'Species', '9606', (18, 23))	('AG-221', 'Gene', (72, 78))	('NCT01915498', 'Var', (166, 177))	('AG-120', 'Gene', (61, 67))	('hematologic malignancies', 'Disease', 'MESH:D019337', (124, 148))	('IDH1/2', 'Gene', '3417;3418', (109, 115))
38135	27621679	Recent studies have investigated vaccination-based immunotherapy to target IDH1 mutations.	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))
38136	27621679	In principle, IDH1/2 mutants are ideal tumor-specific neoantigens due to their uniform occurrence at specific codons and ubiquitous expression throughout all tumor cells.	('mutants', 'Var', (21, 28))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('IDH1/2', 'Gene', '3417;3418', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (39, 44))	('IDH1/2', 'Gene', (14, 20))
38138	27621679	These preliminary results suggest that mutant IDH1-targeted immunotherapies can elicit potent antitumor immune responses.	('IDH1', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('IDH1', 'Gene', '3417', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('elicit', 'Reg', (80, 86))	('mutant', 'Var', (39, 45))	('tumor', 'Disease', (98, 103))
38141	27621679	Interestingly, of the five patients who achieved complete remission with or without incomplete marrow recovery, three had IDH1/2 mutations.	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (129, 138))	('IDH1/2', 'Gene', (122, 128))	('IDH1/2', 'Gene', '3417;3418', (122, 128))
38143	27621679	The discovery of IDH1/2 mutations highlights the unique role of the "oncometabolite" D-2HG in oncogenesis.	('mutations', 'Var', (24, 33))	('IDH1/2', 'Gene', (17, 23))	('IDH1/2', 'Gene', '3417;3418', (17, 23))
38144	27621679	Relevant preclinical models and results of early Phase I trials in adults with hematologic malignancies demonstrate that targeting IDH1/2 mutant is a valid strategy.	('IDH1/2', 'Gene', (131, 137))	('hematologic malignancies', 'Disease', (79, 103))	('mutant', 'Var', (138, 144))	('IDH1/2', 'Gene', '3417;3418', (131, 137))	('hematologic malignancies', 'Disease', 'MESH:D019337', (79, 103))
38177	27456282	Finally, in PIGPCs with ABCG2 or empty control expression under Dox control, the addition of Dox significantly reduced sphere formation in Tet-ABCG2 SP but not Tet-ABCG2 MP, Tet-Empty SP or Tet-Empty MP cells (Fig.	('Tet', 'Chemical', 'MESH:C010349', (174, 177))	('SP', 'Chemical', '-', (184, 186))	('SP', 'Chemical', '-', (149, 151))	('Dox', 'Chemical', 'MESH:D004318', (93, 96))	('reduced', 'NegReg', (111, 118))	('sphere formation', 'CPA', (119, 135))	('Tet', 'Chemical', 'MESH:C010349', (190, 193))	('Tet-ABCG2 SP', 'Var', (139, 151))	('Tet', 'Chemical', 'MESH:C010349', (160, 163))	('Tet', 'Chemical', 'MESH:C010349', (139, 142))	('Dox', 'Chemical', 'MESH:D004318', (64, 67))
38187	27456282	Together, these data suggest that while ABCG2 function promotes stem cell marker expression and self-renewal, other key features of stem-like tumor cells may be independently regulated.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('self-renewal', 'CPA', (96, 108))	('promotes', 'PosReg', (55, 63))	('function', 'Var', (46, 54))	('stem cell marker', 'CPA', (64, 80))	('ABCG2', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
38193	27456282	Intriguingly, gamma-secretase inhibition could not significantly diminish Hes1, Sox2, or Oct4 levels in ABCG2-overexpressing cells (Fig.	('Hes1', 'Gene', (74, 78))	('gamma-secretase', 'Protein', (14, 29))	('inhibition', 'Var', (30, 40))	('Oct4 levels', 'MPA', (89, 100))	('Hes1', 'Gene', '3280', (74, 78))	('Sox2', 'MPA', (80, 84))	('diminish', 'NegReg', (65, 73))
38203	27456282	Cells with high ABCG2 activity show increased levels of transcripts that are involved in stemness such as Mef, Sox2, Oct4, Id1, and Hes1, and the activity of ABCG2 is required for maintaining these stem markers.	('Hes1', 'Gene', '3280', (132, 136))	('ABCG2', 'Gene', (16, 21))	('levels of transcripts', 'MPA', (46, 67))	('increased', 'PosReg', (36, 45))	('high', 'Var', (11, 15))	('activity', 'MPA', (22, 30))	('Hes1', 'Gene', (132, 136))
38212	27456282	This is certainly the case in our tumor models, since the clinically critical stem cell characteristics of in vivo tumor formation and radiation resistance were not affected by ABCG2 function.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('function', 'Var', (183, 191))	('ABCG2', 'Gene', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('radiation resistance', 'CPA', (135, 155))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
38264	27478330	GBMs can have aberrant expression of different growth-control genes and their proteins, including impaired alpha thalassemia/mental retardation syndrome X-linked (ATRX) expression (ATRX-), p53 overexpression (p53+), and mutant IDH1 (H09) expression (IDH1+).	('mental retardation', 'Phenotype', 'HP:0001249', (125, 143))	('ATRX', 'Gene', (181, 185))	('growth-control genes', 'Gene', (47, 67))	('IDH1', 'Gene', '3417', (227, 231))	('ATRX', 'Gene', '546', (181, 185))	('IDH1', 'Gene', '3417', (250, 254))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (113, 161))	('impaired', 'NegReg', (98, 106))	('ATRX', 'Gene', (163, 167))	('expression', 'MPA', (238, 248))	('overexpression', 'PosReg', (193, 207))	('ATRX', 'Gene', '546', (163, 167))	('p53', 'Gene', '7157', (189, 192))	('p53', 'Gene', '7157', (209, 212))	('IDH1', 'Gene', (227, 231))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (113, 161))	('p53', 'Gene', (189, 192))	('expression', 'MPA', (23, 33))	('mutant', 'Var', (220, 226))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('IDH1', 'Gene', (250, 254))	('p53', 'Gene', (209, 212))
38265	27478330	Previous studies have shown that in unselected GBMs, IDH mutations were found in approximately 8.8% of the patients.	('found', 'Reg', (72, 77))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('mutations', 'Var', (57, 66))	('IDH', 'Gene', (53, 56))	('patients', 'Species', '9606', (107, 115))	('IDH', 'Gene', '3417', (53, 56))
38266	27478330	Selectively, IDH mutations were detected in almost 90% of secondary GBM, whereas these mutations are uncommon in primary GBM.	('IDH', 'Gene', '3417', (13, 16))	('secondary GBM', 'Disease', (58, 71))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('detected', 'Reg', (32, 40))	('GBM', 'Phenotype', 'HP:0012174', (121, 124))	('IDH', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
38267	27478330	Moreover, IDH mutations are established markers of better prognosis in GBM.	('IDH', 'Gene', (10, 13))	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('IDH', 'Gene', '3417', (10, 13))	('GBM', 'Disease', (71, 74))	('mutations', 'Var', (14, 23))
38268	27478330	Mutations in p53 have been found in approximately 60% patients with secondary and 25% with primary GBMs.	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('patients', 'Species', '9606', (54, 62))	('p53', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '7157', (13, 16))	('found', 'Reg', (27, 32))
38269	27478330	Association of TP53 mutations with survival outcome in GBM patients has not been consistent; some studies reported better survival in patients with TP53 mutations while others have failed to find such association.	('mutations', 'Var', (153, 162))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('patients', 'Species', '9606', (134, 142))	('TP53', 'Gene', '7157', (15, 19))	('better', 'PosReg', (115, 121))	('TP53', 'Gene', (15, 19))	('patients', 'Species', '9606', (59, 67))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('survival', 'MPA', (122, 130))
38270	27478330	ATRX is frequently mutated in secondary (57%) but rarely in primary GBMs.	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('ATRX', 'Gene', '546', (0, 4))	('mutated', 'Var', (19, 26))	('ATRX', 'Gene', (0, 4))
38271	27478330	In GBMs, ATRX mutations are usually accompanied by IDH and TP53 mutations.	('mutations', 'Var', (14, 23))	('IDH', 'Gene', (51, 54))	('TP53', 'Gene', (59, 63))	('IDH', 'Gene', '3417', (51, 54))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('accompanied', 'Reg', (36, 47))	(', ATRX', 'Gene', '546', (7, 13))	('TP53', 'Gene', '7157', (59, 63))
38273	27478330	Mutations of ATRX are still under study to determine its association with survival outcome in GBM patients and to establish these mutations as prognostic factors.	('ATRX', 'Gene', (13, 17))	('association', 'Reg', (57, 68))	('ATRX', 'Gene', '546', (13, 17))	('GBM', 'Disease', (94, 97))	('patients', 'Species', '9606', (98, 106))	('Mutations', 'Var', (0, 9))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))
38274	27478330	Therefore, the aims of our study were to determine the protein expression signatures of important growth-control genes, i.e., IDH1, p53, and ATRX, in our cohort of GBMs, and to determine whether in GBM altered protein expression of any of these growth-control genes, or their combined variants, were associated with significant increase in patient survival and, thereby, to establish prognostically distinct molecular subgroups of GBM irrespective of the histopathological diagnosis.	('IDH1', 'Gene', '3417', (126, 130))	('patient survival', 'CPA', (340, 356))	('ATRX,', 'Gene', '546', (141, 146))	('GBM', 'Phenotype', 'HP:0012174', (198, 201))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('patient', 'Species', '9606', (340, 347))	('variants', 'Var', (285, 293))	('GBM', 'Phenotype', 'HP:0012174', (164, 167))	('protein expression', 'MPA', (210, 228))	('GBM', 'Disease', (431, 434))	('IDH1', 'Gene', (126, 130))	('increase', 'PosReg', (328, 336))	('GBM', 'Phenotype', 'HP:0012174', (431, 434))
38296	27478330	Kaplan Meier survival analysis showed statistically better OS and PFS in patients with GBMs with mutant protein expression of ATRX (ATRX-) and IDH1 (IDH1+) than the patients with GBMs with counterpart status of these two proteins (Fig.	('IDH1', 'Gene', (149, 153))	('ATRX', 'Gene', (126, 130))	('protein', 'Protein', (104, 111))	('IDH1', 'Gene', (143, 147))	('better', 'PosReg', (52, 58))	('PFS', 'CPA', (66, 69))	('ATRX', 'Gene', (132, 136))	('mutant', 'Var', (97, 103))	('patients', 'Species', '9606', (73, 81))	('IDH1', 'Gene', '3417', (149, 153))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('patients', 'Species', '9606', (165, 173))	('ATRX', 'Gene', '546', (126, 130))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('IDH1', 'Gene', '3417', (143, 147))	('ATRX', 'Gene', '546', (132, 136))
38308	27478330	About 1.8% (3/163) of the samples was consisted of aberrant protein expression of all three proteins, i.e., ATRX-/p53+/IDH1+, while 39.9% (65/163) were wildtype protein expression group, i.e., ATRX+/p53-/IDH1-.	('/IDH', 'Gene', '3417', (118, 122))	('ATRX+', 'Gene', (193, 198))	(', ATRX', 'Gene', '546', (191, 197))	('p53', 'Gene', (199, 202))	('p53', 'Gene', '7157', (199, 202))	('ATRX+', 'Gene', '546', (193, 198))	('IDH1', 'Gene', (204, 208))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('aberrant', 'Var', (51, 59))	('IDH1', 'Gene', '3417', (204, 208))	('/IDH', 'Gene', (203, 207))	('IDH1', 'Gene', (119, 123))	('/IDH', 'Gene', '3417', (203, 207))	(', ATRX', 'Gene', '546', (106, 112))	('IDH1', 'Gene', '3417', (119, 123))	('protein expression', 'MPA', (60, 78))	('/IDH', 'Gene', (118, 122))
38311	27478330	It was previously observed in various studies that some relationship exists between aberrant expression of ATRX, p53, and IDH1 proteins in GBM patients and their OS.	('aberrant', 'Var', (84, 92))	('patients', 'Species', '9606', (143, 151))	('IDH1', 'Gene', (122, 126))	('GBM', 'Disease', (139, 142))	('p53', 'Gene', '7157', (113, 116))	('IDH1', 'Gene', '3417', (122, 126))	('p53', 'Gene', (113, 116))	('ATRX,', 'Gene', '546', (107, 112))	('proteins', 'Protein', (127, 135))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
38316	27478330	To date, some studies have demonstrated a correlation between TP53 gene mutations and decreased median survival, while others have not found such correlation.	('mutations', 'Var', (72, 81))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('decreased', 'NegReg', (86, 95))	('median survival', 'MPA', (96, 111))
38319	27478330	; here, p53 mutations were found to be related to survival in an age specific manner being favorable if mutations are found in younger population (22-40 age group), whereas unfavorable after 40 years old (41-60 and 61-80 age groups).	('p53', 'Gene', '7157', (8, 11))	('mutations', 'Var', (12, 21))	('mutations', 'Var', (104, 113))	('p53', 'Gene', (8, 11))
38323	27478330	Immunohistochemical analysis of ATRX, p53, and IDH1 individually, and in different combinations, revealed that aberrant expression of ATRX and IDH1 proteins and lack of p53 expression, together with combinations of ATRX-/IDH1+, ATRX-/p53-, IDH1+/p53-, and ATRX-/p53-/IDH1+ groups, were associated with a distinct and statistically significant increased survival rates regarding both OS and PFS.	('p53', 'Gene', (234, 237))	('ATRX', 'Gene', (134, 138))	('p53', 'Gene', (169, 172))	('proteins', 'Protein', (148, 156))	('IDH1', 'Gene', (143, 147))	('ATRX', 'Gene', '546', (134, 138))	('p53', 'Gene', '7157', (246, 249))	('/IDH', 'Gene', '3417', (220, 224))	('ATRX', 'Gene', (228, 232))	('IDH1', 'Gene', (221, 225))	('IDH1', 'Gene', '3417', (240, 244))	('lack', 'NegReg', (161, 165))	('/IDH', 'Gene', '3417', (266, 270))	('expression', 'MPA', (120, 130))	('ATRX', 'Gene', '546', (228, 232))	('p53', 'Gene', '7157', (262, 265))	('IDH1', 'Gene', (47, 51))	('p53', 'Gene', (246, 249))	('aberrant', 'Var', (111, 119))	('IDH1', 'Gene', '3417', (143, 147))	('p53', 'Gene', '7157', (38, 41))	('p53', 'Gene', (262, 265))	('ATRX,', 'Gene', '546', (32, 37))	('IDH1', 'Gene', (267, 271))	('IDH1', 'Gene', '3417', (221, 225))	('/IDH', 'Gene', (220, 224))	('ATRX', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (47, 51))	('increased', 'PosReg', (343, 352))	('ATRX', 'Gene', (215, 219))	('survival rates', 'CPA', (353, 367))	('/IDH', 'Gene', (266, 270))	('ATRX', 'Gene', (256, 260))	('p53', 'Gene', '7157', (234, 237))	('ATRX', 'Gene', '546', (215, 219))	('p53', 'Gene', (38, 41))	('ATRX', 'Gene', '546', (32, 36))	('p53', 'Gene', '7157', (169, 172))	('ATRX', 'Gene', '546', (256, 260))	('PFS', 'Disease', (390, 393))	('IDH1', 'Gene', '3417', (267, 271))	(', ATRX', 'Gene', '546', (226, 232))	('IDH1', 'Gene', (240, 244))
38325	26968172	Large number of studies indicates that the intracellular communication between the different cell types of the GBM microenvironment occurs through the functional transfer of oncogenic components such as proteins, non-coding RNAs, DNA and lipids via the release and uptake of extracellular vesicles (EVs).	('lipids', 'Chemical', 'MESH:D008055', (238, 244))	('non-coding RNAs', 'Var', (213, 228))	('proteins', 'Protein', (203, 211))
38331	26968172	There is increasing evidence that communication between tumor cells and the surrounding components such as stromal cells, immune cells, and extracellular matrix may directly affect various hallmark features of GBM.	('GBM', 'Disease', (210, 213))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('affect', 'Reg', (174, 180))	('communication', 'Var', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
38333	26968172	It is now established that the aberrant expression and microRNA activity are closely associated with several human disease including cancers.	('human disease', 'Disease', (109, 122))	('human', 'Species', '9606', (109, 114))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('aberrant expression', 'Var', (31, 50))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('microRNA activity', 'MPA', (55, 72))	('associated', 'Reg', (85, 95))
38340	26968172	Deregulation of microRNA expression has been observed in several cancers, including GBM.	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('GBM', 'Disease', (84, 87))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('observed', 'Reg', (45, 53))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('microRNA', 'Protein', (16, 24))
38342	26968172	Inhibition of miR-21 in GBM cell lines using antisense oligonucleotide regulated cell growth by increasing apoptosis without affecting cell proliferation, which suggested the oncogenic properties of this microRNA.	('miR-21', 'Gene', '406991', (14, 20))	('Inhibition', 'NegReg', (0, 10))	('miR-21', 'Gene', (14, 20))	('cell growth', 'CPA', (81, 92))	('oligonucleotide', 'Chemical', 'MESH:D009841', (55, 70))	('increasing', 'PosReg', (96, 106))	('apoptosis', 'CPA', (107, 116))	('antisense', 'Var', (45, 54))
38347	26968172	The classical subtype demonstrates high rates of epidermal growth factor receptor (EGFR) amplification.	('EGFR', 'Gene', '1956', (83, 87))	('amplification', 'Var', (89, 102))	('epidermal growth factor receptor', 'Gene', (49, 81))	('EGFR', 'Gene', (83, 87))	('epidermal growth factor receptor', 'Gene', '1956', (49, 81))
38348	26968172	The mesenchymal subtype is characterized by frequent mutations in the neurofibromin 1 (NF1) (in 37% of cases), phosphatase and tensin homolog (PTEN) and tumor protein p53 (TP53) genes whereas no distinctive mutation has been associated with neural GBMs.	('mesenchymal', 'Disease', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NF1', 'Gene', '4763', (87, 90))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('PTEN', 'Gene', '5728', (143, 147))	('mutations', 'Var', (53, 62))	('neurofibromin 1', 'Gene', (70, 85))	('tumor', 'Disease', (153, 158))	('p53', 'Gene', '7157', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('PTEN', 'Gene', (143, 147))	('p53', 'Gene', (167, 170))	('neurofibromin 1', 'Gene', '4763', (70, 85))	('NF1', 'Gene', (87, 90))
38349	26968172	The differential expression of microRNAs between GBM subtypes suggests that deregulation of subsets of microRNAs can transform the tumor cell phenotype.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('deregulation', 'Var', (76, 88))	('transform', 'Reg', (117, 126))
38352	26968172	Highly elevated cell proliferation in GBM is ascribed mainly to excessive proliferative signals caused by the aberrant activity of several receptor tyrosine kinases (RTK) such as PI3K/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways.	('AKT', 'Gene', '207', (184, 187))	('elevated', 'PosReg', (7, 15))	('aberrant', 'Var', (110, 118))	('AKT', 'Gene', (184, 187))	('proliferative signals', 'MPA', (74, 95))	('activity', 'MPA', (119, 127))	('excessive', 'PosReg', (64, 73))	('cell proliferation', 'CPA', (16, 34))
38357	26968172	PI3-Kinase/AKT pathway is the major downstream signaling route of active EGFR increasing the proliferation of tumor cells.	('AKT', 'Gene', (11, 14))	('EGFR', 'Gene', '1956', (73, 77))	('increasing', 'PosReg', (78, 88))	('tumor', 'Disease', (110, 115))	('EGFR', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('active', 'Var', (66, 72))	('AKT', 'Gene', '207', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
38364	26968172	Apart from few upregulated pro-oncogenic microRNAs such as miR-21, miR-10b, and miR-26a in general, the majority of microRNAs deregulated in numerous malignancies are expressed at much lower level in cancer tissues compared with their normal counterpart.	('miR-10b', 'Gene', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('miR-21', 'Gene', (59, 65))	('miR-26a', 'Gene', '407015', (80, 87))	('deregulated', 'Var', (126, 137))	('numerous malignancies', 'Disease', 'MESH:D009369', (141, 162))	('miR-10b', 'Gene', '406903', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('numerous malignancies', 'Disease', (141, 162))	('miR-21', 'Gene', '406991', (59, 65))	('miR-26a', 'Gene', (80, 87))	('cancer', 'Disease', (200, 206))
38366	26968172	Knock down of miR-21 and induction of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in GBM cell lines led to significant reduction of tumor growth in vivo by synergistic apoptotic effects via enhanced caspase activity.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('miR-21', 'Gene', '406991', (14, 20))	('tumor necrosis factor-related apoptosis inducing ligand', 'Gene', '8743', (38, 93))	('reduction of tumor', 'Disease', 'MESH:D009369', (139, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('enhanced', 'PosReg', (210, 218))	('activity', 'MPA', (227, 235))	('TRAIL', 'Gene', (95, 100))	('miR-21', 'Gene', (14, 20))	('caspase', 'CPA', (219, 226))	('TRAIL', 'Gene', '8743', (95, 100))	('reduction of tumor', 'Disease', (139, 157))	('Knock down', 'Var', (0, 10))
38386	26968172	Loss of miR-128 expression in neural stem cells precedes the onset of symptoms of tumor in mice and thus indicates that loss of miR-128 is an early event in GBM pathogenesis.	('mice', 'Species', '10090', (91, 95))	('miR-1', 'Gene', '79187', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-1', 'Gene', (8, 13))	('miR-1', 'Gene', (128, 133))	('Loss', 'NegReg', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('loss', 'Var', (120, 124))	('miR-1', 'Gene', '79187', (128, 133))
38388	26968172	Both in vivo and in vitro studies showed that inhibition of these two microRNAs reduced GSC proliferation, normalized tumor vasculature, suppressed tumor growth and increased animal survival via HIF-lalpha dependent Notch signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('animal survival', 'CPA', (175, 190))	('inhibition', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('suppressed', 'NegReg', (137, 147))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('reduced', 'NegReg', (80, 87))	('tumor', 'Disease', (118, 123))	('increased', 'PosReg', (165, 174))	('GSC proliferation', 'CPA', (88, 105))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
38398	26968172	Various HIF-1 target genes have been shown to regulate the angiogenesis by promoting the migratory and mitogenic activities of endothelial cells.	('regulate', 'Reg', (46, 54))	('HIF-1', 'Gene', '3091', (8, 13))	('HIF-1', 'Gene', (8, 13))	('genes', 'Var', (21, 26))	('angiogenesis', 'CPA', (59, 71))	('promoting', 'PosReg', (75, 84))	('mitogenic activities of endothelial cells', 'CPA', (103, 144))
38412	26968172	The AMPK-regulated inactivation of the OCT1 transcriptional activator of miR-451 facilitates GBM cells leaving low glucose areas.	('AMPK', 'Gene', '5563', (4, 8))	('miR-451', 'Gene', (73, 80))	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('OCT1', 'Gene', '5451', (39, 43))	('AMPK', 'Gene', (4, 8))	('miR-451', 'Gene', '574411', (73, 80))	('GBM cells leaving', 'CPA', (93, 110))	('inactivation', 'Var', (19, 31))	('OCT1', 'Gene', (39, 43))	('facilitates', 'PosReg', (81, 92))
38421	26968172	The main surface receptor of cytotoxic T lymphocytes (CTL) CTLA4 is considered as one of the immune checkpoints for tumor-mediated immune suppression and an earlier study showed that inhibition of oncogenic miR-222 and miR-339 increased the susceptibility of GBM cells to CTLs by targeting the activity of intracellular adhesion molecule 1 (ICAM-1).	('CTLA4', 'Gene', '1493', (59, 64))	('increased', 'PosReg', (227, 236))	('ICAM-1', 'Gene', '3383', (341, 347))	('miR-222', 'Gene', '407007', (207, 214))	('susceptibility', 'MPA', (241, 255))	('miR-222', 'Gene', (207, 214))	('CTLA4', 'Gene', (59, 64))	('ICAM-1', 'Gene', (341, 347))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('miR-339', 'Gene', (219, 226))	('miR-339', 'Gene', '442907', (219, 226))	('intracellular adhesion molecule 1', 'Gene', (306, 339))	('activity', 'MPA', (294, 302))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('intracellular adhesion molecule 1', 'Gene', '3383', (306, 339))	('targeting', 'Reg', (280, 289))	('tumor', 'Disease', (116, 121))	('inhibition', 'Var', (183, 193))
38436	26968172	Mutation of these EXO motifs or hnRNPA2B1 reduced expression level resulted in impaired selective loading of microRNAs into the EVs.	('reduced', 'NegReg', (42, 49))	('selective loading of microRNAs into the EVs', 'MPA', (88, 131))	('Mutation', 'Var', (0, 8))	('expression level', 'MPA', (50, 66))	('hnRNPA2B1', 'Gene', (32, 41))	('impaired', 'NegReg', (79, 87))	('hnRNPA2B1', 'Gene', '3181', (32, 41))
38443	26968172	EV-mediated exchange of these oncogenic microRNAs between GBM cells may represent an important mechanism to regulate tumor cell growth, invasion and survival.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('invasion', 'CPA', (136, 144))	('regulate', 'Reg', (108, 116))	('survival', 'CPA', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('exchange', 'Var', (12, 20))
38454	26968172	Our group has recently shown that ectopic expression of the tumor suppressor miR-1 in GBM results in inhibition of tumor growth, invasion and neovascularization.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibition', 'NegReg', (101, 111))	('miR-1', 'Gene', '79187', (77, 82))	('tumor', 'Disease', (115, 120))	('neovascularization', 'CPA', (142, 160))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('miR-1', 'Gene', (77, 82))	('ectopic expression', 'Var', (34, 52))	('GBM', 'Gene', (86, 89))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
38501	24673565	An example is polymer 1:1 R647 that formed nanoparticles that caused -9 +- 11% (essentially zero) loss in metabolic activity versus polymer 1:1 R657, which has a side chain longer by only one hydrocarbon but formed nanoparticles that caused 77 +- 13% loss in metabolic activity.	('hydrocarbon', 'Chemical', 'MESH:D006838', (192, 203))	('metabolic activity', 'MPA', (259, 277))	('carbon', 'Chemical', 'MESH:D002244', (197, 203))	('loss', 'NegReg', (98, 102))	('R647', 'Var', (26, 30))	('loss', 'NegReg', (251, 255))	('metabolic activity', 'MPA', (106, 124))
38511	24673565	The product 2,2'-disulfanediylbis(ethane-2,1-diyl) (BR6) was confirmed via1H NMR: (CDCl3, 400 Hz), delta2.95 (2H, t, CH2CHCOOCH2CH2S), delta3.95 (2H, t, CH2CHCOOCH2CH2S), delta5.8-5.9 (1H, d, CH2CHCOOCH2CH2S), delta6.1-6.2 (1H, dd, CH2CHCOOCH2CH2S), delta6.4-6.5 (1H, d, CH2CHCOOCH2CH2S).	('CH2CHCOOCH2CH2S', 'CellLine', 'CVCL:Z390', (153, 168))	('CH2CHCOOCH2CH2S', 'CellLine', 'CVCL:Z390', (232, 247))	('delta6.4-6.5', 'Var', (250, 262))	('CH2CHCOOCH2CH2S', 'CellLine', 'CVCL:Z390', (192, 207))	('delta6.1-6.2', 'Var', (210, 222))	('delta2.95', 'Var', (99, 108))	('CH2CHCOOCH2CH2S', 'CellLine', 'CVCL:Z390', (271, 286))	('CH2CHCOOCH2CH2S', 'CellLine', 'CVCL:Z390', (117, 132))
38520	24673565	GFP knockdown was determined by finding the geometric mean FL1 fluorescence signal for each sample.	('knockdown', 'Var', (4, 13))	('FL1', 'Gene', (59, 62))	('FL1', 'Gene', '100306940', (59, 62))
38529	24673565	thanks the NIH Cancer Nanotechnology Training Center (R25CA153952) at the JHU Institute for Nanobiotechnology for fellowship support and S.Y.T.	('NIH Cancer', 'Disease', 'MESH:D009369', (11, 21))	('NIH Cancer', 'Disease', (11, 21))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('R25CA153952', 'Var', (54, 65))
38538	32545574	The aberrant activation of RTKs results in deregulation of their downstream signaling cascade which includes activation of MAPK and ERK pathways, as well as activation of non-receptor tyrosine kinases, such as SRC and ABL.	('ERK', 'Gene', '5594', (132, 135))	('SRC', 'Disease', (210, 213))	('ERK', 'Gene', (132, 135))	('RTKs', 'Gene', (27, 31))	('aberrant', 'Var', (4, 12))	('downstream signaling', 'MPA', (65, 85))	('tyrosine', 'Chemical', 'MESH:D014443', (184, 192))	('activation', 'PosReg', (109, 119))	('activation', 'PosReg', (13, 23))	('ABL', 'Gene', '25', (218, 221))	('ABL', 'Gene', (218, 221))	('deregulation', 'MPA', (43, 55))	('MAPK', 'Pathway', (123, 127))	('activation', 'PosReg', (157, 167))	('non-receptor tyrosine kinases', 'Pathway', (171, 200))
38540	32545574	Tumor and nontumor cells in the TME cooperate to promote the aberrant expression of a panel of inflammatory cytokines that trigger neoangiogenesis and evasion from the immune response, further enhancing tumor aggressiveness.	('tumor', 'Disease', (13, 18))	('aberrant', 'Var', (61, 69))	('tumor', 'Disease', (203, 208))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor aggressiveness', 'Disease', (203, 223))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('evasion from the immune response', 'MPA', (151, 183))	('aggressiveness', 'Phenotype', 'HP:0000718', (209, 223))	('expression', 'MPA', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (203, 223))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('promote', 'PosReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('enhancing', 'PosReg', (193, 202))	('neoangiogenesis', 'MPA', (131, 146))
38545	32545574	The main resistance mechanisms are again associated with tumor heterogenicity and evolution, sustained inflammatory cytokines production, rewiring of the metabolism, and finally, with aberrant functionality of DNA damage response and DNA repair mechanisms.	('associated', 'Reg', (41, 51))	('inflammatory cytokines production', 'MPA', (103, 136))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('aberrant', 'Var', (184, 192))	('tumor', 'Disease', (57, 62))
38546	32545574	The connections between the aberrant activation of RTKs signaling and the deregulation of the aforementioned abnormalities that contribute to GBM development and to its resistance to therapy have been only partially uncovered.	('aforementioned abnormalities', 'Disease', (94, 122))	('activation', 'PosReg', (37, 47))	('deregulation', 'MPA', (74, 86))	('aberrant', 'Var', (28, 36))	('aforementioned abnormalities', 'Disease', 'MESH:D018376', (94, 122))
38552	32545574	EGFR expression can be amplified because of amplification of the chromosome 7 region that includes the EGFR gene, or it can be constitutively activated by specific mutations.	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (103, 107))	('amplification', 'Var', (44, 57))	('amplified', 'PosReg', (23, 32))	('mutations', 'Var', (164, 173))	('EGFR', 'Gene', '1956', (0, 4))
38553	32545574	The most common EGFR mutant, EGFR variant (v)III, has an extracellular domain truncation from exons 2 to 7 and is constitutively active in GBM independently of EGF.	('EGF', 'Gene', (29, 32))	('EGF', 'Gene', (160, 163))	('EGF', 'Gene', '1950', (16, 19))	('EGFR', 'Gene', (16, 20))	('extracellular domain truncation', 'MPA', (57, 88))	('EGF', 'Gene', '1950', (29, 32))	('EGF', 'Gene', '1950', (160, 163))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (16, 20))	('variant', 'Var', (34, 41))	('EGF', 'Gene', (16, 19))
38556	32545574	The prevalence of EGFR aberrant activation in GBM makes EGFR an excellent target.	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', (56, 60))	('aberrant activation', 'Var', (23, 42))
38563	32545574	Interestingly, the hyperactivation of SRC in GBM significantly contributes to sustain the rewiring of some of the main networks, including inflammation and metabolism, which contributes to the establishment of TME and tumor development.	('contributes', 'Reg', (174, 185))	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('inflammation', 'Disease', (139, 151))	('metabolism', 'MPA', (156, 166))	('rewiring', 'MPA', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('hyperactivation', 'Var', (19, 34))	('SRC', 'Gene', (38, 41))	('tumor', 'Disease', (218, 223))	('TME', 'CPA', (210, 213))
38585	32545574	SRC hyperactivation, in turn, can promote activation or overexpression of proinflammatory transcription factors, such as STAT3, NF-kB, and AP-1, thereby supporting this inflammatory TME.	('STAT3', 'Gene', '6774', (121, 126))	('AP-1', 'Gene', (139, 143))	('STAT3', 'Gene', (121, 126))	('NF-kB', 'Gene', (128, 133))	('activation', 'PosReg', (42, 52))	('overexpression', 'PosReg', (56, 70))	('SRC', 'Gene', (0, 3))	('AP-1', 'Gene', '3726', (139, 143))	('hyperactivation', 'Var', (4, 19))
38591	32545574	In general, in tumors, oncogenic RAS mutation activates the production of cytokines, such as IL-6 and IL-8.	('oncogenic', 'Var', (23, 32))	('IL-6', 'Gene', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('IL-8', 'Gene', '3576', (102, 106))	('production of cytokines', 'MPA', (60, 83))	('mutation', 'Var', (37, 45))	('IL-6', 'Gene', '3569', (93, 97))	('activates', 'PosReg', (46, 55))	('IL-8', 'Gene', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('RAS', 'Gene', (33, 36))	('tumors', 'Disease', (15, 21))
38592	32545574	Although RAS mutation is generally not involved in the GBM pathophysiology, EGFR amplification or mutant EGFRvIII expression can lead to RAS and PI3K/AKT pathways deregulation.	('lead to', 'Reg', (129, 136))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', '1956', (105, 109))	('AKT', 'Gene', '207', (150, 153))	('deregulation', 'NegReg', (163, 175))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', (105, 109))	('AKT', 'Gene', (150, 153))	('mutant', 'Var', (98, 104))
38593	32545574	Thus, EGFR deregulation in GBM drives a strong induction and secretion of IL-6 and IL-8, triggered, respectively, by AKT/SMAD5 signaling and by the activity of transcription factors, such as AP-1 and NF-kB.	('AKT', 'Gene', '207', (117, 120))	('SMAD5', 'Gene', '4090', (121, 126))	('induction', 'MPA', (47, 56))	('secretion', 'MPA', (61, 70))	('EGFR', 'Gene', (6, 10))	('AP-1', 'Gene', '3726', (191, 195))	('IL-6', 'Gene', (74, 78))	('deregulation', 'Var', (11, 23))	('AKT', 'Gene', (117, 120))	('IL-6', 'Gene', '3569', (74, 78))	('SMAD5', 'Gene', (121, 126))	('IL-8', 'Gene', '3576', (83, 87))	('AP-1', 'Gene', (191, 195))	('IL-8', 'Gene', (83, 87))	('EGFR', 'Gene', '1956', (6, 10))
38594	32545574	Interestingly, EGFR and mutant EGFRvIII promote NF-kB activity in GBM via AKT-dependent and independent mechanisms, further supporting cytokines production.	('mutant', 'Var', (24, 30))	('promote', 'PosReg', (40, 47))	('cytokines production', 'MPA', (135, 155))	('EGFR', 'Gene', '1956', (31, 35))	('AKT', 'Gene', '207', (74, 77))	('EGFR', 'Gene', (31, 35))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('activity', 'MPA', (54, 62))	('AKT', 'Gene', (74, 77))	('NF-kB', 'Protein', (48, 53))	('supporting', 'PosReg', (124, 134))
38596	32545574	Importantly, we have also reported that the aberrant activation of SRC in GBM cell lines promoted caspase-8 phosphorylation on Y380, leading to neoplastic transformation.	('SRC', 'Gene', (67, 70))	('caspase-8', 'Gene', '841', (98, 107))	('activation', 'PosReg', (53, 63))	('promoted', 'PosReg', (89, 97))	('leading to', 'Reg', (133, 143))	('phosphorylation', 'MPA', (108, 123))	('caspase-8', 'Gene', (98, 107))	('aberrant', 'Var', (44, 52))	('Y380', 'Var', (127, 131))	('neoplastic transformation', 'CPA', (144, 169))
38597	32545574	On the basis of these data, we can speculate that SRC can promote NF-kB activity, and therefore TME, by phosphorylating caspase-8 on Y380.	('caspase-8', 'Gene', '841', (120, 129))	('promote', 'PosReg', (58, 65))	('activity', 'MPA', (72, 80))	('phosphorylating', 'MPA', (104, 119))	('Y380', 'Var', (133, 137))	('NF-kB', 'Protein', (66, 71))	('caspase-8', 'Gene', (120, 129))
38618	32545574	On the contrary, glioma cells in the vascularized areas of the tumor are highly proliferating and predominantly sustained by PPP.	('tumor', 'Disease', (63, 68))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PPP', 'Var', (125, 128))	('glioma', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
38623	32545574	Active SRC, indeed, interacts with both HK1 and the isoform hexokinase 2 (HK2) and phosphorylates them, respectively, on Y732 and Y686, therefore, activating the enzymes.	('hexokinase 2', 'Gene', (60, 72))	('HK2', 'Gene', (74, 77))	('HK1', 'Gene', (40, 43))	('activating', 'PosReg', (147, 157))	('HK2', 'Gene', '3099', (74, 77))	('hexokinase 2', 'Gene', '3099', (60, 72))	('interacts', 'Interaction', (20, 29))	('Y686', 'Var', (130, 134))	('Y732', 'Var', (121, 125))	('HK1', 'Gene', '3098', (40, 43))
38624	32545574	This modification induces glycolysis and promotes cell growth, tumorigenesis, and invasion.	('modification', 'Var', (5, 17))	('tumor', 'Disease', (63, 68))	('glycolysis', 'MPA', (26, 36))	('invasion', 'CPA', (82, 90))	('cell growth', 'CPA', (50, 61))	('promotes', 'PosReg', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('induces', 'Reg', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
38637	32545574	The aberrant activity of SRC in GBM along with the important role of MYC in GBM, led to speculate that the SRC-MYC axis could also have a role in this context and strengthen the hypothesis that targeting SRC could help to defeat cancer-associated adaptation, among which MYC-dependent metabolic reprogramming.	('MYC', 'Gene', '4609', (111, 114))	('MYC', 'Gene', (271, 274))	('MYC', 'Gene', (69, 72))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('aberrant', 'Var', (4, 12))	('MYC', 'Gene', (111, 114))	('MYC', 'Gene', '4609', (271, 274))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('MYC', 'Gene', '4609', (69, 72))
38638	32545574	Noteworthily, it has been demonstrated that SRC can affect glycolysis in cancer cells through a direct phosphorylation of pyruvate dehydrogenase (PDH), inhibiting its activity and driving the Warburg effect.	('SRC', 'Var', (44, 47))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PDH', 'Gene', '54704', (146, 149))	('glycolysis', 'MPA', (59, 69))	('driving', 'Reg', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('affect', 'Reg', (52, 58))	('pyruvate dehydrogenase', 'Gene', '54704', (122, 144))	('phosphorylation', 'MPA', (103, 118))	('Warburg effect', 'CPA', (192, 206))	('activity', 'MPA', (167, 175))	('inhibiting', 'NegReg', (152, 162))	('pyruvate dehydrogenase', 'Gene', (122, 144))	('PDH', 'Gene', (146, 149))
38641	32545574	Remarkably, SRC phosphorylates EGFRvIII on Y845, and therefore promotes its translocation to the mitochondria.	('translocation to the mitochondria', 'MPA', (76, 109))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('promotes', 'PosReg', (63, 71))	('Y845', 'Var', (43, 47))
38643	32545574	In addition, its role in the inflammatory response and in the reprogramming of metabolism that overall sustains the tumor microenvironment, point to SRC kinase targeting as a valuable approach to ameliorate GBM treatment.	('targeting', 'Var', (160, 169))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SRC', 'Protein', (149, 152))	('tumor', 'Disease', (116, 121))
38660	32545574	PP2 treatment prevents the SRC-dependent formation of CAS/Crk/RAC complexes responsible for cytoskeletal reorganization, thus, blocking the migration process.	('RAC', 'Gene', '5879', (62, 65))	('migration process', 'CPA', (140, 157))	('CAS', 'Gene', (54, 57))	('CAS', 'Gene', '9564', (54, 57))	('Crk', 'Gene', '1398', (58, 61))	('SRC-dependent', 'MPA', (27, 40))	('RAC', 'Gene', (62, 65))	('prevents', 'NegReg', (14, 22))	('PP2', 'Var', (0, 3))	('blocking', 'NegReg', (127, 135))	('Crk', 'Gene', (58, 61))
38661	32545574	Furthermore, PP2 also inhibits cell migration affecting SRC-mediated caveolin-1 phosphorylation.	('caveolin-1', 'Gene', (69, 79))	('caveolin-1', 'Gene', '857', (69, 79))	('cell migration', 'CPA', (31, 45))	('PP2', 'Var', (13, 16))	('inhibits', 'NegReg', (22, 30))
38662	32545574	Importantly, it has been demonstrated that PP2 increased radiosensitivity in U251 and T98G cells by suppressing the secretion of MMP2, which is well known to promote cell invasion and resistance to therapy.	('secretion', 'MPA', (116, 125))	('MMP2', 'Gene', '4313', (129, 133))	('promote', 'PosReg', (158, 165))	('cell invasion', 'CPA', (166, 179))	('resistance', 'CPA', (184, 194))	('increased', 'PosReg', (47, 56))	('suppressing', 'NegReg', (100, 111))	('PP2', 'Var', (43, 46))	('MMP2', 'Gene', (129, 133))	('U251', 'CellLine', 'CVCL:0021', (77, 81))	('T98G', 'CellLine', 'CVCL:0556', (86, 90))	('radiosensitivity', 'MPA', (57, 73))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (47, 73))
38664	32545574	Interestingly, the combination of PP2 and the standard treatment of glioma (radiotherapy with TMZ) has been shown to affect tumor growth in nude mice.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (94, 97))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('nude mice', 'Species', '10090', (140, 149))	('glioma', 'Disease', (68, 74))	('PP2', 'Var', (34, 37))	('affect', 'Reg', (117, 123))
38665	32545574	SI221 is a novel selective pyrazolo [3,4-d] pyrimidine derivative SFK inhibitor, which is able to reduce cell migration and to promote cell death of GBM cells.	('cell migration', 'CPA', (105, 119))	('promote', 'PosReg', (127, 134))	('reduce', 'NegReg', (98, 104))	('cell death', 'CPA', (135, 145))	('pyrazolo [3,4-d] pyrimidine', 'Chemical', 'MESH:C014175', (27, 54))	('SI221', 'Chemical', 'MESH:C000618489', (0, 5))	('SI221', 'Var', (0, 5))
38669	32545574	Similar to dasatinib, it was approved by the FDA for therapeutic use for CML patients resistant to imatinib treatment due to ABL-BCR mutations.	('ABL', 'Gene', '25', (125, 128))	('ABL', 'Gene', (125, 128))	('patients', 'Species', '9606', (77, 85))	('CML', 'Disease', 'MESH:D015464', (73, 76))	('dasatinib', 'Chemical', 'MESH:D000069439', (11, 20))	('mutations', 'Var', (133, 142))	('CML', 'Phenotype', 'HP:0005506', (73, 76))	('imatinib', 'Chemical', 'MESH:D000068877', (99, 107))	('CML', 'Disease', (73, 76))
38676	32545574	In addition, saracatinib has been demonstrated to inhibit in vitro migration and invasion of breast tumor cells resistant to lapatinib treatment.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('saracatinib', 'Var', (13, 24))	('invasion', 'CPA', (81, 89))	('inhibit', 'NegReg', (50, 57))	('breast tumor', 'Disease', (93, 105))	('lapatinib', 'Chemical', 'MESH:D000077341', (125, 134))	('breast tumor', 'Phenotype', 'HP:0100013', (93, 105))	('saracatinib', 'Chemical', 'MESH:C515233', (13, 24))	('breast tumor', 'Disease', 'MESH:D001943', (93, 105))
38683	32545574	SU6656 is a small-molecule inhibitor of SRC kinase and of the other members of the SRC family (i.e., FYN, YES, and LYN) with a weaker activity towards the non-receptor tyrosine kinase ABL.	('FYN', 'Gene', (101, 104))	('tyrosine', 'Chemical', 'MESH:D014443', (168, 176))	('ABL', 'Gene', '25', (184, 187))	('SU6656', 'Chemical', 'MESH:C416927', (0, 6))	('SRC kinase', 'Enzyme', (40, 50))	('FYN', 'Gene', '2534', (101, 104))	('SU6656', 'Var', (0, 6))	('LYN', 'Gene', (115, 118))	('ABL', 'Gene', (184, 187))	('LYN', 'Gene', '4067', (115, 118))	('activity', 'MPA', (134, 142))
38684	32545574	SU6656 has been demonstrated to inhibit cell growth in U251 glioma cells and to reduce the invasiveness of glioma spheroid implanted in a three-dimensional collagen matrix due to the changes in actin dynamics.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('inhibit', 'NegReg', (32, 39))	('cell growth', 'CPA', (40, 51))	('SU6656', 'Chemical', 'MESH:C416927', (0, 6))	('U251', 'CellLine', 'CVCL:0021', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('SU6656', 'Var', (0, 6))	('invasiveness of glioma spheroid', 'Disease', 'MESH:D005910', (91, 122))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('glioma', 'Disease', (60, 66))	('reduce', 'NegReg', (80, 86))	('invasiveness of glioma spheroid', 'Disease', (91, 122))	('changes', 'Reg', (183, 190))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('glioma', 'Disease', (107, 113))	('actin dynamics', 'MPA', (194, 208))
38685	32545574	In addition, in vitro and in vivo studies have demonstrated that SU6656 increased the tumor sensitivity to radiation inhibiting AKT phosphorylation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased', 'PosReg', (72, 81))	('tumor', 'Disease', (86, 91))	('AKT', 'Gene', (128, 131))	('SU6656', 'Chemical', 'MESH:C416927', (65, 71))	('inhibiting', 'NegReg', (117, 127))	('SU6656', 'Var', (65, 71))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (92, 116))	('AKT', 'Gene', '207', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
38686	32545574	In this way, it promoted radiation-induced apoptosis and destruction of blood vessels inside the tumor, leading to a delay in tumor growth, suggesting that SU6656 antitumoral effect should be considered for GBM treatment.	('destruction', 'CPA', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('promoted', 'PosReg', (16, 24))	('delay', 'NegReg', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SU6656', 'Chemical', 'MESH:C416927', (156, 162))	('SU6656', 'Var', (156, 162))	('tumor', 'Disease', (167, 172))	('radiation-induced apoptosis', 'CPA', (25, 52))	('tumor', 'Disease', (126, 131))
38703	32545574	Indeed, the genetic inhibition of these transporters in BCRP/Pgp KO-mice allowed dasatinib to reach GBM inside the brain and to properly inhibit SRC kinase and its downstream pathways, resulting in reduced tumor growth and increased survival of KO mice as compared with the WT.	('increased', 'PosReg', (223, 232))	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('dasatinib', 'Chemical', 'MESH:D000069439', (81, 90))	('downstream pathways', 'Pathway', (164, 183))	('tumor', 'Disease', (206, 211))	('dasatinib', 'Gene', (81, 90))	('survival', 'CPA', (233, 241))	('mice', 'Species', '10090', (248, 252))	('inhibit', 'NegReg', (137, 144))	('genetic inhibition', 'Var', (12, 30))	('reduced', 'NegReg', (198, 205))	('SRC kinase', 'Pathway', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
38706	32545574	Si306 was chosen for its favorable absorption, distribution, metabolism, and excretion (ADME) and it has been demonstrated to have the ability to selectively and specifically inhibit SRC, and also the Pgp transporter.	('SRC', 'MPA', (183, 186))	('Si306', 'Chemical', '-', (0, 5))	('Pgp', 'Enzyme', (201, 204))	('inhibit', 'NegReg', (175, 182))	('Si306', 'Var', (0, 5))
38707	32545574	Indeed, differently from the commonly used dasatinib, whose treatment strongly affects Pgp expression, Si306 and the prodrug pro-Si306 do not increase the expression or the activity of the Pgp.	('expression', 'MPA', (91, 101))	('Si306', 'Chemical', '-', (129, 134))	('dasatinib', 'Chemical', 'MESH:D000069439', (43, 52))	('Si306', 'Var', (103, 108))	('pro-Si306', 'Chemical', '-', (125, 134))	('expression', 'MPA', (155, 165))	('activity', 'MPA', (173, 181))	('Si306', 'Chemical', '-', (103, 108))	('affects', 'Reg', (79, 86))	('Pgp', 'Gene', (87, 90))
38711	32545574	Overall, these evidences make Si306 a good candidate to inhibit both SRC and Pgp transporters in anticancer therapy, suggesting that it would be worthwhile exploring combinatorial use of this drug with chemotherapeutic agents.	('Pgp transporters', 'MPA', (77, 93))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('Si306', 'Chemical', '-', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Si306', 'Var', (30, 35))	('inhibit', 'NegReg', (56, 63))
38712	32545574	Actually, a combinatorial approach has already been investigated demonstrating that pretreatment with Si306 sensitized U87 GBM cells to proton therapy.	('Si306', 'Var', (102, 107))	('Si306', 'Chemical', '-', (102, 107))	('U87', 'CellLine', 'CVCL:0022', (119, 122))	('sensitized', 'Reg', (108, 118))
38714	32545574	KX2-361 and its related compound KX-391 are indeed inhibitors of both SRC kinase and tubulin polymerization without the collateral effects on neurite outgrowth and neuropathy often observed by canonical antitubulin treatments (i.e, vincristine, polymerization inhibitor or paclitaxel, depolymerization inhibitor).	('neuropathy', 'Disease', 'MESH:D009422', (164, 174))	('neuropathy', 'Phenotype', 'HP:0009830', (164, 174))	('paclitaxel', 'Chemical', 'MESH:D017239', (273, 283))	('KX2-361', 'Var', (0, 7))	('neuropathy', 'Disease', (164, 174))	('vincristine', 'Chemical', 'MESH:D014750', (232, 243))	('SRC kinase', 'Enzyme', (70, 80))
38715	32545574	Although clinical trials with this compound are still missing, it has been clearly demonstrated that KX2-361 had good oral bioavailability and that it easily crossed the BBB, reached the tumor site, and delayed tumor progression, therefore, enhancing long-term survival in mice.	('KX2-361', 'Var', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('long-term survival', 'CPA', (251, 269))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('delayed', 'NegReg', (203, 210))	('enhancing', 'PosReg', (241, 250))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('mice', 'Species', '10090', (273, 277))
38718	32545574	NEO100 is able to affect tumor growth and induce ER-stress dependent apoptotic cell death both in vitro and in vivo.	('NEO100', 'Chemical', 'MESH:C032208', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('ER-stress dependent', 'MPA', (49, 68))	('induce', 'Reg', (42, 48))	('affect', 'Reg', (18, 24))	('tumor', 'Disease', (25, 30))	('apoptotic cell death', 'CPA', (69, 89))	('NEO100', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
38721	32545574	SRC activity is inhibited after NEO100 treatment, together with MAPK, AKT, and STAT3, whereas RhoA is activated.	('AKT', 'Gene', '207', (70, 73))	('inhibited', 'NegReg', (16, 25))	('SRC activity', 'MPA', (0, 12))	('NEO100 treatment', 'Var', (32, 48))	('RhoA', 'Gene', (94, 98))	('AKT', 'Gene', (70, 73))	('RhoA', 'Gene', '387', (94, 98))	('NEO100', 'Chemical', 'MESH:C032208', (32, 38))	('STAT3', 'Gene', '6774', (79, 84))	('STAT3', 'Gene', (79, 84))
38737	32390841	Attenuating the K+ channel function by applying the hERG1 channel inhibitor E4031 modulated Ca2+ signaling, impaired inhibition of the mitosis promoting subunit cdc2, overrode cell cycle arrest, and decreased clonogenic survival of the irradiated cells but did not affect repair of DNA double strand breaks suggesting a critical role of the hERG1 K+ channels for the Ca2+ signaling and the cell cycle control during DNA damage response.	('hERG1', 'Gene', '3757', (52, 57))	('hERG1', 'Gene', (52, 57))	('Ca2+ signaling', 'MPA', (92, 106))	('cdc2', 'Gene', (161, 165))	('modulated', 'Reg', (82, 91))	('Ca2+', 'Chemical', 'MESH:D000069285', (367, 371))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (176, 193))	('inhibition', 'MPA', (117, 127))	('decreased', 'NegReg', (199, 208))	('E4031', 'Var', (76, 81))	('arrest', 'Disease', (187, 193))	('Attenuating', 'NegReg', (0, 11))	('hERG1', 'Gene', '3757', (341, 346))	('hERG1', 'Gene', (341, 346))	('K+ channel function', 'MPA', (16, 35))	('E4031', 'Chemical', 'MESH:C063968', (76, 81))	('arrest', 'Disease', 'MESH:D006323', (187, 193))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))	('impaired', 'NegReg', (108, 116))	('clonogenic survival', 'CPA', (209, 228))
38753	32390841	To this end, K562 CML cells and:in further experiments:primary CML cells were used as in vitro models since K562 cells reportedly express hERG1 and respond to ionizing radiation with elevated Kv3.4 and other plasmalemmal ion channel activity and Ca2+ signaling.	('K562', 'Var', (108, 112))	('hERG1', 'Gene', '3757', (138, 143))	('K562', 'CellLine', 'CVCL:0004', (13, 17))	('hERG1', 'Gene', (138, 143))	('respond', 'MPA', (148, 155))	('Kv3.4', 'Gene', '3749', (192, 197))	('K562', 'CellLine', 'CVCL:0004', (108, 112))	('Kv3.4', 'Gene', (192, 197))	('plasmalemmal ion channel activity', 'MPA', (208, 241))	('Ca2+', 'Chemical', 'MESH:D000069285', (246, 250))	('elevated', 'PosReg', (183, 191))
38757	32390841	According to a meta study reported IC50 values for the blockage of hERG1 by the class III antiarrhythmic agent E4031 in expression systems in vitro range from 8 to 570 nM (mean 81 nM, median 17 nM, n = 14) which suggests a quantitative channel inhibition at a concentration around 200-800 nM in serum-free buffer solution.	('E4031', 'Chemical', 'MESH:C063968', (111, 116))	('E4031', 'Var', (111, 116))	('und', 'Gene', (277, 280))	('hERG1', 'Gene', '3757', (67, 72))	('hERG1', 'Gene', (67, 72))	('und', 'Gene', '7373', (277, 280))	('blockage', 'NegReg', (55, 63))
38762	32390841	To the best of our knowledge, E4031 at the applied concentration does not interfere with the non-hERG1 channels detected in K562 cells.	('hERG1', 'Gene', (97, 102))	('hERG1', 'Gene', '3757', (97, 102))	('K562', 'CellLine', 'CVCL:0004', (124, 128))	('E4031', 'Var', (30, 35))	('E4031', 'Chemical', 'MESH:C063968', (30, 35))
38795	32390841	The survival fraction (SF) was calculated by normalizing in both arms (E4031 and vehicle control) separately the plating efficiency after irradiation (PExGy) to that of the corresponding unirradiated control (PE0Gy) by the formula SF = PExGy/PE0Gy.	('plating', 'CPA', (113, 120))	('E4031', 'Var', (71, 76))	('E4031', 'Chemical', 'MESH:C063968', (71, 76))
38796	32390841	K562 cells were placed in cell culture medium containing E4031 (0 or 3 microM), irradiated (0 or 4 Gy), and post-incubated for 24 h. After several washing steps (PBS), cells were transferred on object slides by cytospin, fixed in 4% formaldehyde in PBS (3 x 5 min at room temperature), and cell membranes were solubilized with 0.1% Triton X-100 in PBS (3 x 5 min at room temperature), washed (PBS), quenched, blocked, incubated with anti-gammaH2AX antibody (Upstate, Millipore, Billerica, MA, clone JBW301; 1:1,000 at room temperature for 1 h), as well as antibody binding visualized by fluorescence microscopy by the use of Alexa Fluor 488 Tyramide Super Boost Kit goat anti-mouse IgG (#B40912, Thermo Fisher Scientific, Schwerte, Germany) according to the protocols supplied by the manufacturer.	('gammaH2AX', 'Gene', '15270', (438, 447))	('PBS', 'Chemical', '-', (162, 165))	('Triton X-100', 'Chemical', 'MESH:D017830', (332, 344))	('PBS', 'Chemical', '-', (348, 351))	('K562', 'CellLine', 'CVCL:0004', (0, 4))	('PBS', 'Chemical', '-', (249, 252))	('gammaH2AX', 'Gene', (438, 447))	('E4031', 'Chemical', 'MESH:C063968', (57, 62))	('mouse', 'Species', '10090', (676, 681))	('#B40912', 'Var', (687, 694))	('PBS', 'Chemical', '-', (393, 396))
38802	32390841	Moreover, bath administration of E4031 (1 microM) inhibited in a more or less reversible manner a fraction of the tail currents (Figure 1A, lower line) suggesting an involvement of hERG1 channels.	('E4031', 'Chemical', 'MESH:C063968', (33, 38))	('tail currents', 'MPA', (114, 127))	('E4031', 'Var', (33, 38))	('hERG1', 'Gene', (181, 186))	('inhibited', 'NegReg', (50, 59))	('hERG1', 'Gene', '3757', (181, 186))
38804	32390841	Irradiation significantly increased the E4031-sensitve fraction of deactivating tail current densities (compare black and red symbols in Figure 1C).	('E4031-sensitve', 'Var', (40, 54))	('deactivating tail current densities', 'MPA', (67, 102))	('E4031', 'Chemical', 'MESH:C063968', (40, 45))
38809	32390841	Notably, E4031 evoked in unirradiated K562 cells a faint but significant increase in steady state c[Ca2+]free (Figure 2A, upper line, closed symbols, and Figure 2B, 1st bar) while TEA did not alter steady state c[Ca2+]free (Figure 2A, upper line, open symbols, and Figure 2B, 3rd bar).	('Ca2+', 'Chemical', 'MESH:D000069285', (213, 217))	('increase', 'PosReg', (73, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (100, 104))	('E4031', 'Chemical', 'MESH:C063968', (9, 14))	('K562', 'CellLine', 'CVCL:0004', (38, 42))	('E4031', 'Var', (9, 14))	('TEA', 'Chemical', 'MESH:D019789', (180, 183))	('c[Ca2+]free', 'MPA', (98, 109))
38810	32390841	In irradiated cells, E4031 elicited a much stronger increase in c[Ca2+]free than in unirradiated cells and TEA evoked a significant decrease of steady state c[Ca2+]free (Figure 2A, lower line, Figure 2B, 2nd and 4th bars).	('E4031', 'Var', (21, 26))	('increase', 'PosReg', (52, 60))	('Ca2+', 'Chemical', 'MESH:D000069285', (66, 70))	('c[Ca2+]free', 'MPA', (64, 75))	('TEA', 'Chemical', 'MESH:D019789', (107, 110))	('Ca2+', 'Chemical', 'MESH:D000069285', (159, 163))	('c[Ca2+]free', 'MPA', (157, 168))	('decrease', 'NegReg', (132, 140))	('E4031', 'Chemical', 'MESH:C063968', (21, 26))
38815	32390841	E4031 when administered during Ca2+ re-entry augmented the basal (s 0Gy-E4031 = 0.9 +- 0.05 min-1) and radiation-stimulated (s 5Gy-E4031 s = 2.1 +- 0.04 min-1) slope of Ca2+ re-entry.	('E4031', 'Chemical', 'MESH:C063968', (72, 77))	('E4031', 'Chemical', 'MESH:C063968', (131, 136))	('augmented', 'PosReg', (45, 54))	('Ca2+', 'Chemical', 'MESH:D000069285', (31, 35))	('Ca2+', 'Chemical', 'MESH:D000069285', (169, 173))	('E4031', 'Var', (0, 5))	('E4031', 'Chemical', 'MESH:C063968', (0, 5))
38816	32390841	Co-administration of E4031 and the Kv3.4 inhibitor TEA during the Ca2+ re-entry, in sharp contrast, re-decreased slope of basal (s 0Gy-E4031+TEA = 0.4 +- 0.04 min-1) and radiation-induced (s 5Gy-E4031+TEA = 0.7 +- 0.07 min-1) Ca2+ re-entry to values observed in the control situations (data not shown) suggesting that Kv3.4 and hERG1 channels exert opposing effects on Ca2+ re-entry in Ca2+-depleted cells.	('Ca2+', 'Chemical', 'MESH:D000069285', (226, 230))	('E4031', 'Var', (21, 26))	('Kv3.4', 'Gene', '3749', (35, 40))	('Ca2+ re-entry', 'MPA', (369, 382))	('Kv3.4', 'Gene', (318, 323))	('E4031', 'Chemical', 'MESH:C063968', (135, 140))	('Ca2+', 'Chemical', 'MESH:D000069285', (66, 70))	('TEA', 'Chemical', 'MESH:D019789', (141, 144))	('Kv3.4', 'Gene', '3749', (318, 323))	('Ca2+', 'Chemical', 'MESH:D000069285', (386, 390))	('hERG1', 'Gene', (328, 333))	('TEA', 'Chemical', 'MESH:D019789', (51, 54))	('hERG1', 'Gene', '3757', (328, 333))	('TEA', 'Chemical', 'MESH:D019789', (201, 204))	('E4031', 'Chemical', 'MESH:C063968', (195, 200))	('Ca2+', 'Chemical', 'MESH:D000069285', (369, 373))	('E4031', 'Chemical', 'MESH:C063968', (21, 26))	('Kv3.4', 'Gene', (35, 40))
38817	32390841	This is also illustrated by the calculated radiation-induced fraction of Ca2+ re-entry under control situation, in the presence of E4031, and in the presence of E4031 and TEA as shown in Supplementary Figure 1C.	('und', 'Gene', '7373', (87, 90))	('TEA', 'Chemical', 'MESH:D019789', (171, 174))	('E4031', 'Chemical', 'MESH:C063968', (131, 136))	('Ca2+', 'Chemical', 'MESH:D000069285', (73, 77))	('E4031', 'Var', (131, 136))	('und', 'Gene', (87, 90))	('E4031', 'Var', (161, 166))	('E4031', 'Chemical', 'MESH:C063968', (161, 166))	('Ca2+ re-entry', 'MPA', (73, 86))
38823	32390841	Importantly, hERG1 inhibition by E4031 (1 microM) prevented radiation-induced CaMKIIs activation and cdc2 inactivation (Figure 2C, 5th-8th lane and Figure 2D, closed bars) suggesting that Ca2+ signals modulated by hERG1 were required for radiation-induced CaMKIIs activation and inhibition of cdc2.	('cdc2', 'Gene', (101, 105))	('Ca2+', 'Chemical', 'MESH:D000069285', (188, 192))	('E4031', 'Chemical', 'MESH:C063968', (33, 38))	('E4031', 'Var', (33, 38))	('inhibition', 'NegReg', (19, 29))	('hERG1', 'Gene', (214, 219))	('hERG1', 'Gene', '3757', (214, 219))	('prevented', 'NegReg', (50, 59))	('hERG1', 'Gene', '3757', (13, 18))	('inactivation', 'NegReg', (106, 118))	('hERG1', 'Gene', (13, 18))
38830	32390841	Instead, E4031 decreased the radiation induced accumulation of BrdU incorporating S phase cells and showed a trend to increase both G2 populations (Figure 3C), suggestive of a hERG1 function in the radiation-induced S phase arrest during the first 8 h after irradiation.	('arrest', 'Disease', 'MESH:D006323', (224, 230))	('accumulation', 'MPA', (47, 59))	('hERG1', 'Gene', '3757', (176, 181))	('increase', 'PosReg', (118, 126))	('hERG1', 'Gene', (176, 181))	('arrest', 'Disease', (224, 230))	('E4031', 'Chemical', 'MESH:C063968', (9, 14))	('E4031', 'Var', (9, 14))	('BrdU', 'Chemical', 'MESH:D001973', (63, 67))	('decreased', 'NegReg', (15, 24))	('G2 populations', 'MPA', (132, 146))	('BrdU incorporating S phase cells', 'MPA', (63, 95))
38834	32390841	In unirradiated K562 cells, E4031 (3 microM for 48 h) slightly increased G1 and decreased S population (Figure 4C, 1st and 2nd bars) with lower (G1) or similar effect size as compared to its action in irradiated cells (Figure 4C, 3rd and 4th bars).	('E4031', 'Chemical', 'MESH:C063968', (28, 33))	('increased', 'PosReg', (63, 72))	('S population', 'MPA', (90, 102))	('decreased', 'NegReg', (80, 89))	('K562', 'CellLine', 'CVCL:0004', (16, 20))	('E4031', 'Var', (28, 33))
38836	32390841	In particular, in irradiated K562 cells, hERG1 inhibition blunted S and G2/M cell cycle arrest.	('hERG1', 'Gene', '3757', (41, 46))	('hERG1', 'Gene', (41, 46))	('inhibition', 'Var', (47, 57))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('blunted', 'NegReg', (58, 65))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('arrest', 'Disease', (88, 94))	('K562', 'CellLine', 'CVCL:0004', (29, 33))
38838	32390841	Upon hERG1 inhibition, the observed accelerated release from S and G2/M cell cycle arrest might, therefore, impair the survival of irradiated K562 cells.	('release', 'MPA', (48, 55))	('survival', 'CPA', (119, 127))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('accelerated', 'PosReg', (36, 47))	('arrest', 'Disease', (83, 89))	('impair', 'NegReg', (108, 114))	('hERG1', 'Gene', '3757', (5, 10))	('K562', 'CellLine', 'CVCL:0004', (142, 146))	('hERG1', 'Gene', (5, 10))	('inhibition', 'Var', (11, 21))
38839	32390841	To test for such a scenario, the population of K562 cells with degraded DNA (subG1 population) was determined in dependence on hERG1 inhibition (0 or 1 microM E4031) by flow cytometry (propidium iodide Nicoletti staining) 24 h after irradiation with 0 or 5 Gy (Figure 5A).	('hERG1', 'Gene', '3757', (127, 132))	('degraded', 'NegReg', (63, 71))	('E4031', 'Chemical', 'MESH:C063968', (159, 164))	('E4031', 'Var', (159, 164))	('inhibition', 'NegReg', (133, 143))	('propidium iodide', 'Chemical', 'MESH:D011419', (185, 201))	('hERG1', 'Gene', (127, 132))	('K562', 'CellLine', 'CVCL:0004', (47, 51))
38844	32390841	The survival fractions were plotted against the radiation dose demonstrating that E4031 decreased survival fractions and, hence, radiosensitized the K562 cells (Figure 5C).	('survival fractions', 'CPA', (98, 116))	('E4031', 'Chemical', 'MESH:C063968', (82, 87))	('E4031', 'Var', (82, 87))	('decreased', 'NegReg', (88, 97))	('K562', 'CellLine', 'CVCL:0004', (149, 153))
38845	32390841	To test, whether this E4031-mediated radiosensitization is associated with impaired DNA repair, gammaH2AX foci [phospho-(139S)-H2A histone family member X] were determined as a surrogate marker of residual (= un-repaired) DNA double strand breaks (DSBs) by immunofluorescence microscopy 24 h after irradiation with 0 or 4 Gy (Figure 5D).	('gammaH2AX', 'Gene', (96, 105))	('H2A histone family member X', 'Gene', (127, 154))	('E4031', 'Chemical', 'MESH:C063968', (22, 27))	('E4031-mediated', 'Var', (22, 36))	('H2A histone family member X', 'Gene', '3014', (127, 154))	('gammaH2AX', 'Gene', '15270', (96, 105))
38846	32390841	E4031 (3 microM) did not increase the number of residual gammaH2AX foci (Figures 5E, F) suggesting that hERG signaling is not involved in DNA DSB repair.	('hERG', 'Gene', '2078', (104, 108))	('hERG', 'Gene', (104, 108))	('E4031', 'Chemical', 'MESH:C063968', (0, 5))	('gammaH2AX', 'Gene', '15270', (57, 66))	('E4031', 'Var', (0, 5))	('gammaH2AX', 'Gene', (57, 66))
38855	32390841	Fast whole cell patch clamp recording revealed E4031-sensitive, time-dependently deactivating inward tail currents at -80 mV clamp voltage that exhibited the hERG1-typical dependence on holding potential (Figure 6A).	('E4031-sensitive', 'Var', (47, 62))	('inward tail currents at', 'MPA', (94, 117))	('deactivating', 'NegReg', (81, 93))	('E4031', 'Chemical', 'MESH:C063968', (47, 52))	('hERG1', 'Gene', '3757', (158, 163))	('hERG1', 'Gene', (158, 163))
38858	32390841	Importantly, the hERG inhibitor E4031 (3 microM) which was administered during irradiation and the following 24 h post-incubation time blunted the G2/M cell cycle arrest (Figure 6E, closed bars).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (152, 169))	('blunted', 'NegReg', (135, 142))	('arrest', 'Disease', 'MESH:D006323', (163, 169))	('arrest', 'Disease', (163, 169))	('hERG', 'Gene', '2078', (17, 21))	('E4031', 'Chemical', 'MESH:C063968', (32, 37))	('E4031', 'Var', (32, 37))	('hERG', 'Gene', (17, 21))
38861	32390841	In K562, radiogenic hERG1 activity contributed to clonogenic survival of the irradiated cells.	('hERG1', 'Gene', (20, 25))	('clonogenic survival of the irradiated cells', 'CPA', (50, 93))	('K562', 'CellLine', 'CVCL:0004', (3, 7))	('K562', 'Var', (3, 7))	('hERG1', 'Gene', '3757', (20, 25))	('activity', 'MPA', (26, 34))
38876	32390841	Furthermore, radiogenic K+ channel activity has been shown to stimulate hypermigration of glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('radiogenic', 'Var', (13, 23))	('stimulate', 'PosReg', (62, 71))	('hypermigration of glioblastoma', 'Disease', (72, 102))	('hypermigration of glioblastoma', 'Disease', 'MESH:D005909', (72, 102))
38878	32390841	In theory, Ca2+ entry may result in local depolarization of the plasma membrane as well as in local rise in c[Ca2+]free beneath the plasma membrane which trigger activation of physically associated voltage-gated K+ channels and Ca2+-dependent K+ channels, respectively.	('Ca2+', 'Var', (11, 15))	('local rise', 'Disease', (94, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (110, 114))	('Ca2+', 'Chemical', 'MESH:D000069285', (11, 15))	('Ca2+', 'Chemical', 'MESH:D000069285', (228, 232))	('local rise', 'Disease', 'MESH:D012594', (94, 104))	('depolarization', 'NegReg', (42, 56))	('activation', 'PosReg', (162, 172))	('c[Ca2+]free beneath the', 'MPA', (108, 131))
38882	32390841	Notably, Kv3.4 blockage reportedly delays Ca2+ re-entry into Ca2+-depleted K562 cells and decreased in the present study in irradiated cells steady state c[Ca2+]free while hERG1 boosted Ca2+ re-entry into Ca2+-depleted K562 cells and increased c[Ca2+]free.	('Ca2+', 'Chemical', 'MESH:D000069285', (61, 65))	('Ca2+ re-entry', 'MPA', (186, 199))	('Kv3.4', 'Gene', (9, 14))	('hERG1', 'Gene', '3757', (172, 177))	('hERG1', 'Gene', (172, 177))	('blockage', 'Var', (15, 23))	('delays', 'NegReg', (35, 41))	('decreased', 'NegReg', (90, 99))	('Ca2+', 'Chemical', 'MESH:D000069285', (186, 190))	('Ca2+ re-entry', 'MPA', (42, 55))	('increased', 'PosReg', (234, 243))	('Ca2+', 'Chemical', 'MESH:D000069285', (42, 46))	('Kv3.4', 'Gene', '3749', (9, 14))	('c[Ca2+]free', 'MPA', (244, 255))	('K562', 'CellLine', 'CVCL:0004', (219, 223))	('c[Ca2+]free', 'MPA', (154, 165))	('Ca2+', 'Chemical', 'MESH:D000069285', (205, 209))	('Ca2+', 'Chemical', 'MESH:D000069285', (246, 250))	('K562', 'CellLine', 'CVCL:0004', (75, 79))	('Ca2+', 'Chemical', 'MESH:D000069285', (156, 160))	('boosted', 'PosReg', (178, 185))
38894	32390841	Although resulting in a decrease and increase of c[Ca2+]free, respectively, inhibition of either hERG1 or Kv3.4 impaired radiogenic activation of CaMKIIs in K562 cells [ and present study].	('radiogenic activation', 'MPA', (121, 142))	('hERG1', 'Gene', (97, 102))	('K562', 'CellLine', 'CVCL:0004', (157, 161))	('Ca2+', 'Chemical', 'MESH:D000069285', (51, 55))	('hERG1', 'Gene', '3757', (97, 102))	('impaired', 'NegReg', (112, 120))	('increase', 'PosReg', (37, 45))	('Kv3.4', 'Gene', (106, 111))	('inhibition', 'Var', (76, 86))	('Kv3.4', 'Gene', '3749', (106, 111))	('c[Ca2+]free', 'MPA', (49, 60))
38897	32390841	CaMKII-mediated inhibitory phosphorylation of cdc25 phosphatases [cdc25B in K562 CML and Jurkat T cell leukemia, and probably cdc25C in glioblastoma cells ] prevents the activating dephosphorylation of the cdc25 target p-(Tyr15)-cdc2 as also observed in the present study.	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('prevents', 'NegReg', (157, 165))	('cdc25', 'Gene', (66, 71))	('cdc25', 'Gene', '995', (66, 71))	('CML and Jurkat T cell leukemia', 'Disease', 'MESH:D015464', (81, 111))	('cdc25', 'Gene', (46, 51))	('cdc25C', 'Gene', (126, 132))	('cdc25', 'Gene', (126, 131))	('activating dephosphorylation', 'MPA', (170, 198))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('cdc25', 'Gene', '995', (46, 51))	('cdc25', 'Gene', (206, 211))	('K562', 'CellLine', 'CVCL:0004', (76, 80))	('cdc25', 'Gene', '995', (126, 131))	('cdc25', 'Gene', '995', (206, 211))	('glioblastoma', 'Disease', (136, 148))	('inhibitory', 'Var', (16, 26))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('cdc25C', 'Gene', '995', (126, 132))	('T cell leukemia', 'Phenotype', 'HP:0005517', (96, 111))
38898	32390841	Cdc2 together with cyclin B forms the mitosis-promoting factor, and the inhibitory phosphorylation results in G2/M arrest of the cell cycle.	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('Cdc2', 'Gene', (0, 4))	('inhibitory phosphorylation', 'Var', (72, 98))	('arrest', 'Disease', (115, 121))	('results in', 'Reg', (99, 109))	('Cdc2', 'Gene', '983', (0, 4))
38908	32390841	Nevertheless, "non-torsadogenic" hERG1 inhibitors might impact tumor biology.	('inhibitors', 'Var', (39, 49))	('tumor', 'Disease', (63, 68))	('hERG1', 'Gene', '3757', (33, 38))	('hERG1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('impact', 'Reg', (56, 62))
38910	32390841	Notably, patients with highly hERG1-expressing glioblastoma but not those with low expression showed in univariate analysis a benefit in terms of overall survival from "non-torsadogenic" hERG1-inhibiting drugs.	('highly', 'Var', (23, 29))	('benefit', 'PosReg', (126, 133))	('patients', 'Species', '9606', (9, 17))	('glioblastoma', 'Disease', (47, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('hERG1', 'Gene', '3757', (187, 192))	('hERG1', 'Gene', (187, 192))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('hERG1', 'Gene', '3757', (30, 35))	('hERG1', 'Gene', (30, 35))
38914	32390841	Inhibitor selectivity for variant 1b over 1a might be a further strategy to develop tumor-specific hERG1 blockers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('variant', 'Var', (26, 33))	('tumor', 'Disease', (84, 89))	('hERG1', 'Gene', (99, 104))	('hERG1', 'Gene', '3757', (99, 104))
38918	32390841	Inhibition of hERG1 by the class III antiarrhythmic agent E4031 overrides cell cycle arrest and impairs clonogenic survival of the cells suggesting hERG1 as potential therapy target.	('hERG1', 'Gene', (14, 19))	('overrides', 'PosReg', (64, 73))	('clonogenic survival of the cells', 'CPA', (104, 136))	('E4031', 'Var', (58, 63))	('hERG1', 'Gene', '3757', (148, 153))	('Inhibition', 'NegReg', (0, 10))	('hERG1', 'Gene', (148, 153))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('impairs', 'NegReg', (96, 103))	('hERG1', 'Gene', '3757', (14, 19))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('arrest', 'Disease', (85, 91))	('E4031', 'Chemical', 'MESH:C063968', (58, 63))
38958	31747788	Targets for intratumorral immunotoxin therapy that have been clinically investigated include transferrin receptor, IL-4, IL-13, EGFR, and its mutant variant (EGFRvIII) among others.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('EGFR', 'Gene', (158, 162))	('tumor', 'Disease', (17, 22))	('IL-4', 'Gene', '3565', (115, 119))	('EGFR', 'Gene', '1956', (128, 132))	('IL-13', 'Gene', (121, 126))	('EGFR', 'Gene', (128, 132))	('mutant', 'Var', (142, 148))	('IL-13', 'Gene', '3596', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('EGFR', 'Gene', '1956', (158, 162))	('IL-4', 'Gene', (115, 119))
38967	31747788	Tf-CRM107 is one of the first immunotoxins to be clinically evaluated, consisting of transferrin conjugated to diphtheria toxin with a point mutation rendering it unable to bind mammalian cells (Figure 1).	('bind', 'Interaction', (173, 177))	('point mutation', 'Var', (135, 149))	('mammalian', 'Species', '9606', (178, 187))	('unable', 'NegReg', (163, 169))
38977	31747788	The PE-38 form results from deletion of the Ia/Ib domains leading to intact ADP ribosylating activity but inability to bind cells, neutralizing its natural toxicity.	('ADP', 'Chemical', 'MESH:D000244', (76, 79))	('Ia/Ib', 'Gene', (44, 49))	('inability', 'NegReg', (106, 115))	('ADP ribosylating activity', 'MPA', (76, 101))	('toxicity', 'Disease', 'MESH:D064420', (156, 164))	('toxicity', 'Disease', (156, 164))	('deletion', 'Var', (28, 36))
39010	31747788	Currently a Phase I trial is recruiting to evaluate the use of D2C7-(scdsFv)-PE38KDEL treatment via CED in patients with recurrent HGG (NCT02303678).	('HGG', 'Disease', (131, 134))	('NCT02303678', 'Chemical', 'MESH:C079985', (136, 147))	('patients', 'Species', '9606', (107, 115))	('D2C7-', 'Var', (63, 68))
39011	31747788	A third form of PE is PE38QQR, which is a modified version of PE38 to optimize its toxicity.	('toxicity', 'Disease', (83, 91))	('PE38QQR', 'Var', (22, 29))	('toxicity', 'Disease', 'MESH:D064420', (83, 91))
39016	31747788	The result is PE38QQR, which has been shown in initial preclinical studies to have better synthetic yield and improved cytotoxicity to target cells.	('synthetic', 'MPA', (90, 99))	('cytotoxicity', 'Disease', (119, 131))	('improved', 'PosReg', (110, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (119, 131))	('PE38QQR', 'Var', (14, 21))
39017	31747788	PE38QQR conjugated to IL-13 (IL13-PE38QQR) has been extensively investigated in clinical studies.	('IL13-PE38QQR', 'Gene', '3596', (29, 41))	('PE38QQR', 'Var', (0, 7))	('IL13-PE38QQR', 'Gene', (29, 41))	('IL-13', 'Gene', (22, 27))	('IL-13', 'Gene', '3596', (22, 27))
39042	31747788	These may include tumor genetics and epigenetics, technique of delivery, and the patient's immune status among other factors that can affect tumor response and patient tolerance.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('patient', 'Species', '9606', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (141, 146))	('affect', 'Reg', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('patient', 'Species', '9606', (160, 167))	('epigenetics', 'Var', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
39056	31637166	EGFRvIII is a unique EGFR mutant subtype in glioma, and the CRISPR-Cas13a system induces death in EGFRvIII-overexpressing glioma cells.	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', (0, 4))	('death', 'Disease', 'MESH:D003643', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('glioma', 'Disease', (122, 128))	('death', 'Disease', (89, 94))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('EGFR', 'Gene', '1956', (98, 102))	('mutant', 'Var', (26, 32))	('EGFR', 'Gene', '1956', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('induces', 'Reg', (81, 88))
39058	31637166	Furthermore, CRISPR-Cas13a inhibits the formation of glioma intracranial tumors in mice.	('inhibits', 'NegReg', (27, 35))	('glioma intracranial tumors', 'Disease', (53, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mice', 'Species', '10090', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('CRISPR-Cas13a', 'Var', (13, 26))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('glioma intracranial tumors', 'Disease', 'MESH:D005910', (53, 79))
39060	31637166	It is reported that a CRISPR/Cas13a system can exert a collateral effect after target recognition in glioma cells, indicating that the CRISPR/Cas13a system has great potential value for tumor elimination, especially for patients with specific oncogene mutations.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('glioma', 'Disease', (101, 107))	('tumor', 'Disease', (186, 191))	('mutations', 'Var', (252, 261))	('patients', 'Species', '9606', (220, 228))	('collateral', 'MPA', (55, 65))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
39069	31637166	To further examine if transduction with Cas13a lentivirus can activate the innate immune system in U87 cells, we examined OAS 1-3 and IFN-alpha,beta after crRNA and/or Cas13 lentiviral treatment.	('OAS 1-3', 'Gene', (122, 129))	('OAS 1-3', 'Gene', '4938;4939;4940', (122, 129))	('IFN-alpha', 'Gene', '3439', (134, 143))	('IFN-alpha', 'Gene', (134, 143))	('Cas13a', 'Var', (40, 46))
39076	31637166	Thus, RTCA revealed that cr-2# transfection ultimately leads to cell death (Figure S4b, Supporting Information).	('cr-2#', 'Gene', (25, 30))	('cr-2', 'Species', '2498238', (25, 29))	('leads to', 'Reg', (55, 63))	('transfection', 'Var', (31, 43))	('death', 'Disease', 'MESH:D003643', (69, 74))	('death', 'Disease', (69, 74))
39077	31637166	Immunofluorescence analysis further confirmed that cr-2#, but not cr-5#, inhibited both EGFRvIII and EGFP expression in U87-Cas13a-EGFRvIII-EGFP cells, resulting in dysregulated beta-tubulin morphology (Figure 1g).	('cr-2', 'Var', (51, 55))	('cr-2', 'Species', '2498238', (51, 55))	('beta-tubulin morphology', 'MPA', (178, 201))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('inhibited', 'NegReg', (73, 82))	('dysregulated', 'Reg', (165, 177))	('EGFP expression', 'Gene', (101, 116))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', (88, 92))
39078	31637166	Furthermore, cr-2# transfection induced ribosomal RNA cleavage in U87-Cas13a-EGFRvIII cells (Figure 1h).	('transfection', 'Var', (19, 31))	('ribosomal RNA cleavage', 'MPA', (40, 62))	('EGFR', 'Gene', '1956', (77, 81))	('cr-2#', 'Gene', (13, 18))	('EGFR', 'Gene', (77, 81))	('cr-2', 'Species', '2498238', (13, 17))	('induced', 'Reg', (32, 39))
39081	31637166	Principal component analysis (PCA) revealed that the samples at 8 h distributed separately from those of the other groups, suggesting that distinct transcriptomic alterations occurred after cr-2# transfection (Figure 2b).	('transcriptomic alterations', 'MPA', (148, 174))	('cr-2#', 'Gene', (190, 195))	('transfection', 'Var', (196, 208))	('cr-2', 'Species', '2498238', (190, 194))
39086	31637166	All six mice in the EGFRvIII-control and crRNA5 groups formed tumors on day 14, while tumors were detected in only four of the six mice in the crRNA2 group.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EGFR', 'Gene', (20, 24))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('mice', 'Species', '10090', (131, 135))	('mice', 'Species', '10090', (8, 12))	('EGFR', 'Gene', '1956', (20, 24))	('crRNA5', 'Var', (41, 47))
39088	31637166	The immunofluorescence analysis further revealed tumor cell proliferation and angiogenesis in the control and crRNA5 groups but not in the crRNA2 group, confirming the tumor-inhibiting potential of the CRISPR-Cas13a system (Figure 3d).	('revealed', 'Reg', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('angiogenesis', 'CPA', (78, 90))	('crRNA5', 'Var', (110, 116))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
39093	31637166	It is interesting to note that the growth of yeast is significantly inhibited when the tdh1 target gene is knocked down.	('tdh1', 'Gene', (87, 91))	('inhibited', 'NegReg', (68, 77))	('knocked down', 'Var', (107, 119))	('yeast', 'Species', '4932', (45, 50))	('growth', 'MPA', (35, 41))
39137	30925291	Inhibition of TRPM2 expression or function results in decreased tumor proliferation and/or viability in many malignancies including breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, and T-cell and acute myelogenous leukemia.	('decreased tumor', 'Disease', 'MESH:D002303', (54, 69))	('myelogenous leukemia', 'Disease', (240, 260))	('gastric', 'Disease', (140, 147))	('function', 'MPA', (34, 42))	('pancreatic', 'Disease', (149, 159))	('neck cancers', 'Disease', (180, 192))	('decreased tumor', 'Disease', (54, 69))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('neck cancers', 'Disease', 'MESH:D006258', (180, 192))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (240, 260))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('breast', 'Disease', (132, 138))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('leukemia', 'Phenotype', 'HP:0001909', (252, 260))	('T-cell', 'Disease', (223, 229))	('malignancies', 'Disease', (109, 121))	('neuroblastoma', 'Disease', (204, 217))	('neuroblastoma', 'Phenotype', 'HP:0003006', (204, 217))	('Inhibition', 'Var', (0, 10))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))	('viability', 'CPA', (91, 100))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (240, 260))	('expression', 'MPA', (20, 30))	('neuroblastoma', 'Disease', 'MESH:D009447', (204, 217))	('head and neck cancers', 'Phenotype', 'HP:0012288', (171, 192))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('TRPM2', 'Gene', (14, 19))	('prostate', 'Disease', (161, 169))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (234, 260))
39172	30925291	In humans, a TRPM2 mutant (P1018L) was found in a subset of Guamanian amyotrophic lateral sclerosis and Parkinson dementia patients.	('TRPM2', 'Gene', (13, 18))	('found', 'Reg', (39, 44))	('Parkinson dementia', 'Disease', (104, 122))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (70, 99))	('patients', 'Species', '9606', (123, 131))	('amyotrophic lateral sclerosis', 'Disease', (70, 99))	('dementia', 'Phenotype', 'HP:0000726', (114, 122))	('Guamanian', 'Disease', (60, 69))	('humans', 'Species', '9606', (3, 9))	('P1018L', 'Var', (27, 33))	('Parkinson dementia', 'Disease', 'MESH:C537240', (104, 122))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (70, 99))	('P1018L', 'Mutation', 'rs145947009', (27, 33))
39173	30925291	Unlike wild type TRPM2 which does not inactivate, the P1018L mutant inactivates after channel opening by ADPR, limiting calcium entry and strongly suggesting that TRPM2 is required for normal neuronal function.	('limiting', 'NegReg', (111, 119))	('ADPR', 'Chemical', 'MESH:D000246', (105, 109))	('P1018L', 'Var', (54, 60))	('calcium entry', 'MPA', (120, 133))	('inactivates', 'NegReg', (68, 79))	('calcium', 'Chemical', 'MESH:D002118', (120, 127))	('P1018L', 'Mutation', 'rs145947009', (54, 60))	('after channel opening', 'MPA', (80, 101))
39177	30925291	In some models, primarily nonmalignant, TRPM2 expression can enhance cell death through elevated intracellular Ca2+ or Zn2+, but the predominance of data in cancer models support the conclusion that TRPM2 expression and function have an important role in preserving cancer cell viability and survival.	('enhance', 'PosReg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('expression', 'Var', (46, 56))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('TRPM2', 'Gene', (199, 204))	('cancer', 'Disease', (266, 272))	('intracellular Ca2+ or Zn2+', 'MPA', (97, 123))	('elevated', 'PosReg', (88, 96))	('Ca2+', 'Chemical', 'MESH:D000069285', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('elevated intracellular Ca2+', 'Phenotype', 'HP:0003575', (88, 115))	('Zn2+', 'Chemical', '-', (119, 123))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cell death', 'CPA', (69, 79))	('TRPM2', 'Gene', (40, 45))
39185	30925291	These results were confirmed by Almasi et al in gastric cancer cells, who also found that TRPM2 knockdown was associated with a decrease in autophagy and mitophagy and impaired mitochondrial metabolism and ATP production.	('knockdown', 'Var', (96, 105))	('impaired mitochondrial metabolism', 'Phenotype', 'HP:0003287', (168, 201))	('ATP production', 'MPA', (206, 220))	('Almasi', 'Disease', (32, 38))	('impaired mitochondrial metabolism', 'Disease', 'MESH:D028361', (168, 201))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('mitophagy', 'CPA', (154, 163))	('ATP', 'Chemical', 'MESH:D000255', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TRPM2', 'Gene', (90, 95))	('gastric cancer', 'Disease', (48, 62))	('decrease', 'NegReg', (128, 136))	('impaired mitochondrial metabolism', 'Disease', (168, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))	('autophagy', 'CPA', (140, 149))	('Almasi', 'Disease', 'None', (32, 38))
39195	30925291	The ability of TRPM2 to enhance growth of neuroblastoma tumors was confirmed in mouse xenografts using human neuroblastoma cells expressing TRPM2-L or TRPM2-S.	('growth', 'MPA', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('human', 'Species', '9606', (103, 108))	('neuroblastoma', 'Phenotype', 'HP:0003006', (42, 55))	('TRPM2-L', 'Var', (140, 147))	('neuroblastoma', 'Disease', 'MESH:D009447', (109, 122))	('enhance', 'PosReg', (24, 31))	('neuroblastoma tumors', 'Disease', 'MESH:D009447', (42, 62))	('mouse', 'Species', '10090', (80, 85))	('neuroblastoma', 'Disease', (109, 122))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('neuroblastoma tumors', 'Disease', (42, 62))	('neuroblastoma', 'Disease', 'MESH:D009447', (42, 55))	('TRPM2', 'Gene', (15, 20))	('neuroblastoma', 'Phenotype', 'HP:0003006', (109, 122))	('TRPM2-S', 'Var', (151, 158))	('neuroblastoma', 'Disease', (42, 55))
39202	30925291	Expression of wild type TRPM2 but not the TRPM2 pore mutant E960D in depleted cells restored cell viability, mitochondrial function and reduced ROS.	('E960D', 'Mutation', 'rs1225516513', (60, 65))	('TRPM2', 'Gene', (24, 29))	('mitochondrial function', 'MPA', (109, 131))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('cell viability', 'CPA', (93, 107))	('E960D', 'Var', (60, 65))	('reduced', 'NegReg', (136, 143))	('restored', 'PosReg', (84, 92))	('ROS', 'MPA', (144, 147))
39212	30925291	Inhibition of TRPM2 reduced phosphorylation of Src and Pyk2, and expression of total Pyk2 and CREB in the mitochondria, and phosphorylated Src, CREB, and total CREB in the nucleus, impacting expression of a number of cellular and mitochondrial genes involved in cell survival.	('Src', 'Gene', '6714', (139, 142))	('reduced', 'NegReg', (20, 27))	('CREB', 'Gene', (144, 148))	('Pyk2', 'Gene', '2185', (55, 59))	('CREB', 'Gene', '1385', (160, 164))	('Src', 'Gene', (47, 50))	('Pyk2', 'Gene', (85, 89))	('CREB', 'Gene', '1385', (144, 148))	('CREB', 'Gene', (94, 98))	('expression', 'MPA', (191, 201))	('Src', 'Gene', '6714', (47, 50))	('Pyk2', 'Gene', '2185', (85, 89))	('Inhibition', 'Var', (0, 10))	('impacting', 'NegReg', (181, 190))	('CREB', 'Gene', '1385', (94, 98))	('Src', 'Gene', (139, 142))	('TRPM2', 'Gene', (14, 19))	('phosphorylation', 'MPA', (28, 43))	('Pyk2', 'Gene', (55, 59))	('CREB', 'Gene', (160, 164))
39214	30925291	Reconstitution with TRPM2 but not the TRPM2 pore mutant E960D restored expression and phosphorylation of Pyk2 and CREB, particularly after doxorubicin.	('Pyk2', 'Gene', (105, 109))	('expression', 'MPA', (71, 81))	('doxorubicin', 'Chemical', 'MESH:D004317', (139, 150))	('CREB', 'Gene', '1385', (114, 118))	('restored', 'PosReg', (62, 70))	('E960D', 'Mutation', 'rs1225516513', (56, 61))	('phosphorylation', 'MPA', (86, 101))	('CREB', 'Gene', (114, 118))	('Pyk2', 'Gene', '2185', (105, 109))	('E960D', 'Var', (56, 61))
39228	30925291	Of the three major molecular subtypes of breast cancer, triple-negative is the most aggressive and has the worst outcome, but a significant percentage of patients with the most common type, estrogen-receptor-positive breast cancer, also fail therapy.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Disease', (217, 230))	('estrogen-receptor', 'Gene', (190, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('estrogen-receptor', 'Gene', '2099', (190, 207))	('patients', 'Species', '9606', (154, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('triple-negative', 'Var', (56, 71))
39230	30925291	In human breast adenocarcinoma cell lines, TRPM2 showed a protective effect in minimizing DNA damage, whereas pharmacological inhibition of TRPM2 with 2-APB or TRPM2 mRNA silencing decreased cell proliferation and significantly increased DNA damage.	('TRPM2', 'Gene', (160, 165))	('2-APB', 'Chemical', 'MESH:C109986', (151, 156))	('TRPM2', 'Gene', (140, 145))	('DNA damage', 'MPA', (238, 248))	('human', 'Species', '9606', (3, 8))	('breast adenocarcinoma', 'Disease', (9, 30))	('inhibition', 'Var', (126, 136))	('minimizing DNA damage', 'MPA', (79, 100))	('mRNA silencing', 'Var', (166, 180))	('breast adenocarcinoma', 'Disease', 'MESH:D001943', (9, 30))	('increased', 'PosReg', (228, 237))	('cell proliferation', 'CPA', (191, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (9, 30))	('decreased', 'NegReg', (181, 190))
39236	30925291	These data suggest that targeting of TRPM2 could be a synergistic approach to enhance treatment of breast cancer patients including those with chemotherapy resistance, similar to that proposed in neuroblastoma.	('enhance', 'PosReg', (78, 85))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('neuroblastoma', 'Phenotype', 'HP:0003006', (196, 209))	('breast cancer', 'Disease', (99, 112))	('patients', 'Species', '9606', (113, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('targeting', 'Var', (24, 33))	('neuroblastoma', 'Disease', 'MESH:D009447', (196, 209))	('TRPM2', 'Gene', (37, 42))	('neuroblastoma', 'Disease', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
39246	30925291	In Jurkat cells stably expressing Bcl-2 or empty vector, inhibition of TRPM2 with N-(p-amylcinnamoyl)anthranilic acid (ACA) followed by irradiation decreased phosphorylation of CAMKII and blocked radiation-induced phosphorylation-dependent inactivation of cdc2.	('TRPM2', 'Gene', (71, 76))	('cdc2', 'Gene', (256, 260))	('inhibition', 'Var', (57, 67))	('ACA', 'Chemical', 'MESH:C085901', (119, 122))	('phosphorylation', 'MPA', (158, 173))	('cdc2', 'Gene', '983', (256, 260))	('decreased', 'NegReg', (148, 157))	('blocked', 'NegReg', (188, 195))	('CAMKII', 'Gene', (177, 183))	('CAMKII', 'Gene', '818', (177, 183))	('N-(p-amylcinnamoyl)anthranilic acid', 'Chemical', 'MESH:C085901', (82, 117))	('Bcl-2', 'Gene', (34, 39))	('Bcl-2', 'Gene', '596', (34, 39))	('Jurkat', 'CellLine', 'CVCL:0065', (3, 9))
39248	30925291	TRPM2 knockdown also significantly decreased the number of cells arrested in G2/M and reduced viability.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('reduced', 'NegReg', (86, 93))	('TRPM2', 'Gene', (0, 5))	('arrest', 'Disease', (65, 71))	('decreased', 'NegReg', (35, 44))	('viability', 'CPA', (94, 103))	('knockdown', 'Var', (6, 15))
39251	30925291	These data suggest that TRPM2 inhibition may be a therapeutic approach to increase radiation sensitivity in T-cell leukemia.	('T-cell leukemia', 'Disease', (108, 123))	('inhibition', 'Var', (30, 40))	('TRPM2', 'Gene', (24, 29))	('increase', 'PosReg', (74, 82))	('T-cell leukemia', 'Disease', 'MESH:D015458', (108, 123))	('leukemia', 'Phenotype', 'HP:0001909', (115, 123))
39256	30925291	These findings suggest that depletion of TRPM2 may be a therapeutic approach to control prostate cancer growth.	('prostate cancer', 'Disease', (88, 103))	('TRPM2', 'Gene', (41, 46))	('depletion', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))
39258	30925291	When TRPM2-AS is knocked down, cell apoptosis increased coupled to cell cycle arrest and a large increase in TRPM2 expression was detected.	('arrest', 'Disease', (78, 84))	('increase', 'PosReg', (97, 105))	('TRPM2', 'Gene', (109, 114))	('knocked down', 'Var', (17, 29))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('increased', 'PosReg', (46, 55))	('TRPM2-AS', 'Gene', '101928607', (5, 13))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('expression', 'MPA', (115, 125))	('TRPM2-AS', 'Gene', (5, 13))	('cell apoptosis', 'CPA', (31, 45))
39259	30925291	These results appear to be in conflict, because in the first report knockdown of TRPM2 reduced cell proliferation, whereas in the second expression of a long noncoding TRPM2 antisense transcript was linked to poor patient outcome and knockdown of the antisense transcript was associated with increased TRPM2 expression, increased cell cycle arrest and apoptosis.	('cell proliferation', 'CPA', (95, 113))	('expression', 'MPA', (308, 318))	('apoptosis', 'CPA', (352, 361))	('arrest', 'Disease', 'MESH:D006323', (341, 347))	('patient', 'Species', '9606', (214, 221))	('increased', 'PosReg', (292, 301))	('TRPM2', 'Gene', (168, 173))	('arrest', 'Disease', (341, 347))	('reduced', 'NegReg', (87, 94))	('TRPM2', 'Gene', (302, 307))	('increased', 'PosReg', (320, 329))	('knockdown', 'Var', (68, 77))	('TRPM2', 'Gene', (81, 86))	('knockdown', 'Var', (234, 243))	('antisense', 'Var', (251, 260))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (330, 347))
39264	30925291	Silencing of TRPM2-AS with siRNA significantly reduced cell proliferation and increased apoptosis.	('apoptosis', 'CPA', (88, 97))	('cell proliferation', 'CPA', (55, 73))	('TRPM2-AS', 'Gene', '101928607', (13, 21))	('increased', 'PosReg', (78, 87))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (47, 54))	('TRPM2-AS', 'Gene', (13, 21))
39272	30925291	Activation of TRPM2 by H2O2 has been shown to induce filopodia formation, loss of actin stress fibers, and disassembly of focal adhesions, leading to increased migration of both HeLa cells and prostate cancer cells.	('prostate cancer', 'Disease', (193, 208))	('HeLa', 'CellLine', 'CVCL:0030', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('actin stress fibers', 'Protein', (82, 101))	('migration', 'CPA', (160, 169))	('TRPM2', 'Gene', (14, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (193, 208))	('loss', 'NegReg', (74, 78))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('H2O2', 'Var', (23, 27))	('filopodia formation', 'CPA', (53, 72))	('Activation', 'PosReg', (0, 10))	('induce', 'Reg', (46, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (193, 208))	('increased', 'PosReg', (150, 159))
39274	30925291	These data suggest that either TRPM2 inhibition or chelators of free Zn2+ may reduce or prevent metastatic progression.	('Zn2+', 'Chemical', '-', (69, 73))	('inhibition', 'NegReg', (37, 47))	('prevent', 'NegReg', (88, 95))	('metastatic progression', 'CPA', (96, 118))	('chelators', 'Var', (51, 60))	('TRPM2', 'Protein', (31, 36))
39275	30925291	High TRPM2 expression was recently associated with shorter survival time in patient with pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('shorter', 'NegReg', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('patient', 'Species', '9606', (76, 83))	('survival', 'MPA', (59, 67))	('TRPM2', 'Gene', (5, 10))	('pancreatic cancer', 'Disease', (89, 106))
39283	30925291	ATM is a serine/threonine kinase activated by DNA double-strand breaks.	('ATM', 'Gene', (0, 3))	('serine', 'Chemical', 'MESH:D012694', (9, 15))	('DNA double-strand breaks', 'Var', (46, 70))	('ATM', 'Gene', '472', (0, 3))
39288	30925291	ATP activates the purinergic P2Y6 and P2Y12 receptors, which induce the DNA damage response.	('P2Y6', 'Gene', '5031', (29, 33))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('P2Y6', 'Gene', (29, 33))	('DNA damage response', 'MPA', (72, 91))	('activates', 'PosReg', (4, 13))	('induce', 'Reg', (61, 67))	('P2Y12', 'Var', (38, 43))
39289	30925291	Activation of the P2Y6 receptor is involved in nuclear translocation of EGFR, which is suppressed in TRPM2 depletion, and in induction of antioxidants.	('P2Y6 receptor', 'Gene', (18, 31))	('EGFR', 'Gene', '1956', (72, 76))	('induction', 'Reg', (125, 134))	('EGFR', 'Gene', (72, 76))	('P2Y6 receptor', 'Gene', '5031', (18, 31))	('suppressed', 'NegReg', (87, 97))	('nuclear translocation', 'MPA', (47, 68))	('depletion', 'Var', (107, 116))
39290	30925291	In T-cell leukemia, after irradiation TRPM2 inhibition or knockdown decreased the number of cell accumulating in G2/M and increased the number of dead cells.	('decreased', 'NegReg', (68, 77))	('inhibition', 'Var', (44, 54))	('TRPM2', 'Gene', (38, 43))	('T-cell leukemia', 'Disease', 'MESH:D015458', (3, 18))	('leukemia', 'Phenotype', 'HP:0001909', (10, 18))	('T-cell leukemia', 'Disease', (3, 18))	('increased', 'PosReg', (122, 131))	('knockdown', 'Var', (58, 67))
39294	30925291	In T24 bladder cancer cells, overexpression of TRPM2 promoted apoptosis and TRPM2 depletion antagonized histone deacetylase inhibition induced apoptosis.	('promoted', 'PosReg', (53, 61))	('overexpression', 'PosReg', (29, 43))	('depletion', 'Var', (82, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (7, 21))	('TRPM2', 'Gene', (76, 81))	('apoptosis', 'CPA', (62, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (7, 21))	('antagonized', 'NegReg', (92, 103))	('bladder cancer', 'Disease', (7, 21))	('TRPM2', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
39298	30925291	However, in another study, high TRPM2 expression in glioblastoma was associated with worse patient survival (unpublished results, Miller laboratory).	('patient survival', 'CPA', (91, 107))	('high', 'Var', (27, 31))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('TRPM2', 'Gene', (32, 37))	('patient', 'Species', '9606', (91, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('worse', 'NegReg', (85, 90))
39309	30925291	These data suggested that while TRPM2 inhibition reduces primary tumor growth and increases chemotherapy sensitivity, it may reduce neutrophil cytotoxicity and has the potential to increase metastatic spread in some settings which need to be better understood.	('chemotherapy sensitivity', 'MPA', (92, 116))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('reduces', 'NegReg', (49, 56))	('tumor', 'Disease', (65, 70))	('metastatic spread', 'CPA', (190, 207))	('neutrophil cytotoxicity', 'Disease', (132, 155))	('inhibition', 'Var', (38, 48))	('reduce', 'NegReg', (125, 131))	('increases', 'PosReg', (82, 91))	('neutrophil cytotoxicity', 'Disease', 'MESH:D064420', (132, 155))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TRPM2', 'Gene', (32, 37))	('increase', 'PosReg', (181, 189))
39311	30925291	Inhibition of TRPM2 has been demonstrated to enhance cell death and increase sensitivity to doxorubicin and other chemotherapeutic agents in a number of malignancies including neuroblastoma, T cell leukemia, gastric cancer, and triple-negative and estrogen-receptor positive breast cancer cell lines.	('gastric cancer', 'Disease', 'MESH:D013274', (208, 222))	('T cell leukemia', 'Phenotype', 'HP:0005517', (191, 206))	('neuroblastoma', 'Phenotype', 'HP:0003006', (176, 189))	('leukemia', 'Phenotype', 'HP:0001909', (198, 206))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))	('estrogen-receptor', 'Gene', '2099', (248, 265))	('malignancies', 'Disease', (153, 165))	('enhance', 'PosReg', (45, 52))	('neuroblastoma, T cell leukemia', 'Disease', 'MESH:D009447', (176, 206))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('increase', 'PosReg', (68, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (208, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('sensitivity to doxorubicin', 'MPA', (77, 103))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('Inhibition', 'Var', (0, 10))	('breast cancer', 'Disease', (275, 288))	('cell death', 'CPA', (53, 63))	('estrogen-receptor', 'Gene', (248, 265))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('gastric cancer', 'Disease', (208, 222))	('doxorubicin', 'Chemical', 'MESH:D004317', (92, 103))	('TRPM2', 'Gene', (14, 19))
39312	30925291	The preponderance of data in cancer models support the concept that TRPM2 expression and function have an important role in preserving cancer cell viability, and TRPM2 inhibition may be a novel therapeutic approach (Table 1).	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (135, 141))	('TRPM2', 'Gene', (68, 73))	('function', 'MPA', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('inhibition', 'Var', (168, 178))	('TRPM2', 'Gene', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
39320	30925291	TRPM2 inhibition reduces antioxidant defenses and increases ROS levels.	('reduces', 'NegReg', (17, 24))	('TRPM2', 'Gene', (0, 5))	('antioxidant defenses', 'MPA', (25, 45))	('increases ROS levels', 'Phenotype', 'HP:0025464', (50, 70))	('increases', 'PosReg', (50, 59))	('inhibition', 'Var', (6, 16))	('ROS levels', 'MPA', (60, 70))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))
39327	29108308	One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion.	('patients', 'Species', '9606', (13, 21))	('K27M', 'Mutation', 'p.K27M', (103, 107))	('H3.3', 'Gene', (98, 102))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('K27M', 'Var', (103, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
39341	29108308	DRD2 blockade is sufficient to inactivate growth factor signaling and induce tumor cell death in preclinical models of glioblastoma and other malignancies.	('glioblastoma', 'Disease', (119, 131))	('blockade', 'Var', (5, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('DRD2', 'Gene', (0, 4))	('tumor', 'Disease', (77, 82))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('induce', 'Reg', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('DRD2', 'Gene', '1813', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('growth factor signaling', 'MPA', (42, 65))	('malignancies', 'Disease', (142, 154))	('inactivate', 'NegReg', (31, 41))
39351	29108308	Only 2 patients had methylated MGMT tumors and 7 patients had prior gross total tumor resections.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('methylated', 'Var', (20, 30))	('patients', 'Species', '9606', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MGMT tumors', 'Disease', (31, 42))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (49, 57))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('MGMT tumors', 'Disease', 'MESH:D009369', (31, 42))	('tumor', 'Disease', (36, 41))
39356	29108308	One 22 year-old female with a recurrent secondary glioblastoma that advanced from a H3.3 K27M mutant Grade III astrocytoma achieved a partial response by RANO occurring after 7 doses, and the response has been sustained for >6 months (Figure 2; Supplemental Figure 1).	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('K27M', 'Mutation', 'p.K27M', (89, 93))	('astrocytoma', 'Disease', 'MESH:D001254', (111, 122))	('astrocytoma', 'Disease', (111, 122))	('astrocytoma', 'Phenotype', 'HP:0009592', (111, 122))	('H3.3', 'Var', (84, 88))	('glioblastoma', 'Disease', (50, 62))
39364	29108308	Although the study did not achieve the primary endpoint, single agent ONC201 showed signs of anti-tumor activity in this pilot study of recurrent glioblastoma patients that was enriched for several poor prognosis features: unmethylated MGMT, age >50, subtotal resections, and baseline corticosteroid use.	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('tumor', 'Disease', (98, 103))	('ONC201', 'Gene', (70, 76))	('unmethylated', 'Var', (223, 235))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MGMT', 'Gene', '4255', (236, 240))	('MGMT', 'Gene', (236, 240))	('glioblastoma', 'Disease', (146, 158))	('patients', 'Species', '9606', (159, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))
39366	29108308	Cancer stem cells have been shown to express relatively high levels of DRD2 compared to the bulk population and ONC201 effectively depletes cancer stem cells in numerous malignancies.	('DRD2', 'Gene', (71, 75))	('ONC201', 'Var', (112, 118))	('depletes', 'NegReg', (131, 139))	('DRD2', 'Gene', '1813', (71, 75))	('numerous malignancies', 'Disease', 'MESH:D009369', (161, 182))	('cancer', 'Disease', (140, 146))	('numerous malignancies', 'Disease', (161, 182))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
39369	29108308	Further investigation of the relevance of this mutation to the activity of ONC201 may be warranted, especially given lack of effective treatment options for H3.3 K27M mutant gliomas and the prevalence of this mutation in diffuse intrinsic pontine glioma (DIPG).	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('K27M', 'Mutation', 'p.K27M', (162, 166))	('glioma', 'Disease', (174, 180))	('H3.3 K27M', 'Var', (157, 166))	('gliomas', 'Disease', 'MESH:D005910', (174, 181))	('gliomas', 'Disease', (174, 181))	('gliomas', 'Phenotype', 'HP:0009733', (174, 181))	('glioma', 'Disease', (247, 253))
39375	29108308	DRD2 has emerging as a novel therapeutic target in glioblastoma and other cancers based on a series of studies that have demonstrated its selective overexpression in malignant tissues and the anticancer effects of its antagonism.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('overexpression', 'PosReg', (148, 162))	('antagonism', 'Var', (218, 228))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('DRD2', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (74, 80))	('cancers', 'Disease', (74, 81))	('glioblastoma', 'Disease', (51, 63))	('DRD2', 'Gene', '1813', (0, 4))	('glioblastoma', 'Disease', 'MESH:D005909', (51, 63))	('cancer', 'Disease', (196, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
39383	29108308	Prior bevacizumab was not allowed and patients with tumors harboring known IDH1/2 mutations were excluded.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('IDH1/2', 'Gene', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (38, 46))	('bevacizumab', 'Chemical', 'MESH:D000068258', (6, 17))	('IDH1/2', 'Gene', '3417;3418', (75, 81))
39393	29108308	This study was designed to detect a PFS-6 of >30% with an accrual of 30 subjects via a two-stage design with appropriate stopping rules for poor efficacy and unexpected toxicity.	('toxicity', 'Disease', 'MESH:D064420', (169, 177))	('toxicity', 'Disease', (169, 177))	('PFS-6', 'Var', (36, 41))
39400	28512247	Mibefradil treatment or RNAi-mediated attenuation of Cav3.2 was sufficient to inhibit the growth, survival and stemness of GSC, and also sensitized them to temozolomide (TMZ) chemotherapy.	('sensitized', 'Reg', (137, 147))	('survival', 'CPA', (98, 106))	('growth', 'CPA', (90, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (170, 173))	('Mibefradil', 'Chemical', 'MESH:D020748', (0, 10))	('inhibit', 'NegReg', (78, 85))	('stemness', 'Disease', 'MESH:D020295', (111, 119))	('attenuation', 'Var', (38, 49))	('temozolomide', 'Chemical', 'MESH:D000077204', (156, 168))	('stemness', 'Disease', (111, 119))	('Cav3.2', 'Gene', (53, 59))
39402	28512247	Cav3.2 inhibition suppressed GSC growth in part by inhibiting pro-survival AKT/mTOR pathways and stimulating pro-apoptotic survivin and BAX pathways.	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (79, 83))	('BAX', 'Gene', (136, 139))	('AKT', 'Gene', '207', (75, 78))	('BAX', 'Gene', '581', (136, 139))	('inhibition', 'Var', (7, 17))	('GSC growth', 'CPA', (29, 39))	('Cav3.2', 'Gene', (0, 6))	('AKT', 'Gene', (75, 78))	('inhibiting', 'NegReg', (51, 61))	('stimulating', 'PosReg', (97, 108))	('suppressed', 'NegReg', (18, 28))
39409	28512247	Additionally, alteration of free cytosolic calcium results in the transcription of immediate early genes such as c-fos, c-jun, the cyclic AMP response element and the serum response element.	('free cytosolic calcium', 'MPA', (28, 50))	('c-jun', 'Gene', (120, 125))	('c-fos', 'Gene', (113, 118))	('c-jun', 'Gene', '3725', (120, 125))	('cyclic AMP', 'Chemical', 'MESH:D000242', (131, 141))	('transcription', 'MPA', (66, 79))	('calcium', 'Chemical', 'MESH:D002118', (43, 50))	('serum', 'MPA', (167, 172))	('cyclic AMP response element', 'MPA', (131, 158))	('alteration', 'Var', (14, 24))	('c-fos', 'Gene', '2353', (113, 118))	('results in', 'Reg', (51, 61))
39410	28512247	Calcium influx is mediated by voltage-gated Ca++ (Cav) channels of which there are five types: L-type, P-type, N-type, R-type and T-type.	('P-type', 'Var', (103, 109))	('Cav', 'Gene', '858', (50, 53))	('mediated', 'Reg', (18, 26))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('Cav', 'Gene', (50, 53))	('Calcium influx', 'MPA', (0, 14))
39411	28512247	Aberrant expression and activity of T-type calcium channels (Cav3.2) has been implicated in cancer through their role in the regulation of cell cycle progression.	('Aberrant expression', 'Var', (0, 19))	('activity', 'MPA', (24, 32))	('Cav3.2', 'Gene', (61, 67))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('calcium', 'Chemical', 'MESH:D002118', (43, 50))	('cell cycle progression', 'CPA', (139, 161))	('implicated', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
39416	28512247	Mibefradil (C29H38FN3O3) (Supplementary Figure 1) is a T-type FDA-approved calcium channel blocker previously marketed by Roche as Posicor for the treatment of hypertension.	('hypertension', 'Disease', (160, 172))	('C29H38FN3O3', 'Var', (12, 23))	('hypertension', 'Phenotype', 'HP:0000822', (160, 172))	('Mibefradil', 'Chemical', 'MESH:D020748', (0, 10))	('calcium', 'Chemical', 'MESH:D002118', (75, 82))	('hypertension', 'Disease', 'MESH:D006973', (160, 172))
39418	28512247	Inhibition of Cav3.2 suppressed both GSC growth and stemness and in vivo xenograft growth and sensitized GSCs to chemotherapy.	('suppressed', 'NegReg', (21, 31))	('GSC growth', 'CPA', (37, 47))	('Inhibition', 'Var', (0, 10))	('stemness', 'Disease', 'MESH:D020295', (52, 60))	('Cav3.2', 'Gene', (14, 20))	('stemness', 'Disease', (52, 60))
39452	28512247	The TCGA analysis showed that 11% of GBM patients display either amplification, mutations or mRNA upregulation of Cav3.2.	('mRNA', 'MPA', (93, 97))	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (41, 49))	('upregulation', 'PosReg', (98, 110))	('Cav3.2', 'Gene', (114, 120))	('amplification', 'Var', (65, 78))
39453	28512247	Patients with an alteration of Cav3.2 demonstrated a trend towards worse survival than patients with normal Cav3.2 (Cav3.2 mRNA Expression z-Scores (RNA-Seq V2 RSEM), with a z-score threshold 1.0) (Fig.	('survival', 'MPA', (73, 81))	('alteration', 'Var', (17, 27))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (87, 95))	('worse', 'NegReg', (67, 72))
39472	28512247	To assess whether Cav3.2 silencing affected cell death, cells were infected as above and a trypan blue assay was performed.	('silencing', 'Var', (25, 34))	('trypan blue', 'Chemical', 'MESH:D014343', (91, 102))	('Cav3.2', 'Gene', (18, 24))
39473	28512247	The above data show that silencing of Cav3.2 expression leads to comparable anti-cancer effects on GSCs as mibefradil treatment.	('silencing', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('Cav3.2', 'Gene', (38, 44))	('GSCs', 'Disease', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mibefradil', 'Chemical', 'MESH:D020748', (107, 117))
39489	28512247	To determine if BAX and p27 mediate the pro-apoptotic effect of mibefradil, we assessed the effects of silencing p27 and BAX on mibefradil-induced cell death.	('silencing', 'Var', (103, 112))	('mibefradil', 'Chemical', 'MESH:D020748', (128, 138))	('p27', 'Gene', (113, 116))	('p27', 'Gene', '3429', (24, 27))	('BAX', 'Gene', (121, 124))	('p27', 'Gene', (24, 27))	('BAX', 'Gene', '581', (121, 124))	('mibefradil', 'Chemical', 'MESH:D020748', (64, 74))	('BAX', 'Gene', (16, 19))	('p27', 'Gene', '3429', (113, 116))	('BAX', 'Gene', '581', (16, 19))
39490	28512247	We transfected GSC cells with either si-control, si-BAX or si-p27 before treating them with mibefradil for 48 h. Inhibition of either BAX or p27 abrogated mibefradil-induced cell death (Fig.	('p27', 'Gene', '3429', (62, 65))	('BAX', 'Gene', (134, 137))	('p27', 'Gene', (62, 65))	('abrogated', 'NegReg', (145, 154))	('Inhibition', 'Var', (113, 123))	('p27', 'Gene', '3429', (141, 144))	('BAX', 'Gene', '581', (134, 137))	('mibefradil', 'Chemical', 'MESH:D020748', (92, 102))	('p27', 'Gene', (141, 144))	('BAX', 'Gene', (52, 55))	('BAX', 'Gene', '581', (52, 55))	('mibefradil', 'Chemical', 'MESH:D020748', (155, 165))
39511	28512247	Changes in intracellular Ca2+ levels can modulate signaling pathways and gene transcription that control a broad range of cellular events, including those important to tumorigenesis and cancer progression.	('signaling pathways', 'Pathway', (50, 68))	('tumor', 'Disease', (168, 173))	('Ca2+', 'Chemical', 'MESH:D000069285', (25, 29))	('gene transcription', 'Gene', (73, 91))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('modulate', 'Reg', (41, 49))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
39523	28512247	Silencing of Cav3.2 displayed similar anticancer effects as mibefradil treatment.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Cav3.2', 'Gene', (13, 19))	('mibefradil', 'Chemical', 'MESH:D020748', (60, 70))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Silencing', 'Var', (0, 9))
39529	28512247	Using proteomic screening, immunoblot validation and functional rescue experiments, we found that cell cycle and apoptosis signaling pathways are significantly activated by mibefradil in GSCs, including decreased phosphorylation of AKT, mTOR and 4EBP1 and upregulation of p27 KIP1, BAX, FOXO1 and cleaved PARP leading to decreased tumor cell proliferation through downregulation of key survival pathways and cell cycle arrest, respectively.	('mTOR', 'Gene', '2475', (237, 241))	('decreased', 'NegReg', (321, 330))	('FOXO1', 'Gene', (287, 292))	('key survival pathways', 'Pathway', (382, 403))	('AKT', 'Gene', '207', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('downregulation', 'NegReg', (364, 378))	('cell cycle', 'Pathway', (98, 108))	('upregulation', 'PosReg', (256, 268))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (408, 425))	('PARP', 'Gene', '1302', (305, 309))	('phosphorylation', 'MPA', (213, 228))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('mibefradil', 'Chemical', 'MESH:D020748', (173, 183))	('p27 KIP1', 'Gene', (272, 280))	('4EBP1', 'Gene', '1978', (246, 251))	('p27 KIP1', 'Gene', '1027', (272, 280))	('apoptosis signaling pathways', 'Pathway', (113, 141))	('activated', 'PosReg', (160, 169))	('PARP', 'Gene', (305, 309))	('AKT', 'Gene', (232, 235))	('FOXO1', 'Gene', '2308', (287, 292))	('mTOR', 'Gene', (237, 241))	('decreased', 'NegReg', (203, 212))	('cell cycle arrest', 'CPA', (408, 425))	('4EBP1', 'Gene', (246, 251))	('tumor', 'Disease', (331, 336))	('cleaved', 'Var', (297, 304))	('BAX', 'Gene', '581', (282, 285))	('BAX', 'Gene', (282, 285))	('mibefradil', 'Gene', (173, 183))
39530	28512247	Furthermore, silencing of p27 or Bax, both of which are upregulated in response to mibefradil treatment, abrogated drug-induced cell death, suggesting a role for p27 and BAX in mediating mibefradil toxicity.	('BAX', 'Gene', '581', (170, 173))	('mibefradil', 'Chemical', 'MESH:D020748', (83, 93))	('mibefradil', 'Chemical', 'MESH:D020748', (187, 197))	('Bax', 'Gene', (33, 36))	('toxicity', 'Disease', 'MESH:D064420', (198, 206))	('abrogated', 'NegReg', (105, 114))	('drug-induced cell death', 'CPA', (115, 138))	('p27', 'Gene', (162, 165))	('p27', 'Gene', '3429', (162, 165))	('Bax', 'Gene', '581', (33, 36))	('p27', 'Gene', (26, 29))	('p27', 'Gene', '3429', (26, 29))	('BAX', 'Gene', (170, 173))	('upregulated', 'PosReg', (56, 67))	('silencing', 'Var', (13, 22))	('toxicity', 'Disease', (198, 206))
39601	25681350	The anti-YKL-40, anti-RelB, anti-p65, anti-p50, anti-beta-tubulin, and anti-GAPDH antibodies were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA) and anti-Stat3 antibody was obtained from Cell Signaling Technology (Danvers, MA).	('p65', 'Gene', (33, 36))	('Stat3', 'Gene', '6774', (169, 174))	('GAPDH', 'Gene', '2597', (76, 81))	('Stat3', 'Gene', (169, 174))	('GAPDH', 'Gene', (76, 81))	('YKL-40', 'Gene', '1116', (9, 15))	('p65', 'Gene', '5970', (33, 36))	('anti-p50', 'Var', (38, 46))	('YKL-40', 'Gene', (9, 15))
39602	25681350	The following oligonucleotides were synthesized to introduce mutations in the YKL-40 promoter: -669 NF-KB, 5'-CTGAATTCGATAGCTGTCTTTCCCTCTAA-3' and 5'-ACAGCTATCGAA TTCAGAATGCTTTAAGC-3'; -717 NF-KB, 5'-ATCTCGAGAATAAAACAGAAGCAAAAT AG-3' and 5'-TTATTCTCGAGATAAAGAGAGAGGATCTT-3'.	('YKL-40', 'Gene', (78, 84))	('YKL-40', 'Gene', '1116', (78, 84))	('mutations', 'Var', (61, 70))	('oligonucleotides', 'Chemical', 'MESH:D009841', (14, 30))
39604	25681350	Anti-RelB, anti-p50, anti-p65 (Santa Cruz Biotechnology, Santa Cruz, CA) antibodies were used for supershift studies.	('p65', 'Gene', '5970', (26, 29))	('p65', 'Gene', (26, 29))	('anti-p50', 'Var', (11, 19))
39615	25681350	To corroborate these findings in a central nervous system model of sterile inflammation, expression of YKL-40, IL-1, and IL-6 was subsequently analyzed using a mouse EAE model of MS. Immunization of mice with MOG35-50 peptide resulted in the induction of EAE, and modest upregulation of YKL-40 mRNA expression in the spinal cords of animals (Fig.	('MOG35-50 peptide', 'Var', (209, 225))	('YKL-40', 'Gene', (287, 293))	('EAE', 'Disease', (255, 258))	('mice', 'Species', '10090', (199, 203))	('mRNA expression', 'MPA', (294, 309))	('YKL-40', 'Gene', '1116', (103, 109))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))	('YKL-40', 'Gene', (103, 109))	('upregulation', 'PosReg', (271, 283))	('mouse', 'Species', '10090', (160, 165))	('YKL-40', 'Gene', '1116', (287, 293))
39619	25681350	We also used the HIV transactivator of transcription (TAT) transgenic mouse model in which induction of TAT protein expression in the brain induces local sterile inflammation and enhances expression of IL-1 and IL-6.	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('transgenic', 'Species', '10090', (59, 69))	('induces', 'Reg', (140, 147))	('expression', 'MPA', (188, 198))	('local sterile', 'Disease', (148, 161))	('inflammation', 'Disease', (162, 174))	('TAT', 'Gene', (104, 107))	('mouse', 'Species', '10090', (70, 75))	('protein', 'Protein', (108, 115))	('enhances', 'PosReg', (179, 187))	('induction', 'Var', (91, 100))
39636	25681350	Surprisingly, knockdown of p65 had no effect on YKL-40 mRNA expression (Fig.	('YKL-40', 'Gene', '1116', (48, 54))	('YKL-40', 'Gene', (48, 54))	('p65', 'Gene', (27, 30))	('knockdown', 'Var', (14, 23))	('p65', 'Gene', '5970', (27, 30))
39638	25681350	To identify the mechanism of cytokine-induced YKL-40 expression, putative NF-kappaB and STAT3 binding sites of the YKL-40 promoter were mutated and the generated reporters were analyzed in astrocytes (Fig.	('YKL-40', 'Gene', (115, 121))	('YKL-40', 'Gene', (46, 52))	('STAT3', 'Gene', '6774', (88, 93))	('STAT3', 'Gene', (88, 93))	('YKL-40', 'Gene', '1116', (115, 121))	('mutated', 'Var', (136, 143))	('YKL-40', 'Gene', '1116', (46, 52))
39640	25681350	In addition, mutation of the STAT3 site also drastically diminished reporter activity.	('diminished', 'NegReg', (57, 67))	('STAT3', 'Gene', '6774', (29, 34))	('mutation', 'Var', (13, 21))	('STAT3', 'Gene', (29, 34))	('reporter activity', 'MPA', (68, 85))
39645	25681350	Knockdown of either RelB or p50 significantly diminished cytokine-induced YKL-40 mRNA expression, whereas knockdown of p65, cRel and p52 had no effect (Fig.	('p52', 'Gene', '4791', (133, 136))	('YKL-40', 'Gene', '1116', (74, 80))	('p65', 'Gene', (119, 122))	('cRel', 'Gene', (124, 128))	('YKL-40', 'Gene', (74, 80))	('cRel', 'Gene', '5966', (124, 128))	('cytokine-induced', 'MPA', (57, 73))	('p65', 'Gene', '5970', (119, 122))	('p50', 'Var', (28, 31))	('diminished', 'NegReg', (46, 56))	('p52', 'Gene', (133, 136))
39657	25681350	These experiments were performed in U373 glioma cells, which similarly to human and mouse astrocytes, upregulate expression of both YKL-40 and RelB in response to IL-1 and OSM, and this cytokine-induced expression is diminished by the knockdown of p50 and RelB (Suppl.	('YKL-40', 'Gene', (132, 138))	('expression', 'MPA', (113, 123))	('human', 'Species', '9606', (74, 79))	('U373', 'CellLine', 'CVCL:2219', (36, 40))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('IL-1 and OSM', 'Gene', '111343;18413', (163, 175))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('diminished', 'NegReg', (217, 227))	('YKL-40', 'Gene', '1116', (132, 138))	('upregulate', 'PosReg', (102, 112))	('mouse', 'Species', '10090', (84, 89))	('p50', 'Var', (248, 251))	('glioma', 'Disease', (41, 47))	('RelB', 'Gene', (143, 147))
39662	25681350	Cytokine stimulation facilitated the binding of protein complexes to the proximal NF-kappaB element in vitro, which super-shifted with anti-p65, anti-RelB and anti-p50 antibodies (Fig.	('anti-RelB', 'Var', (145, 154))	('binding', 'Interaction', (37, 44))	('protein complexes', 'Protein', (48, 65))	('p65', 'Gene', (140, 143))	('anti-p50', 'Var', (159, 167))	('p65', 'Gene', '5970', (140, 143))	('super-shifted', 'PosReg', (116, 129))
39687	25681350	However, it has recently been recognized that in dendritic cells, RelB can also be activated by a canonical pathway in response to TNF, LPS and CpG, and this activation results in RelB/p50 complex formation.	('canonical pathway', 'Pathway', (98, 115))	('results in', 'Reg', (169, 179))	('RelB', 'Gene', (66, 70))	('LPS', 'MPA', (136, 139))	('TNF', 'Gene', (131, 134))	('CpG', 'Var', (144, 147))	('TNF', 'Gene', '7124', (131, 134))	('activated', 'PosReg', (83, 92))	('RelB/p50 complex formation', 'MPA', (180, 206))
39696	25681350	However, chronic inflammation may also lead to pathological RelB/p50-dependent gene expression.	('lead to', 'Reg', (39, 46))	('pathological', 'Var', (47, 59))	('RelB/p50-dependent gene', 'Gene', (60, 83))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	('inflammation', 'Disease', (17, 29))
39705	24717239	Critical Role of Aberrant Angiogenesis in the Development of Tumor Hypoxia and Associated Radioresistance Newly formed microvessels in most solid tumors show an abnormal morphology and thus do not fulfil the metabolic demands of the growing tumor mass.	('Angiogenesis', 'CPA', (26, 38))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Aberrant', 'Var', (17, 25))	('solid tumors', 'Disease', (140, 152))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', (146, 151))	('Tumor Hypoxia', 'Disease', 'MESH:D000860', (61, 74))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Tumor Hypoxia', 'Disease', (61, 74))
39773	24717239	Aberrant microcirculation is a major causative factor for the development of hypoxia in solid tumors.	('hypoxia', 'Disease', (77, 84))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('solid tumors', 'Disease', 'MESH:D009369', (88, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('solid tumors', 'Disease', (88, 100))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
39795	24717239	Despite some promising results in clinical trials, the blockade of VEGF signalling also exerts adverse effects such as resistance to VEGF inhibitors as well as hemorrhagic and thrombotic events due to the damage of healthy vessels.	('hemorrhagic', 'Disease', (160, 171))	('thrombotic events', 'Phenotype', 'HP:0001907', (176, 193))	('hemorrhagic', 'Disease', 'MESH:D006470', (160, 171))	('thrombotic', 'Disease', 'MESH:D013927', (176, 186))	('resistance', 'MPA', (119, 129))	('thrombotic', 'Disease', (176, 186))	('blockade', 'Var', (55, 63))	('VEGF', 'Protein', (67, 71))
39818	24717239	Moreover, NVP-AUY922 in combination with radiotherapy resulted in a delayed growth of human prostate cancer cells in a mouse model in a supra-additive manner.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('mouse', 'Species', '10090', (119, 124))	('delayed growth', 'Phenotype', 'HP:0001510', (68, 82))	('delayed growth', 'CPA', (68, 82))	('prostate cancer', 'Disease', (92, 107))	('human', 'Species', '9606', (86, 91))	('NVP-AUY922', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))
39831	31320597	The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant.	('ICT-107', 'Chemical', '-', (60, 67))	('ICT-107', 'Var', (60, 67))	('overall', 'MPA', (29, 36))
39903	31320597	PFS, for ICT-107 of 11.4 months was statistically significantly increased compared with the 10.1 months for the control group (HR = 0.64; P = 0.033).	('PFS', 'MPA', (0, 3))	('ICT-107', 'Var', (9, 16))	('increased', 'PosReg', (64, 73))	('ICT-107', 'Chemical', '-', (9, 16))
39907	31320597	For HLA-A2+ patients with unmethylated MGMT promoter, median PFS for the ICT-107 group was 10.5 months compared with 6.0 months for the control group (HR = 0.72; P = 0.37), while median OS was 15.8 months for the ICT-107 group compared with 11.8 months for the control group (HR = 0.70; P = 0.33).	('patients', 'Species', '9606', (12, 20))	('PFS', 'MPA', (61, 64))	('ICT-107', 'Chemical', '-', (73, 80))	('MGMT', 'Gene', (39, 43))	('MGMT', 'Gene', '4255', (39, 43))	('unmethylated', 'Var', (26, 38))	('ICT-107', 'Chemical', '-', (213, 220))
39925	31320597	KPS was significantly higher during the treatment period in those receiving ICT-107 (cycles 1-4 or maintenance phase).	('higher', 'PosReg', (22, 28))	('men', 'Species', '9606', (45, 48))	('ICT-107', 'Var', (76, 83))	('ICT-107', 'Chemical', '-', (76, 83))	('KPS', 'MPA', (0, 3))
39928	31320597	There was a trend toward less initiation of steroids over time in the ICT-107 arm versus the control (P= 0.1395, log-rank; Supplementaryl Data Fig.	('ICT-107', 'Chemical', '-', (70, 77))	('initiation of steroids', 'MPA', (30, 52))	('ICT-107', 'Var', (70, 77))	('less', 'NegReg', (25, 29))	('men', 'Species', '9606', (129, 132))	('steroids', 'Chemical', 'MESH:D013256', (44, 52))
39929	31320597	On the basis of these initial analyses of clinical benefit, increased PFS time with ICT-107 was not associated with a detrimental impact on self-reported QoL, and was associated with maintenance of KPS and a longer corticosteroid-free period than those in the control arm.	('steroid', 'Chemical', 'MESH:D013256', (222, 229))	('QoL', 'MPA', (154, 157))	('KPS', 'MPA', (198, 201))	('ICT-107', 'Var', (84, 91))	('ICT-107', 'Chemical', '-', (84, 91))	('PFS', 'MPA', (70, 73))	('men', 'Species', '9606', (123, 126))	('increased', 'PosReg', (60, 69))
39937	31320597	Overall survival for the HLA-A2+patients with methylated MGMT promoter and OS and PFS for HLA-A2+ patients with unmethylated MGMT promoter were greater in the ICT-107 group compared with controls but were not statistically significant with the small patient numbers.	('patients', 'Species', '9606', (32, 40))	('MGMT', 'Gene', (125, 129))	('patient', 'Species', '9606', (98, 105))	('greater', 'PosReg', (144, 151))	('PFS', 'CPA', (82, 85))	('MGMT', 'Gene', '4255', (125, 129))	('ICT-107', 'Chemical', '-', (159, 166))	('patients', 'Species', '9606', (98, 106))	('MGMT', 'Gene', '4255', (57, 61))	('MGMT', 'Gene', (57, 61))	('Overall survival', 'CPA', (0, 16))	('patient', 'Species', '9606', (32, 39))	('patient', 'Species', '9606', (250, 257))	('methylated', 'Var', (46, 56))
39938	31320597	Testing for immune response using IFNgamma ELISpot in the ITT population showed an increase in responders treated with ICT-107 (50%) compared with control (33%; alpha = 0.10; P = 0.058).	('IFNgamma ELISpot', 'Gene', '3439', (34, 50))	('increase', 'PosReg', (83, 91))	('IFNgamma ELISpot', 'Gene', (34, 50))	('ICT-107', 'Var', (119, 126))	('ICT-107', 'Chemical', '-', (119, 126))
39939	31320597	In the HLA-A2+ group, 86% of the patients treated with ICT-107 were responders by both ELISpot and multimer assays, compared with only 33% of the controls.	('ICT-107', 'Var', (55, 62))	('responders', 'MPA', (68, 78))	('patients', 'Species', '9606', (33, 41))	('ICT-107', 'Chemical', '-', (55, 62))
39943	31320597	However, the majority of the patients in the HLA-A1+ subgroup did not express the target antigens and most of the benefit was derived from patients in the HLA-A2+ subgroup.	('patients', 'Species', '9606', (29, 37))	('HLA-A2+', 'Var', (155, 162))	('benefit', 'PosReg', (114, 121))	('patients', 'Species', '9606', (139, 147))
39969	33884377	Though MGMT status is perhaps the most accepted biomarker for medical management of patients with glioblastoma, several other molecular markers include mutation of epidermal growth factor receptor (EGFR) and isocitrate dehydrogenase (IDH) may have prognostic value.	('MGMT', 'Gene', '4255', (7, 11))	('MGMT', 'Gene', (7, 11))	('glioblastoma', 'Disease', (98, 110))	('epidermal growth factor receptor', 'Gene', (164, 196))	('IDH', 'Gene', (234, 237))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('isocitrate dehydrogenase', 'Gene', (208, 232))	('patients', 'Species', '9606', (84, 92))	('IDH', 'Gene', '3417', (234, 237))	('epidermal growth factor receptor', 'Gene', '1956', (164, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('isocitrate dehydrogenase', 'Gene', '3417', (208, 232))	('EGFR', 'Gene', '1956', (198, 202))	('EGFR', 'Gene', (198, 202))	('mutation', 'Var', (152, 160))
39986	33884377	This 40-plex assay included Proinflammatory Panel 1 (K15049D), Vascular Injury Panel 2 (K15198D), Angiogenesis Panel 1 (K15190D), Cytokine Panel 1 (K15050D), Chemokine Panel 1 (K15047D).	('K15049D', 'Mutation', 'p.K15049D', (53, 60))	('K15190D', 'Mutation', 'p.K15190D', (120, 127))	('K15047D', 'Var', (177, 184))	('K15050D', 'Var', (148, 155))	('K15047D', 'Mutation', 'p.K15047D', (177, 184))	('K15190D', 'Var', (120, 127))	('K15049D', 'Var', (53, 60))	('K15198D', 'Var', (88, 95))	('K15198D', 'Mutation', 'p.K15198D', (88, 95))	('K15050D', 'Mutation', 'p.K15050D', (148, 155))
40010	33884377	As shown in Figure 5C in patients that had a GTR the prognostic index split the patients into two cohorts with statistically significantly difference in survival.	('difference', 'Reg', (139, 149))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (80, 88))	('GTR', 'Var', (45, 48))
40028	33528916	Taken together, our findings suggest that targeting BRG1 in GBM may have therapeutic benefit in the treatment of this deadly form of brain cancer.	('brain cancer', 'Phenotype', 'HP:0030692', (133, 145))	('BRG1', 'Gene', (52, 56))	('BRG1', 'Gene', '6597', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('brain cancer', 'Disease', (133, 145))	('targeting', 'Var', (42, 51))	('brain cancer', 'Disease', 'MESH:D001932', (133, 145))
40031	33528916	1   Chromatin regulation and epigenetically-centred processes are tightly linked to cancer, and more than 20% of human cancers bear one or more mutations in the mammalian ATP-dependent chromatin remodelling SWI/SNF complex.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('ATP', 'Chemical', 'MESH:D000255', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancer', 'Disease', (119, 125))	('cancers', 'Disease', (119, 126))	('SWI/SNF complex', 'Gene', (207, 222))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mammalian', 'Species', '9606', (161, 170))	('mutations', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
40034	33528916	In cancers of the lung, ovaries, skin and blood (lymphoma), BRG1 functions as a tumour suppressor with silencing or loss-of-function mutations being enriched.	('tumour', 'Disease', (80, 86))	('loss-of-function', 'NegReg', (116, 132))	('ovaries', 'Disease', 'MESH:D010051', (24, 31))	('BRG1', 'Gene', (60, 64))	('lymphoma', 'Disease', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('BRG1', 'Gene', '6597', (60, 64))	('cancers', 'Disease', (3, 10))	('ovaries', 'Disease', (24, 31))	('mutations', 'Var', (133, 142))	('lymphoma', 'Disease', 'MESH:D008223', (49, 57))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('lymphoma', 'Phenotype', 'HP:0002665', (49, 57))	('silencing', 'NegReg', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
40035	33528916	6 ,  10 ,  11  However, BRG1 mutations are relatively rare in GBM.	('mutations', 'Var', (29, 38))	('BRG1', 'Gene', (24, 28))	('BRG1', 'Gene', '6597', (24, 28))
40039	33528916	In addition, BRG1 silencing in CSCs increased the tyrosine phosphorylation of the STAT3 transcription factor, which was basally high in these cells.	('silencing', 'Var', (18, 27))	('BRG1', 'Gene', '6597', (13, 17))	('STAT3', 'Gene', '6774', (82, 87))	('BRG1', 'Gene', (13, 17))	('increased', 'PosReg', (36, 45))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('STAT3', 'Gene', (82, 87))	('tyrosine phosphorylation', 'MPA', (50, 74))
40040	33528916	In the present study, we examined the functional consequences of knocking out BRG1 in relatively proliferative, non-stem differentiated GBM cell lines by CRISPR-CAS9 gene editing.	('BRG1', 'Gene', (78, 82))	('BRG1', 'Gene', '6597', (78, 82))	('knocking out', 'Var', (65, 77))
40041	33528916	In contrast to our previous findings that BRG1 shRNA knockdown increased the proliferation of GBM CSCs, knockout (KO) of BRG1 slightly reduced GBM cell proliferation.	('BRG1', 'Gene', (121, 125))	('BRG1', 'Gene', '6597', (42, 46))	('increased', 'PosReg', (63, 72))	('BRG1', 'Gene', '6597', (121, 125))	('GBM cell proliferation', 'CPA', (143, 165))	('reduced', 'NegReg', (135, 142))	('knockout', 'Var', (104, 112))	('BRG1', 'Gene', (42, 46))	('proliferation', 'CPA', (77, 90))
40047	33528916	Nonetheless, targeting BRG1 may have therapeutic benefit in the treatment of this deadly form of brain cancer by targeting both differentiated GBM tumour cells and CSCs.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('brain cancer', 'Disease', (97, 109))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('BRG1', 'Gene', (23, 27))	('brain cancer', 'Disease', 'MESH:D001932', (97, 109))	('targeting', 'Var', (13, 22))	('BRG1', 'Gene', '6597', (23, 27))	('GBM tumour', 'Disease', 'MESH:D005910', (143, 153))	('brain cancer', 'Phenotype', 'HP:0030692', (97, 109))	('GBM tumour', 'Disease', (143, 153))
40056	33528916	14   Several cancer genomic data sets for GBM patients 15 ,  16 ,  17  were queried for epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN) and SMARCA4/BRG1 mutations, deletions and amplifications using the cBioPortal tool.	('amplifications', 'Var', (209, 223))	('patients', 'Species', '9606', (46, 54))	('SMARCA4', 'Gene', (171, 178))	('phosphatase and tensin homolog', 'Gene', '5728', (129, 159))	('SMARCA4', 'Gene', '6597', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (184, 193))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('deletions', 'Var', (195, 204))	('PTEN', 'Gene', '5728', (161, 165))	('BRG1', 'Gene', '6597', (179, 183))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('BRG1', 'Gene', (179, 183))	('PTEN', 'Gene', (161, 165))	('EGFR', 'Gene', '1956', (122, 126))	('epidermal growth factor receptor', 'Gene', (88, 120))	('EGFR', 'Gene', (122, 126))
40064	33528916	Mutation and deletion of BRG1/SMARCA4 have been shown to contribute to a range of human malignancies.	('BRG1', 'Gene', '6597', (25, 29))	('contribute', 'Reg', (57, 67))	('malignancies', 'Disease', (88, 100))	('human', 'Disease', (82, 87))	('Mutation', 'Var', (0, 8))	('human', 'Species', '9606', (82, 87))	('deletion', 'Var', (13, 21))	('BRG1', 'Gene', (25, 29))	('SMARCA4', 'Gene', (30, 37))	('SMARCA4', 'Gene', '6597', (30, 37))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
40065	33528916	12 ,  22  Previous studies have established that mutations in EGFR result in its overexpression, while genomic mutations in PTEN tumour suppressor leads to its down-regulation in GBM.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (111, 120))	('PTEN tumour', 'Disease', (124, 135))	('EGFR', 'Gene', '1956', (62, 66))	('mutations', 'Var', (49, 58))	('down-regulation', 'NegReg', (160, 175))	('EGFR', 'Gene', (62, 66))	('overexpression', 'MPA', (81, 95))	('PTEN tumour', 'Disease', 'MESH:D006223', (124, 135))
40066	33528916	23  Consistent with previous findings, analysis of cancer genomics data in several GBM patient databases using the cBioPortal tool 18  showed that EGFR amplification (46%) and PTEN deletion (25%) frequently occur in GBM (Figure 1A).	('amplification', 'Var', (152, 165))	('GBM', 'Disease', (216, 219))	('EGFR', 'Gene', (147, 151))	('PTEN', 'Gene', (176, 180))	('EGFR', 'Gene', '1956', (147, 151))	('PTEN', 'Gene', '5728', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patient', 'Species', '9606', (87, 94))	('deletion', 'Var', (181, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('occur', 'Reg', (207, 212))
40078	33528916	To define the functional significance of the expression of BRG1 in differentiated GBM cells grown in vitro, we used CRISPR/Cas9 lentivirus encoding three different gRNAs to delete the BRG1 gene from LN229 and MT330 GBM cells.	('BRG1', 'Gene', '6597', (59, 63))	('BRG1', 'Gene', (184, 188))	('delete', 'Var', (173, 179))	('BRG1', 'Gene', '6597', (184, 188))	('BRG1', 'Gene', (59, 63))	('LN229', 'CellLine', 'CVCL:0393', (199, 204))
40081	33528916	To validate that BRG1 was indeed knocked out at the protein level, lysates of EV and three individual BRG1-KO MT330 cell lines were prepared, fractionated on SDS-PAGE, and immunoblotted for BRG1.	('BRG1', 'Gene', (190, 194))	('SDS', 'Chemical', 'MESH:D012967', (158, 161))	('BRG1', 'Gene', '6597', (190, 194))	('knocked out', 'Var', (33, 44))	('BRG1', 'Gene', (102, 106))	('BRG1', 'Gene', (17, 21))	('EV', 'Chemical', '-', (78, 80))	('BRG1', 'Gene', '6597', (102, 106))	('BRG1', 'Gene', '6597', (17, 21))
40083	33528916	BRG1 knockdown by shRNA in GSCs isolated from several patient-derived xenografts was previously found to increase STAT3 tyrosine 705 phosphorylation (pTyr-STAT3).	('patient', 'Species', '9606', (54, 61))	('BRG1', 'Gene', '6597', (0, 4))	('STAT3', 'Gene', '6774', (114, 119))	('pTyr', 'Chemical', '-', (150, 154))	('knockdown', 'Var', (5, 14))	('STAT3', 'Gene', (155, 160))	('STAT3', 'Gene', (114, 119))	('increase', 'PosReg', (105, 113))	('BRG1', 'Gene', (0, 4))	('tyrosine', 'Chemical', 'MESH:D014443', (120, 128))	('STAT3', 'Gene', '6774', (155, 160))
40090	33528916	To further characterize the functional consequences of BRG1 deletion, we then assessed how BRG1 deletion affects GBM cell proliferation, migration and invasion.	('BRG1', 'Gene', '6597', (55, 59))	('affects', 'Reg', (105, 112))	('GBM cell proliferation', 'CPA', (113, 135))	('BRG1', 'Gene', (91, 95))	('invasion', 'CPA', (151, 159))	('migration', 'CPA', (137, 146))	('deletion', 'Var', (96, 104))	('BRG1', 'Gene', '6597', (91, 95))	('BRG1', 'Gene', (55, 59))
40091	33528916	While knockout of BRG1 expression in MT330 cells only slightly inhibited GBM cell proliferation as determined by Incucyte live cell analysis (Figure 4A), BRG1-KO significantly reduced cell invasion in Matrigel transwell assays (Figure 4B) and cell migration in wound healing assays (Figure 4C).	('BRG1', 'Gene', '6597', (18, 22))	('BRG1', 'Gene', '6597', (154, 158))	('cell migration in wound healing assays', 'CPA', (243, 281))	('reduced', 'NegReg', (176, 183))	('cell invasion in Matrigel transwell assays', 'CPA', (184, 226))	('BRG1', 'Gene', (154, 158))	('knockout', 'Var', (6, 14))	('inhibited', 'NegReg', (63, 72))	('BRG1', 'Gene', (18, 22))	('GBM cell proliferation', 'CPA', (73, 95))
40096	33528916	3 ,  4  By microarray analysis of gene expression, we previously found that knockdown of BRG1 in GSCs selectively up-regulated and down-regulated the expression of a specific subset of genes, including several IFN stimulated genes (ISGs).	('BRG1', 'Gene', '6597', (89, 93))	('expression', 'MPA', (150, 160))	('knockdown', 'Var', (76, 85))	('up-regulated', 'PosReg', (114, 126))	('IFN', 'Gene', '3439', (210, 213))	('down-regulated', 'NegReg', (131, 145))	('IFN', 'Gene', (210, 213))	('BRG1', 'Gene', (89, 93))
40101	33528916	33 ,  34  Mutation and deletion of BRG1 have been shown to contribute to a range of human malignancies.	('malignancies', 'Disease', (90, 102))	('BRG1', 'Gene', (35, 39))	('deletion', 'Var', (23, 31))	('BRG1', 'Gene', '6597', (35, 39))	('human', 'Species', '9606', (84, 89))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('contribute', 'Reg', (59, 69))
40103	33528916	In contrast, EGFR amplification (46%) and PTEN deletion (25%) are known to frequently occur.	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('deletion', 'Var', (47, 55))	('amplification', 'Var', (18, 31))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
40106	33528916	Furthermore, high BRG1 expression was found to be selectively localized to distinct regions on GBM tumour specimens as determined by RNA-ISH.	('BRG1', 'Gene', '6597', (18, 22))	('high', 'Var', (13, 17))	('GBM tumour', 'Disease', 'MESH:D005910', (95, 105))	('GBM tumour', 'Disease', (95, 105))	('BRG1', 'Gene', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('expression', 'MPA', (23, 33))
40112	33528916	We employed the approach of knocking out BRG1 expression in two different GBM cell lines by CRISPR-CAS9 gene editing using three different guide RNAs and then isolated pools of KO cells.	('knocking', 'Var', (28, 36))	('BRG1', 'Gene', (41, 45))	('BRG1', 'Gene', '6597', (41, 45))
40114	33528916	The effects of BRG1 on STAT phosphorylation were selective for STAT3, which is consistent with previous findings that silencing BRG1 with shRNA in GBM cancer stem cells resulted in high STAT3 tyrosine phosphorylation but not in the phosphorylation of other STAT proteins.	('STAT', 'Gene', (186, 190))	('STAT', 'Gene', '6772;6774', (257, 261))	('STAT3', 'Gene', '6774', (63, 68))	('STAT', 'Gene', '6772;6774', (186, 190))	('BRG1', 'Gene', '6597', (128, 132))	('silencing', 'Var', (118, 127))	('cancer', 'Disease', (151, 157))	('STAT', 'Gene', (63, 67))	('BRG1', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('STAT3', 'Gene', (186, 191))	('STAT', 'Gene', (23, 27))	('high', 'PosReg', (181, 185))	('BRG1', 'Gene', '6597', (15, 19))	('STAT', 'Gene', '6772;6774', (63, 67))	('tyrosine', 'Chemical', 'MESH:D014443', (192, 200))	('STAT3', 'Gene', '6774', (186, 191))	('BRG1', 'Gene', (15, 19))	('STAT', 'Gene', '6772;6774', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('STAT', 'Gene', (257, 261))	('STAT3', 'Gene', (63, 68))
40123	33528916	Deletion of CDKN2A gene or silencing of its expression by promoter methylation is prevalent in several human cancers, consistent with CDKN2A being a tumour suppressor gene.	('silencing', 'NegReg', (27, 36))	('expression', 'MPA', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CDKN2A', 'Gene', (12, 18))	('human', 'Species', '9606', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('CDKN2A', 'Gene', (134, 140))	('cancers', 'Disease', (109, 116))	('CDKN2A', 'Gene', '1029', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('prevalent', 'Reg', (82, 91))	('CDKN2A', 'Gene', '1029', (134, 140))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))	('Deletion', 'Var', (0, 8))
40128	33528916	Knockdown of BRG1 in embryonic stem cells and in GBM CSCs was reported to reduce cell proliferation.	('cell proliferation', 'CPA', (81, 99))	('Knockdown', 'Var', (0, 9))	('reduce', 'NegReg', (74, 80))	('BRG1', 'Gene', (13, 17))	('BRG1', 'Gene', '6597', (13, 17))
40129	33528916	48 ,  49 ,  50  However, we previously showed that BRG1 knockdown in GBM CSCs increased cell proliferation in vitro and in vivo.	('BRG1', 'Gene', '6597', (51, 55))	('increased', 'PosReg', (78, 87))	('cell proliferation', 'CPA', (88, 106))	('BRG1', 'Gene', (51, 55))	('knockdown', 'Var', (56, 65))
40132	33528916	This finding is in stark contrast to the marked increase in the proliferation of GBM CSCs upon BRG1 knockdown.	('BRG1', 'Gene', (95, 99))	('knockdown', 'Var', (100, 109))	('BRG1', 'Gene', '6597', (95, 99))	('increase', 'PosReg', (48, 56))
40138	33528916	Consistent with our findings that BRG1-KO increases TMZ sensitivity of GBM cell lines, BRG1 knockdown in GBM CSCs also increased TMZ sensitivity in vitro.	('BRG1', 'Gene', '6597', (87, 91))	('TMZ sensitivity', 'MPA', (129, 144))	('BRG1', 'Gene', '6597', (34, 38))	('increases', 'PosReg', (42, 51))	('TMZ', 'Chemical', 'MESH:D000077204', (52, 55))	('knockdown', 'Var', (92, 101))	('TMZ sensitivity', 'MPA', (52, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (129, 132))	('BRG1', 'Gene', (34, 38))	('BRG1', 'Gene', (87, 91))	('increased', 'PosReg', (119, 128))
40139	33528916	BRG1 knockdown also increased the proliferation of GBM CSCs, which may increase chemosensitivity, because CSCs proliferate relatively slowly, and chemotherapeutic drugs target proliferating cancer cells.	('increased', 'PosReg', (20, 29))	('proliferation', 'CPA', (34, 47))	('cancer', 'Disease', (190, 196))	('BRG1', 'Gene', '6597', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('knockdown', 'Var', (5, 14))	('slowly', 'NegReg', (134, 140))	('increase', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('BRG1', 'Gene', (0, 4))	('chemosensitivity', 'MPA', (80, 96))
40169	33413577	Each subtype shows high expression of its characteristic markers, such as SOX2 and OLIG2 for the PN subtype and CD44 and YKL40 for the MES subtype.	('PN', 'Gene', '79650', (97, 99))	('OLIG2', 'Gene', '50913', (83, 88))	('expression', 'MPA', (24, 34))	('CD44', 'Gene', '12505', (112, 116))	('CD44', 'Gene', (112, 116))	('MES', 'Chemical', '-', (135, 138))	('YKL40', 'Var', (121, 126))	('OLIG2', 'Gene', (83, 88))	('SOX2', 'Gene', (74, 78))	('SOX2', 'Gene', '20674', (74, 78))
40176	33413577	Previous studies have demonstrated that csGRP78 is involved in the malignant behaviors of high-grade glioma and that blocking csGRP78 suppresses the radioresistance of GBM.	('GRP78', 'Gene', (42, 47))	('GRP78', 'Gene', '14828', (128, 133))	('glioma', 'Disease', (101, 107))	('suppresses', 'NegReg', (134, 144))	('GRP78', 'Gene', (128, 133))	('radioresistance of GBM', 'CPA', (149, 171))	('GRP78', 'Gene', '14828', (42, 47))	('involved', 'Reg', (51, 59))	('blocking', 'Var', (117, 125))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
40186	33413577	Poly-L-ornithine solution (P4957; Sigma-Aldrich) and Laminin (L4544; Sigma-Aldrich) were used to pre-coat cell culture plates.	('Poly-L-ornithine', 'Chemical', 'MESH:C008973', (0, 16))	('L4544;', 'Var', (62, 68))	('P4957;', 'Var', (27, 33))
40200	33413577	The persistent knockdown of GRP78 and BACE2 was performed by Lentivirus (GenChem, China) expressing shRNA (shGRP78 or shBACE2).	('GRP78', 'Gene', (28, 33))	('knockdown', 'Var', (15, 24))	('GRP78', 'Gene', '14828', (109, 114))	('GRP78', 'Gene', '14828', (28, 33))	('BACE2', 'Gene', (38, 43))	('GRP78', 'Gene', (109, 114))
40216	33413577	Next, the cells were washed gently with PBS three times and incubated with fluorophore-conjugated secondary antibodies at room temperature for 1 h. The secondary antibodies used were as follows: Alexa Fluor 488 goat anti-rabbit antibody (A-11034; Invitrogen; 1:400) and Alexa Fluor 594 goat anti-mouse antibody (A-11032; Invitrogen; 1:400).	('PBS', 'Chemical', 'MESH:D007854', (40, 43))	('A-11034', 'Var', (238, 245))	('mouse', 'Species', '10090', (296, 301))	('Alexa Fluor 594', 'Chemical', '-', (270, 285))	('A-11032', 'Var', (312, 319))	('Alexa Fluor 488', 'Chemical', '-', (195, 210))
40244	33413577	Through TCGA database, we confirmed that GRP78 mRNA increased with WHO grade and was associated with poor prognosis (Figure S1A, B) and that GRP78 was highest in MES-subtype GBM (Fig.	('increased', 'PosReg', (52, 61))	('GRP78', 'Gene', (41, 46))	('mRNA', 'Var', (47, 51))	('GRP78', 'Gene', (141, 146))	('MES', 'Chemical', '-', (162, 165))	('GRP78', 'Gene', '14828', (141, 146))	('GRP78', 'Gene', '14828', (41, 46))
40250	33413577	Next, stable knockdown of GRP78 caused significant inhibition of tumorsphere expansion (Fig.	('inhibition', 'NegReg', (51, 61))	('GRP78', 'Gene', '14828', (26, 31))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('GRP78', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
40253	33413577	The dual staining apoptosis assay and TUNEL assay results showed that the number of apoptotic tumor cells was the highest in the group treated with the combination of GRP78 knockdown and irradiation (Figure S1F, G), coinciding with the western blotting results for the apoptosis-related protein cleaved PARP (c-PARP) and the radiation injury marker gamma-H2AX (Figure S1H).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('PARP', 'Gene', (311, 315))	('radiation injury', 'Disease', (325, 341))	('gamma-H2AX', 'Gene', '15270', (349, 359))	('PARP', 'Gene', '11545', (311, 315))	('GRP78', 'Gene', '14828', (167, 172))	('knockdown', 'Var', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('gamma-H2AX', 'Gene', (349, 359))	('PARP', 'Gene', (303, 307))	('GRP78', 'Gene', (167, 172))	('PARP', 'Gene', '11545', (303, 307))	('radiation injury', 'Disease', 'MESH:D011832', (325, 341))
40257	33413577	The expression of csGRP78 decreased partly with siGRP78 transfection (Figure S2B).	('GRP78', 'Gene', '14828', (50, 55))	('expression', 'MPA', (4, 14))	('GRP78', 'Gene', '14828', (20, 25))	('GRP78', 'Gene', (50, 55))	('transfection', 'Var', (56, 68))	('decreased', 'NegReg', (26, 35))	('GRP78', 'Gene', (20, 25))
40268	33413577	These data suggest that blocking csGRP78 with an antibody effectively disrupts MES GSCs but has no detectable effects on the stemness and viability of NPCs.	('MES', 'Disease', (79, 82))	('GRP78', 'Gene', (35, 40))	('MES GSCs', 'Chemical', '-', (79, 87))	('blocking', 'Var', (24, 32))	('disrupts', 'NegReg', (70, 78))	('GRP78', 'Gene', '14828', (35, 40))
40270	33413577	Thus, we determined whether blocking csGRP78 could enhance the therapeutic efficacy of radiotherapy (Fig.	('GRP78', 'Gene', '14828', (39, 44))	('therapeutic efficacy of radiotherapy', 'CPA', (63, 99))	('enhance', 'PosReg', (51, 58))	('GRP78', 'Gene', (39, 44))	('blocking', 'Var', (28, 36))
40294	33413577	To experimentally investigate the function of BACE2 in MES GSCs, we utilized two independent siRNA sequences to knock down BACE2.	('MES GSCs', 'Chemical', '-', (55, 63))	('BACE2', 'Gene', (123, 128))	('knock down', 'Var', (112, 122))
40296	33413577	Moreover, knockdown of BACE2 dramatically decreased the self-renewal of MES GSCs (Fig.	('self-renewal of MES GSCs', 'CPA', (56, 80))	('decreased', 'NegReg', (42, 51))	('BACE2', 'Gene', (23, 28))	('MES GSCs', 'Chemical', '-', (72, 80))	('knockdown', 'Var', (10, 19))
40300	33413577	Bioluminescence imaging 7 days after GSC implantation as well as the survival data demonstrated that BACE2 knockdown inhibited tumor growth compared with that in the shNT group, and radiotherapy was administered at this time.	('knockdown', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BACE2', 'Gene', (101, 106))	('tumor', 'Disease', (127, 132))	('inhibited', 'NegReg', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
40308	33413577	First, we measured BACE2 mRNA expression via qRT-PCR after csGRP78 blockade or lentiviral GRP78 knockdown.	('blockade', 'Var', (67, 75))	('GRP78', 'Gene', '14828', (61, 66))	('GRP78', 'Gene', (90, 95))	('BACE2', 'Gene', (19, 24))	('GRP78', 'Gene', (61, 66))	('measured', 'Reg', (10, 18))	('qRT-PCR', 'MPA', (45, 52))	('GRP78', 'Gene', '14828', (90, 95))
40313	33413577	Moreover, blocking csGRP78 for 48 h markedly downregulated BACE2 protein expression, which could be rescued by chloroquine but not MG-132 (Figure S6B, C; Fig.	('GRP78', 'Gene', (21, 26))	('MG-132', 'Chemical', 'MESH:C072553', (131, 137))	('blocking', 'Var', (10, 18))	('expression', 'MPA', (73, 83))	('downregulated', 'NegReg', (45, 58))	('GRP78', 'Gene', '14828', (21, 26))	('BACE2', 'Gene', (59, 64))	('chloroquine', 'Chemical', 'MESH:D002738', (111, 122))
40315	33413577	Consistent with the results presented above, blocking csGRP78 increased the distribution of BACE2 in lysosomes, manifested as a larger overlapping region and greater coherence of the two channels in the image analysis plots.	('greater', 'PosReg', (158, 165))	('increased', 'PosReg', (62, 71))	('BACE2', 'Protein', (92, 97))	('GRP78', 'Gene', (56, 61))	('larger', 'PosReg', (128, 134))	('coherence', 'MPA', (166, 175))	('blocking', 'Var', (45, 53))	('overlapping region', 'MPA', (135, 153))	('distribution', 'MPA', (76, 88))	('GRP78', 'Gene', '14828', (56, 61))
40316	33413577	Collectively, these results indicate that blocking csGRP78 in MES-subtype GSCs can disrupt the stabilization of BACE2, leading to its lysosomal degradation.	('GRP78', 'Gene', '14828', (53, 58))	('lysosomal degradation', 'MPA', (134, 155))	('stabilization', 'MPA', (95, 108))	('disrupt', 'NegReg', (83, 90))	('blocking', 'Var', (42, 50))	('GRP78', 'Gene', (53, 58))	('BACE2', 'Gene', (112, 117))	('MES', 'Chemical', '-', (62, 65))	('GSCs', 'Chemical', '-', (74, 78))
40320	33413577	For the optimal dose to reinforce the MES phenotype, transfection with 1 mug of FLAG-GRP78 showed the most significant increase in CD44, p-p65 and C/EBPbeta, as well as BACE2 protein expression (Fig.	('p65', 'Gene', (139, 142))	('CD44', 'Gene', (131, 135))	('transfection', 'Var', (53, 65))	('p65', 'Gene', '19697', (139, 142))	('MES', 'Chemical', '-', (38, 41))	('CD44', 'Gene', '12505', (131, 135))	('BACE2 protein', 'Protein', (169, 182))	('GRP78', 'Gene', '14828', (85, 90))	('C/EBPbeta', 'Gene', (147, 156))	('increase', 'PosReg', (119, 127))	('C/EBPbeta', 'Gene', '12606', (147, 156))	('GRP78', 'Gene', (85, 90))
40333	33413577	Further study indicated that targeting csGRP78 might be a promising adjuvant strategy to prohibit the malignant progression and recurrence of GBM.	('GBM', 'Disease', (142, 145))	('GRP78', 'Gene', (41, 46))	('malignant progression', 'CPA', (102, 123))	('GRP78', 'Gene', '14828', (41, 46))	('targeting', 'Var', (29, 38))	('recurrence', 'CPA', (128, 138))	('prohibit', 'NegReg', (89, 97))
40337	33413577	In our study, we verified a positive correlation between GRP78 and the MES phenotype by using TCGA data and silencing GRP78 in MES-subtype GSCs (Fig.	('silencing', 'Var', (108, 117))	('GRP78', 'Gene', '14828', (118, 123))	('GRP78', 'Gene', '14828', (57, 62))	('MES-subtype', 'Disease', (127, 138))	('GRP78', 'Gene', (118, 123))	('MES', 'Disease', (71, 74))	('MES', 'Chemical', '-', (71, 74))	('GRP78', 'Gene', (57, 62))	('GSCs', 'Chemical', '-', (139, 143))	('MES', 'Chemical', '-', (127, 130))
40339	33413577	Accumulating studies have shown that csGRP78 participates in the control of tumor biological behaviors and signaling and that blocking csGRP78 on C-terminus or N-terminus epitopes leads to cancer cell death and increased radiosensitivity in pancreatic cancer.	('GRP78', 'Gene', '14828', (39, 44))	('death', 'Disease', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Disease', (76, 81))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (241, 258))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('blocking', 'Var', (126, 134))	('radiosensitivity', 'CPA', (221, 237))	('increased', 'PosReg', (211, 220))	('death', 'Disease', 'MESH:D003643', (201, 206))	('cancer', 'Disease', (252, 258))	('pancreatic cancer', 'Disease', 'MESH:D010190', (241, 258))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('leads to', 'Reg', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('GRP78', 'Gene', (137, 142))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (211, 237))	('cancer', 'Disease', (189, 195))	('pancreatic cancer', 'Disease', (241, 258))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('GRP78', 'Gene', (39, 44))	('GRP78', 'Gene', '14828', (137, 142))
40345	33413577	Therefore, targeting csGRP78 in patients with glioblastoma could be a novel specific therapeutic strategy aimed at MES GSC-derived resistance to therapy.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('patients', 'Species', '9606', (32, 40))	('GRP78', 'Gene', '14828', (23, 28))	('GRP78', 'Gene', (23, 28))	('MES', 'Chemical', '-', (115, 118))	('targeting', 'Var', (11, 20))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))
40353	33413577	Targeting csGRP78 in MES GSCs successfully downregulated MES phenotypic signatures and pathways, leading to the suppression of self-renewal and radioresistance of tumor cells without hampering NPC stemness.	('NPC stemness', 'Disease', 'MESH:D000077274', (193, 205))	('downregulated', 'NegReg', (43, 56))	('MES GSCs', 'Chemical', '-', (21, 29))	('GRP78', 'Gene', '14828', (12, 17))	('self-renewal', 'CPA', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('MES', 'Chemical', '-', (21, 24))	('GRP78', 'Gene', (12, 17))	('tumor', 'Disease', (163, 168))	('Targeting', 'Var', (0, 9))	('NPC stemness', 'Disease', (193, 205))	('suppression', 'NegReg', (112, 123))	('MES', 'Chemical', '-', (57, 60))
40354	33413577	Therefore, targeting csGRP78 in MES GSCs might be a promising approach to overcome the recurrence and therapeutic resistance of GBMs.	('GRP78', 'Gene', (23, 28))	('GRP78', 'Gene', '14828', (23, 28))	('MES GSCs', 'Chemical', '-', (32, 40))	('targeting', 'Var', (11, 20))
40390	29901110	miR-141 inhibits glioma vasculogenic mimicry by controlling EphA2 expression Human glioma is a pernicious tumor from the central nervous system; it has been reported that microRNAs (miRs) may have carcinogenic or tumor suppressor effects on human glioma.	('human', 'Species', '9606', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('glioma vasculogenic', 'Disease', 'MESH:D005910', (17, 36))	('tumor', 'Disease', (106, 111))	('glioma', 'Disease', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('EphA2', 'Gene', (60, 65))	('glioma', 'Disease', (17, 23))	('glioma', 'Disease', (247, 253))	('miR-141', 'Gene', '406933', (0, 7))	('EphA2', 'Gene', '1969', (60, 65))	('Human', 'Species', '9606', (77, 82))	('glioma', 'Disease', 'MESH:D005910', (247, 253))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miR-141', 'Gene', (0, 7))	('glioma vasculogenic', 'Disease', (17, 36))	('carcinogenic', 'Disease', (197, 209))	('tumor', 'Disease', (213, 218))	('glioma', 'Phenotype', 'HP:0009733', (247, 253))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('inhibits', 'NegReg', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('microRNAs', 'Var', (171, 180))	('tumor from the central nervous system', 'Phenotype', 'HP:0100006', (106, 143))	('carcinogenic', 'Disease', 'MESH:D063646', (197, 209))
40396	29901110	Furthermore, exogenous miR-141 expression resulted in decreased proliferation, migration and invasion, as well as in apoptosis and cell cycle arrest in vitro.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (131, 148))	('rat', 'Species', '10116', (71, 74))	('miR-141', 'Gene', (23, 30))	('cell cycle arrest', 'CPA', (131, 148))	('proliferation', 'CPA', (64, 77))	('rat', 'Species', '10116', (82, 85))	('decreased', 'NegReg', (54, 63))	('apoptosis', 'CPA', (117, 126))	('invasion', 'CPA', (93, 101))	('exogenous', 'Var', (13, 22))
40407	29901110	As a novel blood supply's form, the inhibition of VM could serve as an alternative therapeutic target for gliomas.	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('inhibition', 'Var', (36, 46))	('gliomas', 'Disease', 'MESH:D005910', (106, 113))	('gliomas', 'Phenotype', 'HP:0009733', (106, 113))	('gliomas', 'Disease', (106, 113))
40408	29901110	Anomalous miRNA expression has been found to have some effects on the developing process of a wide range of tumors and, as such, miRNAs may be used for their diagnosis, prognosis and treatment.	('Anomalous', 'Var', (0, 9))	('effects', 'Reg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('miRNA', 'Protein', (10, 15))	('developing process of', 'CPA', (70, 91))
40409	29901110	Various miR-200 family members, i.e., miR-141, 200c, 200b, 200a and 429, have been reported to play important roles in a variety of cancers, including proliferation, invasion and apoptosis.	('invasion', 'CPA', (166, 174))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('proliferation', 'CPA', (151, 164))	('apoptosis', 'CPA', (179, 188))	('play', 'Reg', (95, 99))	('miR-141', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('miR-200', 'Gene', (8, 15))	('rat', 'Species', '10116', (158, 161))	('roles', 'Reg', (110, 115))
40460	29901110	Briefly, 50 microl ECM matrigel (Sigma-Aldrich; Merck KGaA) was added and dropped onto 18 mm glass coverslips in 6-well plates and incubated for 1 h at 37 C. Next, A172 and U251 cells transfected with miR-141 mimic and miR-NC were seeded onto the coverslips coated.	('ECM', 'Gene', (19, 22))	('miR-141', 'Var', (201, 208))	('ECM', 'Gene', '22915', (19, 22))	('U251', 'CellLine', 'CVCL:0021', (173, 177))
40477	29901110	By doing so, we found that the invasive capacities were markedly reduced in the A172 and U251 cells with miR-141 mimic transfected, i.e., by 42.1 and 55.2%, respectively (P<0.05; Fig.	('reduced', 'NegReg', (65, 72))	('U251', 'CellLine', 'CVCL:0021', (89, 93))	('invasive capacities', 'CPA', (31, 50))	('miR-141', 'Gene', (105, 112))	('transfected', 'Var', (119, 130))
40479	29901110	Next, we set out to assess the effect of miR-141 on the regulation of apoptosis and cell cycle progression using A172 and U251 cells which were transfected with either the miR-141 mimic or the control miR-NC mimic.	('mimic', 'Var', (180, 185))	('miR-141', 'Gene', (172, 179))	('U251', 'CellLine', 'CVCL:0021', (122, 126))
40480	29901110	By doing so, we found that the apoptotic rates increased in the cells with miR-141 transfected (19.1% in A172 cells and 17.8% in U251 cells; Fig.	('transfected', 'Var', (83, 94))	('miR-141', 'Gene', (75, 82))	('apoptotic rates', 'CPA', (31, 46))	('increased', 'PosReg', (47, 56))	('U251', 'CellLine', 'CVCL:0021', (129, 133))	('rat', 'Species', '10116', (41, 44))
40481	29901110	Subsequent cell cycle analyses revealed that miR-141 mimic transfected cells were arrested at G2/M phase, i.e., the percentages of G2/M phase cells were found to be 23.48 and 26.61% for the miR-141 transfected A172 and U251 cells, respectively, while the percentages were 1.34 and 7.87%, respectively, in the miR-NC group (P<0.05; Fig.	('G2/M phase cells', 'CPA', (131, 147))	('U251', 'CellLine', 'CVCL:0021', (219, 223))	('miR-141', 'Var', (190, 197))
40487	29901110	We found that the tumor weights in the miR-141 mimic group were significantly much lower than those in the miR-NC group (P<0.05; Fig.	('tumor', 'Disease', (18, 23))	('lower', 'NegReg', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('miR-141 mimic', 'Var', (39, 52))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
40496	29901110	In vivo, the tumor tissue, which stably transfected with miR-141, formed classical VM vessels, compared with miR-NC group (Fig.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('miR-141', 'Var', (57, 64))
40503	29901110	Accumulating evidence indicates that miRNAs may have key effect on both initiation and progression of tumor.	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('miRNAs', 'Var', (37, 43))
40506	29901110	Numerous of reports have shown that miRNAs could regulate tumor progression through various signaling or target proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('miRNAs', 'Var', (36, 42))	('regulate', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
40508	29901110	In glioma, Peng et al found that miR-141 was a tumor inhibitor by targeting TGF-beta2.	('miR-141', 'Var', (33, 40))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('TGF-beta2', 'Gene', (76, 85))	('TGF-beta2', 'Gene', '7042', (76, 85))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('glioma', 'Disease', (3, 9))	('targeting', 'Reg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
40514	29901110	Therefore, we conclude that miR-141 is involved in regulating glioma tumor progression, and may act as an anti-oncogenic factor.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glioma tumor', 'Disease', 'MESH:D005910', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('miR-141', 'Var', (28, 35))	('glioma tumor', 'Disease', (62, 74))
40546	29865195	These seminal studies introduced the notion that lack of GJ coupling could be a fundamental process in cancer leading to the formation of solid tumours by uncontrolled cell growth.	('solid tumours', 'Disease', (138, 151))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('GJ coupling', 'Protein', (57, 68))	('lack', 'Var', (49, 53))	('solid tumours', 'Disease', 'MESH:D009369', (138, 151))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
40553	29865195	This example was relevant to rodent and human situations for which liver tumours were correlated with lack of GJIC either by loss of expression or aberrant cytoplasmic localization of Cx32, respectively.	('expression', 'MPA', (133, 143))	('aberrant', 'Var', (147, 155))	('liver tumours', 'Disease', 'MESH:D008113', (67, 80))	('Cx32', 'Gene', (184, 188))	('loss of', 'NegReg', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('liver tumours', 'Disease', (67, 80))	('human', 'Species', '9606', (40, 45))
40563	29865195	Most data attempting to elucidate how Cxs control cell growth came from Cx cDNA transfection in cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('transfection', 'Var', (80, 92))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
40569	29865195	For instance, Cx43 re-expression but not Cx32, in C6 glioma cells is related to a decreased amount of milk fat globule-EGF factor 8 (MFG-E8) mRNA through an unknown mechanism (Figure 2).	('mRNA', 'MPA', (141, 145))	('MFG-E8', 'Gene', (133, 139))	('milk fat globule-EGF factor 8', 'Gene', (102, 131))	('milk fat globule-EGF factor 8', 'Gene', '4240', (102, 131))	('Cx43', 'Var', (14, 18))	('amount', 'MPA', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('C6 glioma', 'Disease', 'MESH:C567307', (50, 59))	('MFG-E8', 'Gene', '4240', (133, 139))	('C6 glioma', 'Disease', (50, 59))	('decreased', 'NegReg', (82, 91))
40576	29865195	Another example finally could explain the specific tumour suppressor effect of Cx26 on HeLa cells that was described two decades ago.	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('Cx26', 'Var', (79, 83))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('HeLa', 'CellLine', 'CVCL:0030', (87, 91))	('tumour', 'Disease', (51, 57))
40579	29865195	As an example, the transmission of anti-proliferative effects from miR-124-3p-transfected to non-transfected glioma cells was mediated by GJIC.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('miR-124-3p', 'Chemical', '-', (67, 77))	('miR-124-3p-transfected', 'Var', (67, 89))	('rat', 'Species', '10116', (47, 50))	('glioma', 'Disease', (109, 115))	('anti-proliferative effects', 'MPA', (35, 61))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
40583	29865195	Such a behaviour has been described for Cx32 with Discs large homolog 1 (hDlg1) in hepatocytes and for Cx43 with CCN3 in rat C6 glioma cells.	('hDlg1', 'Gene', (73, 78))	('Discs large homolog 1', 'Gene', '25252', (50, 71))	('rat C6', 'CellLine', 'CVCL:0492', (121, 127))	('Cx32', 'MPA', (40, 44))	('Discs large homolog 1', 'Gene', (50, 71))	('CCN3', 'Gene', (113, 117))	('C6 glioma', 'Disease', 'MESH:C567307', (125, 134))	('CCN3', 'Gene', '4856', (113, 117))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('C6 glioma', 'Disease', (125, 134))	('Cx43', 'Var', (103, 107))	('hDlg1', 'Gene', '1739', (73, 78))
40588	29865195	Even if it has not been described yet, it would explain the down regulation of growth which was observed in human glioblastoma cells after transfection of Cx43 which was mainly localized in the cytoplasm.	('human', 'Species', '9606', (108, 113))	('glioblastoma', 'Disease', (114, 126))	('down regulation', 'NegReg', (60, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('Cx43', 'Var', (155, 159))	('growth', 'MPA', (79, 85))	('transfection', 'Var', (139, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
40589	29865195	The anti-proliferative effect associated with a nuclear signal of Cx43 is more intriguing.	('Cx43', 'Gene', (66, 70))	('anti-proliferative effect', 'CPA', (4, 29))	('rat', 'Species', '10116', (16, 19))	('nuclear signal', 'Var', (48, 62))
40590	29865195	This effect could be due to the Cx43 CT domain since the transfection of that part only was followed by decreased growth in several cell types (HeLa, Neuro2a and HEK293 cells).	('transfection', 'Var', (57, 69))	('decreased', 'NegReg', (104, 113))	('HeLa', 'CellLine', 'CVCL:0030', (144, 148))	('HEK293', 'CellLine', 'CVCL:0045', (162, 168))	('decreased growth', 'Phenotype', 'HP:0001510', (104, 120))	('growth', 'MPA', (114, 120))
40593	29865195	Study of those Hcs has been growing this last decade, especially for Cx43 but their link with cell proliferation is still not obvious even if adenosine triphosphate (ATP) release and modulation of Ca2+ concentrations were correlated with decreased cell proliferation in several cell types.	('cell proliferation in several cell types', 'CPA', (248, 288))	('Hcs', 'Chemical', '-', (15, 18))	('rat', 'Species', '10116', (260, 263))	('modulation', 'Var', (183, 193))	('rat', 'Species', '10116', (209, 212))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (142, 164))	('decreased', 'NegReg', (238, 247))	('ATP', 'Chemical', 'MESH:D000255', (166, 169))	('rat', 'Species', '10116', (106, 109))	('Ca2+', 'Chemical', 'MESH:D000069285', (197, 201))
40594	29865195	In osteocytes, they have been found to be involved in suppression of breast cancer cell growth and bone metastasis using transgenic mouse models expressing dominant-negative mutants inhibiting either GJIC and/or Hcs.	('bone metastasis', 'CPA', (99, 114))	('inhibiting', 'NegReg', (182, 192))	('suppression of breast cancer', 'Disease', 'MESH:D001943', (54, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('mouse', 'Species', '10090', (132, 137))	('Hcs', 'Gene', (212, 215))	('suppression of breast cancer', 'Disease', (54, 82))	('mutants', 'Var', (174, 181))	('Hcs', 'Chemical', '-', (212, 215))	('transgenic', 'Species', '10090', (121, 131))
40599	29865195	At the transcriptional level, similar to other genes which are shut down during tumour progression, Cx genes could be the target of epigenetic control.	('tumour', 'Disease', (80, 86))	('epigenetic', 'Var', (132, 142))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('Cx genes', 'Gene', (100, 108))
40602	29865195	Loss of Cx32 function through hypermethylation is necessary for the development of renal cell carcinoma at the early carcinogenic process.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('renal cell carcinoma', 'Disease', (83, 103))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (83, 103))	('carcinogenic process', 'Disease', (117, 137))	('Loss', 'NegReg', (0, 4))	('carcinogenic process', 'Disease', 'MESH:D009385', (117, 137))	('Cx32', 'Protein', (8, 12))	('hypermethylation', 'Var', (30, 46))
40603	29865195	The CpG island hypermethylation level was associated with heavy smoking, poorly-differentiated tumour and low expression of Cx43 in non-small cell lung cancer.	('expression of Cx43', 'MPA', (110, 128))	('hypermethylation level', 'Var', (15, 37))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('associated', 'Reg', (42, 52))	('non-small cell lung cancer', 'Disease', (132, 158))	('heavy smoking', 'Disease', (58, 71))	('tumour', 'Disease', (95, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('low', 'NegReg', (106, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
40604	29865195	More recently, hypermethylation of the Cx45 gene has been linked to its reduced expression in colon cancer.	('reduced', 'NegReg', (72, 79))	('colon cancer', 'Disease', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Cx45', 'Gene', (39, 43))	('hypermethylation', 'Var', (15, 31))	('expression', 'MPA', (80, 90))	('Cx45', 'Gene', '10052', (39, 43))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
40608	29865195	For instance, mi-R-221/222 complex and miR-125b have been shown to downregulate Cx43 expression in glioma or miR-20a in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('mi-R-221/222 complex', 'Var', (14, 34))	('miR-125b', 'Var', (39, 47))	('Cx43 expression', 'MPA', (80, 95))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('miR-20a', 'Gene', '406982', (109, 116))	('downregulate', 'NegReg', (67, 79))	('glioma', 'Disease', (99, 105))	('prostate cancer', 'Disease', (120, 135))	('miR-20a', 'Gene', (109, 116))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))
40610	29865195	), such mutations have been rarely reported in the cancer context.	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
40611	29865195	The most convincing result revealed a mutation affecting the Cx43 CT domain in human colon adenocarcinomas, which resulted in a restricted expression in invasive parts of the tumours.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('colon adenocarcinomas', 'Disease', (85, 106))	('restricted', 'NegReg', (128, 138))	('human', 'Species', '9606', (79, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (85, 106))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumours', 'Disease', 'MESH:D009369', (175, 182))	('Cx43', 'Gene', (61, 65))	('mutation', 'Var', (38, 46))	('expression', 'MPA', (139, 149))	('tumours', 'Disease', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
40613	29865195	So far, none of these diseases are known to be associated with a particular cancer susceptibility except for Cx26 mutations in the case of keratitis ichthyosis deafness (KID) syndrome which are associated with squamous cell carcinomas in 15% of patients.	('keratitis ichthyosis deafness (KID) syndrome', 'Disease', 'MESH:C536168', (139, 183))	('patients', 'Species', '9606', (245, 253))	('mutations', 'Var', (114, 123))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (210, 234))	('keratitis', 'Phenotype', 'HP:0000491', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('squamous cell carcinomas', 'Disease', (210, 234))	('associated', 'Reg', (194, 204))	('ichthyosis', 'Phenotype', 'HP:0008064', (149, 159))	('deafness', 'Phenotype', 'HP:0000365', (160, 168))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (210, 234))	('Cx26', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
40621	29865195	In those cells, Panx1 expression had a wide range of anti-tumour activity by reducing in vitro cell proliferation, cell motility, anchorage-independent growth and tumour growth in nude mice.	('nude mice', 'Species', '10090', (180, 189))	('anchorage-independent growth', 'CPA', (130, 158))	('reducing', 'NegReg', (77, 85))	('expression', 'Var', (22, 32))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour growth', 'Disease', (163, 176))	('tumour', 'Disease', (58, 64))	('cell motility', 'CPA', (115, 128))	('Panx1', 'Gene', (16, 21))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour growth', 'Disease', 'MESH:D006130', (163, 176))	('tumour', 'Disease', (163, 169))	('rat', 'Species', '10116', (107, 110))
40637	29865195	For example, transfection of poorly coupled mouse epidermal cells with an E-cadherin expression construct increased GJIC.	('increased', 'PosReg', (106, 115))	('GJIC', 'MPA', (116, 120))	('mouse', 'Species', '10090', (44, 49))	('transfection', 'Var', (13, 25))
40639	29865195	High levels of Cx43 and Snail-1 resulted in increased tumour cell invasion and Cx43 was downregulated upon Snail-1 silencing and vice versa.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('silencing', 'Var', (115, 124))	('Snail-1', 'Gene', (24, 31))	('tumour', 'Disease', (54, 60))	('Snail-1', 'Gene', '6615', (24, 31))	('Snail-1', 'Gene', (107, 114))	('Snail-1', 'Gene', '6615', (107, 114))	('increased', 'PosReg', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('downregulated', 'NegReg', (88, 101))
40645	29865195	Conversely, knocking down Cx43 abrogated p38 MAPK activation and radiation-induced C6 cell migration.	('activation', 'MPA', (50, 60))	('MAPK', 'Gene', '5595;5594;26413;5595', (45, 49))	('rat', 'Species', '10116', (94, 97))	('radiation-induced C6 cell migration', 'CPA', (65, 100))	('abrogated', 'NegReg', (31, 40))	('MAPK', 'Gene', (45, 49))	('p38', 'Gene', '5594', (41, 44))	('C6', 'CellLine', 'CVCL:X905', (83, 85))	('Cx43', 'Gene', (26, 30))	('knocking down', 'Var', (12, 25))	('p38', 'Gene', (41, 44))
40646	29865195	Although GJIC was decreased upon Cx43 small interfering RNA (siRNA) depletion in the high Cx43 expressing C6 cells, GJ inhibitors did not alter motility indicating that Cx43 itself was responsible for the pro-metastatic effects.	('decreased', 'NegReg', (18, 27))	('GJIC', 'MPA', (9, 13))	('C6', 'CellLine', 'CVCL:X905', (106, 108))	('depletion', 'Var', (68, 77))
40648	29865195	Another study found that blocking GJIC in GL15 glioblastoma cells increased motility in an in vitro 3D culture model.	('increased', 'PosReg', (66, 75))	('glioblastoma', 'Disease', (47, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('blocking', 'Var', (25, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('GJIC', 'Gene', (34, 38))	('motility in an in vitro 3D culture model', 'CPA', (76, 116))
40653	29865195	Breast cancer cells that formed functional Cx43 GJs with endothelial cells facilitated migration out of the endothelial layer in in vitro culture implicating Cx43 in the extravasation phase of metastasis.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Cx43', 'Var', (43, 47))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('migration out of the', 'CPA', (87, 107))	('facilitated', 'PosReg', (75, 86))	('Breast cancer', 'Disease', (0, 13))	('rat', 'Species', '10116', (90, 93))
40654	29865195	In zebrafish and chick embryo models, breast cancer and melanoma cell metastasis was dependent upon Cx43 and Cx26 to initiate brain metastatic lesions in association with the vasculature.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('zebrafish', 'Species', '7955', (3, 12))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('melanoma cell metastasis', 'Disease', 'MESH:D009362', (56, 80))	('brain metastatic lesions', 'CPA', (126, 150))	('melanoma cell metastasis', 'Disease', (56, 80))	('chick', 'Species', '9031', (17, 22))	('Cx26', 'Var', (109, 113))
40662	29865195	In another study, GJIC was restored in the same metastatic breast cancer cell line upon ectopic expression of the breast cancer metastasis suppressor gene BRMS1.	('ectopic expression', 'Var', (88, 106))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (114, 138))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer metastasis', 'Disease', (114, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('BRMS1', 'Gene', (155, 160))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))
40664	29865195	An in vivo murine study revealed that metastatic breast cancer cells in the bone formed more active GJs with osteoblasts than with themselves and BRMS1 expression increased homotypic GJIC.	('expression', 'Var', (152, 162))	('increased', 'PosReg', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('homotypic GJIC', 'CPA', (173, 187))	('BRMS1', 'Gene', (146, 151))	('osteoblasts', 'CPA', (109, 120))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('murine', 'Species', '10090', (11, 17))
40665	29865195	The breast cancer cells with increased heterotypic, relative to homotypic, GJ channels with osteoblasts were more metastatic than those that did not.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('metastatic', 'CPA', (114, 124))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('increased', 'PosReg', (29, 38))	('heterotypic', 'Var', (39, 50))
40666	29865195	This suggests that the relative percentage of homo- and heterotypic GJ channels in tumour cells can influence metastasis.	('tumour', 'Disease', (83, 89))	('metastasis', 'CPA', (110, 120))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('heterotypic', 'Var', (56, 67))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('homo-', 'Var', (46, 51))	('GJ channels', 'Protein', (68, 79))	('influence', 'Reg', (100, 109))
40667	29865195	Moreover, it suggests that heterotypic GJs could be an important survival mechanism of tumour cells in the metastatic tumour microenvironment.	('tumour', 'Disease', (87, 93))	('tumour', 'Disease', (118, 124))	('heterotypic', 'Var', (27, 38))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (118, 124))
40673	29865195	Analysis of a dominant negative Cx43 mutant that blocks GJs but not Hcs, revealed that Cx43 Hcs protected against tumour progression and metastasis.	('tumour', 'Disease', (114, 120))	('Cx43', 'Gene', (32, 36))	('Hcs', 'Chemical', '-', (68, 71))	('Cx43', 'Var', (87, 91))	('mutant', 'Var', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('Hcs', 'Chemical', '-', (92, 95))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('negative', 'NegReg', (23, 31))
40675	29865195	It is clear that the tumour microenvironment drives cancer metastasis and Cx43 seems to stimulate growth of brain metastases after extravasation and tumour vasculature remodelling.	('tumour vasculature remodelling', 'Disease', 'MESH:C565633', (149, 179))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('stimulate', 'PosReg', (88, 97))	('brain metastases', 'Disease', 'MESH:D009362', (108, 124))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour vasculature remodelling', 'Disease', (149, 179))	('growth', 'MPA', (98, 104))	('brain metastases', 'Disease', (108, 124))	('cancer metastasis', 'Disease', (52, 69))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('cancer metastasis', 'Disease', 'MESH:D009362', (52, 69))	('growth of brain', 'Phenotype', 'HP:0001355', (98, 113))	('tumour', 'Disease', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))	('Cx43', 'Var', (74, 78))
40679	29865195	In agreement with the hypothesis that Cxs control the microenvironment, Cx43-transfected glioma cells, which formed GJs with astrocytes in the striata of rats, were able to disseminate throughout the brain parenchyma.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('rats', 'Species', '10116', (154, 158))	('glioma', 'Disease', (89, 95))	('Cx43-transfected', 'Var', (72, 88))
40686	29865195	GJ transmission of miRNAs between immune cells in the microenvironment and tumour cells is also expected to be a major regulator of metastasis because of the key role of many miRNAs in tumour suppression, while others can promote tumour progression.	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour suppression', 'Disease', (185, 203))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('promote', 'PosReg', (222, 229))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('miRNAs', 'Var', (175, 181))	('tumour suppression', 'Disease', 'OMIM:146850', (185, 203))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('tumour', 'Disease', (230, 236))	('tumour', 'Disease', (185, 191))
40690	29865195	PANX1 knock down reverted BL6 cells to a more normal melanocyte phenotype and these cells had reduced levels of vimentin and beta-catenin, both markers of melanoma progression.	('knock down', 'Var', (6, 16))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('levels', 'MPA', (102, 108))	('vimentin', 'MPA', (112, 120))	('reduced', 'NegReg', (94, 101))	('PANX1', 'Gene', (0, 5))	('beta-catenin', 'MPA', (125, 137))	('BL6', 'CellLine', 'CVCL:M564', (26, 29))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))
40692	29865195	A recent RNASeq analysis of breast cancer cells with different metastatic capacities revealed that cell lines with high metastatic potential had significantly enriched mutant mRNA encoding a N-terminal truncated PANX1 channel.	('mutant', 'Var', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('mRNA', 'Gene', (175, 179))
40693	29865195	Truncated PANX-1, in association with wild type PANX1, seemed to confer a gain-of-function to channel activity and was found to promote metastatic cell survival.	('metastatic cell survival', 'CPA', (136, 160))	('gain-of-function', 'PosReg', (74, 90))	('PANX-1', 'Gene', '24145', (10, 16))	('channel activity', 'MPA', (94, 110))	('promote', 'PosReg', (128, 135))	('PANX-1', 'Gene', (10, 16))	('Truncated', 'Var', (0, 9))
40716	29865195	This effect occurs at high cell density where GJIC forms and decreased GJIC by inhibitors or knocking down Cx43 by siRNA attenuates cell protective role of simvastatin.	('cell protective role', 'CPA', (132, 152))	('Cx43', 'MPA', (107, 111))	('attenuates', 'NegReg', (121, 131))	('knocking', 'Var', (93, 101))	('GJIC', 'MPA', (71, 75))	('decreased', 'NegReg', (61, 70))	('simvastatin', 'Chemical', 'MESH:D019821', (156, 167))
40719	29865195	CO donors inhibit Hc uptake in tumour cell lines (MCF-7 and HeLa cells) expressing exogenous Cx43 or Cx46.	('Cx46', 'Gene', '2700', (101, 105))	('Hc uptake', 'MPA', (18, 27))	('HeLa', 'CellLine', 'CVCL:0030', (60, 64))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('CO', 'Chemical', 'MESH:D002248', (0, 2))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('Cx46', 'Gene', (101, 105))	('Hc', 'Chemical', '-', (18, 20))	('Cx43', 'Var', (93, 97))	('inhibit', 'NegReg', (10, 17))	('tumour', 'Disease', (31, 37))	('MCF-7', 'CellLine', 'CVCL:0031', (50, 55))
40726	29865195	The Cx43 enhanced apoptotic effect of sunitinib was via enhancement of activation of Bax localized at the mitochondrial membrane and the phosphorylation of c-Jun N-terminal kinase (JNK).	('JNK', 'Gene', '5599', (181, 184))	('sunitinib', 'Chemical', 'MESH:D000077210', (38, 47))	('activation', 'PosReg', (71, 81))	('phosphorylation', 'MPA', (137, 152))	('apoptotic effect', 'CPA', (18, 34))	('enhancement', 'PosReg', (56, 67))	('Cx43', 'Var', (4, 8))	('Bax', 'Gene', (85, 88))	('c-Jun N-terminal kinase', 'Gene', '5599', (156, 179))	('c-Jun N-terminal kinase', 'Gene', (156, 179))	('JNK', 'Gene', (181, 184))	('Bax', 'Gene', '581', (85, 88))
40751	29865195	Reduced levels of Cx37 are associated with higher apoptotic index of tumour cells in vivo.	('tumour', 'Disease', (69, 75))	('higher', 'PosReg', (43, 49))	('Reduced', 'NegReg', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('Cx37', 'Var', (18, 22))	('tumour', 'Disease', 'MESH:D009369', (69, 75))
40754	29865195	During cancer differentiation, Cx46 is reduced associated with an increase of Cx43 and knocking down Cx46 by short hairpin RNA (shRNA) reduces stem cell maintenance.	('increase', 'PosReg', (66, 74))	('Cx46', 'Gene', '2700', (31, 35))	('Cx46', 'Gene', '2700', (101, 105))	('stem cell maintenance', 'CPA', (143, 164))	('knocking down', 'Var', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Cx46', 'Gene', (31, 35))	('Cx46', 'Gene', (101, 105))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('reduces', 'NegReg', (135, 142))	('Cx43', 'MPA', (78, 82))
40757	29865195	Overexpression of Cx43 reverses EMT and cisplatin resistance while Cx43 deletion initiates EMT and drug resistance in human lung cancer cell line A549.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('drug resistance', 'Phenotype', 'HP:0020174', (99, 114))	('EMT', 'MPA', (32, 35))	('drug resistance', 'MPA', (99, 114))	('lung cancer', 'Disease', (124, 135))	('human', 'Species', '9606', (118, 123))	('Cx43', 'Gene', (67, 71))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('reverses', 'NegReg', (23, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('cisplatin resistance', 'MPA', (40, 60))	('deletion', 'Var', (72, 80))
40763	29865195	Given that Cx43 Hcs are involved in vascular leakage and endothelial cell death, modulation of these channels may provide an alternative for cancer treatment.	('Hcs', 'Chemical', '-', (16, 19))	('modulation', 'Var', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('involved', 'Reg', (24, 32))	('Cx43', 'Var', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
40771	29865195	A follow up study by the same group shows that activation of Panx1 channels by ATP is determined by expression level of particular ectonnucleotidases in tumour cell variants in Jurkat cell lines with and without the Fas-associated death domain (FADD) or receptor-interacting protein kinase 1 (RIP1) cell death regulatory proteins.	('Panx1', 'Gene', (61, 66))	('tumour', 'Disease', (153, 159))	('RIP1', 'Gene', (293, 297))	('variants', 'Var', (165, 173))	('receptor-interacting protein kinase 1', 'Gene', (254, 291))	('activation', 'PosReg', (47, 57))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('RIP1', 'Gene', '8737', (293, 297))	('receptor-interacting protein kinase 1', 'Gene', '8737', (254, 291))	('Jurkat', 'CellLine', 'CVCL:0065', (177, 183))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumour', 'Disease', 'MESH:D009369', (153, 159))
40774	29865195	In support of the role of ATP and Panx1 channels in mediating immune response, a very recent study shows that ATP increases migration of dendritic cells through the activation of Panx1 channel and P2X7 receptor (P2X7R).	('activation', 'PosReg', (165, 175))	('ATP', 'Chemical', 'MESH:D000255', (26, 29))	('P2X7 receptor', 'Gene', '5027', (197, 210))	('ATP', 'Var', (110, 113))	('P2X7R', 'Gene', '5027', (212, 217))	('P2X7 receptor', 'Gene', (197, 210))	('increases', 'PosReg', (114, 123))	('migration of dendritic cells', 'CPA', (124, 152))	('rat', 'Species', '10116', (127, 130))	('ATP', 'Chemical', 'MESH:D000255', (110, 113))	('P2X7R', 'Gene', (212, 217))	('Panx1', 'Protein', (179, 184))
40784	29865195	In contrast to general belief of Panx channels in promoting cancer cell death, this paper suggests that ATP release by Panx1 suppresses deformation-induced apoptosis through P2Y receptor signalling and inhibition of Panx1 channels could reduce the efficiency of breast cancer metastasis.	('P2Y receptor signalling', 'MPA', (174, 197))	('efficiency of breast cancer metastasis', 'Disease', 'MESH:D009362', (248, 286))	('deformation-induced apoptosis', 'CPA', (136, 165))	('Panx1', 'Gene', (119, 124))	('efficiency of breast cancer metastasis', 'Disease', (248, 286))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('cancer', 'Disease', (60, 66))	('inhibition', 'Var', (202, 212))	('ATP release', 'MPA', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('reduce', 'NegReg', (237, 243))	('ATP', 'Chemical', 'MESH:D000255', (104, 107))	('suppresses', 'NegReg', (125, 135))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
40785	29865195	This could be partially explained by excess release of ATP by mutated Panx1 channels.	('ATP', 'Chemical', 'MESH:D000255', (55, 58))	('release of ATP', 'MPA', (44, 58))	('Panx1', 'Gene', (70, 75))	('mutated', 'Var', (62, 69))
40792	29865195	Consistently, a recent study shows that Panx1 expressed in immune cells plays a critical role for pain-like effects after nerve injury and this response is abrogated in Panx1 gene deficient mice.	('abrogated', 'NegReg', (156, 165))	('mice', 'Species', '10090', (190, 194))	('pain', 'Disease', 'MESH:D010146', (98, 102))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('Panx1', 'Gene', (169, 174))	('pain', 'Disease', (98, 102))	('Panx1', 'Gene', (40, 45))	('deficient', 'Var', (180, 189))
40793	29865195	These studies suggest that therapeutic modulation of Panx1 could be useful for treating neuropathic pain associated with cancer and cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('therapeutic modulation', 'Var', (27, 49))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('neuropathic pain', 'Disease', 'MESH:D009437', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('modulation', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('neuropathic pain', 'Disease', (88, 104))	('Panx1', 'Gene', (53, 58))	('cancer', 'Disease', (121, 127))	('pain', 'Phenotype', 'HP:0012531', (100, 104))
40798	29865195	First, GJs and Cxs did not behave as classical tumour suppressors since Cx gene mutations never appeared in tumours as commonly shown as for p53, Rb and so forth.	('tumour', 'Disease', (108, 114))	('tumours', 'Disease', (108, 115))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('mutations', 'Var', (80, 89))	('tumour', 'Disease', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('Cx gene', 'Gene', (72, 79))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
40813	29865195	In the first case, the establishment of heterologous GJIC between cancer cells and cells of the tumour microenvironment may increase motility (such as glioma cells communicating with astrocytes) and further, helps to intravasation and extravasation.	('increase', 'PosReg', (124, 132))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('heterologous', 'Var', (40, 52))	('tumour', 'Disease', (96, 102))	('intravasation', 'MPA', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('motility', 'CPA', (133, 141))	('helps', 'Reg', (208, 213))	('extravasation', 'MPA', (235, 248))	('glioma', 'Disease', (151, 157))	('cancer', 'Disease', (66, 72))
40840	29792187	In WHO grade II-IV astrocytomas, CARPs were associated with molecular events related to more benign behavior, which was the case with CARP VIII in oligodendrogliomas and oligoastrocytomas as well.	('astrocytoma', 'Phenotype', 'HP:0009592', (19, 30))	('VIII', 'Gene', (139, 143))	('CARPs', 'Var', (33, 38))	('benign behavior', 'Disease', (93, 108))	('astrocytomas', 'Disease', (19, 31))	('astrocytomas', 'Disease', 'MESH:D001254', (175, 187))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('astrocytoma', 'Phenotype', 'HP:0009592', (175, 186))	('CARP', 'Species', '7962', (134, 138))	('CARPs', 'Species', '7962', (33, 38))	('grade II-IV', 'Var', (7, 18))	('astrocytomas', 'Disease', (175, 187))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('astrocytomas', 'Disease', 'MESH:D001254', (19, 31))	('VIII', 'Gene', '1351', (139, 143))	('oligodendrogliomas and oligoastrocytomas', 'Disease', 'MESH:D001254', (147, 187))	('CARP', 'Species', '7962', (33, 37))
40858	29792187	A homozygous missense mutation in human CA8 gene that codes for CARP VIII, leads to reduction in cerebellar volume causing mild mental retardation and cerebellar ataxia and some patients exhibit quadrupedal gait.	('human', 'Species', '9606', (34, 39))	('missense mutation', 'Var', (13, 30))	('mental retardation', 'Disease', (128, 146))	('reduction', 'NegReg', (84, 93))	('exhibit', 'Reg', (187, 194))	('VIII', 'Gene', (69, 73))	('cerebellar ataxia', 'Disease', 'MESH:D002524', (151, 168))	('CARP', 'Species', '7962', (64, 68))	('patients', 'Species', '9606', (178, 186))	('cerebellar volume', 'MPA', (97, 114))	('ataxia', 'Phenotype', 'HP:0001251', (162, 168))	('cerebellar ataxia', 'Phenotype', 'HP:0001251', (151, 168))	('mild mental retardation', 'Phenotype', 'HP:0001256', (123, 146))	('quadrupedal gait', 'CPA', (195, 211))	('VIII', 'Gene', '1351', (69, 73))	('CA8', 'Gene', (40, 43))	('cerebellar ataxia', 'Disease', (151, 168))	('mental retardation', 'Disease', 'MESH:D008607', (128, 146))	('mental retardation', 'Phenotype', 'HP:0001249', (128, 146))
40860	29792187	In zebrafish, knockdown of the CA8 gene leads to reduction in cerebellar volume and abnormal swim pattern, which are similar to the consequences of CA8 gene mutation in humans and mice.	('CA8', 'Gene', (31, 34))	('cerebellar volume', 'CPA', (62, 79))	('reduction', 'NegReg', (49, 58))	('zebrafish', 'Species', '7955', (3, 12))	('humans', 'Species', '9606', (169, 175))	('mutation', 'Var', (157, 165))	('mice', 'Species', '10090', (180, 184))	('knockdown', 'Var', (14, 23))
40865	29792187	The presence of CCG repeats in the CA10 gene indicates that CARP X could be involved in neurologic disorders due to mutations expanding the number of repeats.	('CA10', 'Gene', '56934', (35, 39))	('CARP', 'Species', '7962', (60, 64))	('expanding', 'PosReg', (126, 135))	('mutations', 'Var', (116, 125))	('CA10', 'Gene', (35, 39))	('neurologic disorders', 'Disease', 'MESH:D009422', (88, 108))	('involved', 'Reg', (76, 84))	('neurologic disorders', 'Disease', (88, 108))	('neurologic disorders', 'Phenotype', 'HP:0000707', (88, 108))
40866	29792187	Studies in humans and cultured cells showed that CARP XI is associated with spinocerebellar ataxia 3/Machado Joseph's disease.	('ataxia', 'Phenotype', 'HP:0001251', (92, 98))	('CARP', 'Species', '7962', (49, 53))	("spinocerebellar ataxia 3/Machado Joseph's disease", 'Disease', (76, 125))	('cerebellar ataxia', 'Phenotype', 'HP:0001251', (81, 98))	('humans', 'Species', '9606', (11, 17))	('CARP XI', 'Var', (49, 56))	("spinocerebellar ataxia 3/Machado Joseph's disease", 'Disease', 'MESH:D017827', (76, 125))	('associated', 'Reg', (60, 70))
40867	29792187	The latest studies on CARP X and CARP XI in zebrafish showed that these genes are predominantly expressed in CNS, and knockout of these genes induces to apoptosis in the brain leading to ataxic swim pattern in the ca10a and ca10b mutant zebrafish.	('induces to', 'Reg', (142, 152))	('ca10a', 'Gene', '641327', (214, 219))	('zebrafish', 'Species', '7955', (237, 246))	('CARP', 'Species', '7962', (22, 26))	('ca10b', 'Gene', (224, 229))	('ca10b', 'Gene', '568543', (224, 229))	('ataxic', 'Disease', 'MESH:D001259', (187, 193))	('zebrafish', 'Species', '7955', (44, 53))	('ca10a', 'Gene', (214, 219))	('CARP', 'Species', '7962', (33, 37))	('apoptosis', 'CPA', (153, 162))	('knockout', 'Var', (118, 126))	('ataxic', 'Disease', (187, 193))
40873	29792187	Most of the gastrointestinal stromal tumors (GIST) overexpress both CARP VIII and XI, and especially CARP XI seems to enhance proliferation and invasion of these tumors.	('gastrointestinal stromal tumors', 'Disease', (12, 43))	('overexpress', 'PosReg', (51, 62))	('VIII', 'Gene', '1351', (73, 77))	('enhance', 'PosReg', (118, 125))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('proliferation', 'CPA', (126, 139))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('CARP XI', 'Var', (101, 108))	('invasion', 'CPA', (144, 152))	('VIII', 'Gene', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (12, 43))	('CARP', 'Species', '7962', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (12, 43))	('CARP', 'Species', '7962', (68, 72))	('tumors', 'Disease', (162, 168))
40922	29792187	In astrocytomas and oligodendrogliomas, there were no association between CARPs and proliferation by Ki-67 / MIB-1 (p = n.s, Kruskal-Wallis test).	('rat', 'Species', '10116', (91, 94))	('astrocytomas and oligodendrogliomas', 'Disease', 'MESH:D009837', (3, 38))	('astrocytoma', 'Phenotype', 'HP:0009592', (3, 14))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('Ki-67', 'Var', (101, 106))	('proliferation', 'CPA', (84, 97))	('CARPs', 'Species', '7962', (74, 79))	('CARPs', 'Disease', (74, 79))	('gliomas', 'Phenotype', 'HP:0009733', (31, 38))
40930	29792187	In our study, the majority of the tumors expressing either CARP VIII or CARP XI were negative concerning VEGF.	('VIII', 'Gene', (64, 68))	('CARP', 'Var', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('VIII', 'Gene', '1351', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('VEGF', 'Gene', (105, 109))	('CARP', 'Species', '7962', (59, 63))	('CARP', 'Species', '7962', (72, 76))	('VEGF', 'Gene', '7422', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
40941	29792187	In a recent study, a negative correlation was found between CA IX and enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) mutation in astrocytomas.	('negative', 'NegReg', (21, 29))	('IDH1', 'Gene', (115, 119))	('astrocytoma', 'Phenotype', 'HP:0009592', (133, 144))	('astrocytomas', 'Disease', (133, 145))	('mutation', 'Var', (121, 129))	('rat', 'Species', '10116', (93, 96))	('astrocytomas', 'Disease', 'MESH:D001254', (133, 145))
40942	29792187	In our study, no correlation was found between CARP VIII expression and the other CAs (p = n.s., chi-square test) or IDH1 mutations (p = n.s., chi-square test).	('CARP', 'Species', '7962', (47, 51))	('CAs', 'Disease', (82, 85))	('VIII', 'Gene', (52, 56))	('VIII', 'Gene', '1351', (52, 56))	('mutations', 'Var', (122, 131))	('IDH1', 'Gene', (117, 121))
40948	29792187	1p/19q co-deletion is an independent prognostic and predictive marker in oligodendroglial tumors.	('1p/19q co-deletion', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (73, 96))	('oligodendroglial tumors', 'Disease', (73, 96))
40972	29792187	The second cluster of predicted TFBSs all overlap one another immediately upstream of the same most strongly expressed CAGE peak, and on both positive and negative DNA strands: LHX3, ARID3B, PHOX2A, PROP1, PHOX2B, FOXB1, ARID5A, HOXD8, and HOXD9 at locations + 64 to + 83 nt.	('HOXD9', 'Gene', (240, 245))	('LHX3', 'Var', (177, 181))	('PHOX2A', 'Var', (191, 197))	('HOXD9', 'Gene', '3235', (240, 245))
41011	29133513	Our primary endpoint was PFS6, with secondary endpoints being OS, PFS, radiographic response, and safety/tolerability.	('PFS', 'Disease', (66, 69))	('OS', 'Chemical', '-', (62, 64))	('PFS6', 'Var', (25, 29))
41033	29133513	The phase II BRAIN trial reported PFS6 with bevacizumab monotherapy to be 42.6% and median overall survival (OS) 9.2 months, and this trial established the groundwork for the U.S. Food and Drug Administration (FDA) approval of bevacizumab for recurrent GBM [2].	('GBM', 'Phenotype', 'HP:0012174', (253, 256))	('bevacizumab', 'Chemical', 'MESH:D000068258', (44, 55))	('OS', 'Chemical', '-', (109, 111))	('GBM', 'Disease', (253, 256))	('bevacizumab', 'Chemical', 'MESH:D000068258', (227, 238))	('PFS6', 'Var', (34, 38))
41089	29267253	As reported by other groups, we confirmed that activating the PKA system results in rodent glioma cell apoptosis.	('activating', 'Var', (47, 57))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Disease', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
41094	29267253	Moreover, targeting of PKA activity in four human glioblastoma cell lines, harboring different mutations, resulted in cell death, suggesting that selective activation of PKA may be an additional strategy for tumor therapy.	('human', 'Species', '9606', (44, 49))	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('rat', 'Species', '10116', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('mutations', 'Var', (95, 104))	('cell death', 'CPA', (118, 128))	('glioblastoma', 'Disease', (50, 62))
41104	29267253	Interference with the cAMP-PKA pathway induced cell death (Figure 2).	('cAMP', 'Gene', '820', (22, 26))	('Interference', 'Var', (0, 12))	('cell death', 'CPA', (47, 57))	('cAMP', 'Gene', (22, 26))
41121	29267253	This balance is important for the maintenance of cell homeostasis, and its disruption may drive cells to the tumorigenic phenotype.	('disruption', 'Var', (75, 85))	('cells', 'CPA', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('drive', 'Reg', (90, 95))	('tumor', 'Disease', (109, 114))
41125	29267253	Moreover, PKA imbalance has been linked to tumorigenesis.	('imbalance', 'Phenotype', 'HP:0002172', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('linked', 'Reg', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('imbalance', 'Var', (14, 23))	('tumor', 'Disease', (43, 48))
41126	29267253	We showed in murine GBM models that the PKA R2 subunit is concentrated in the Golgi area, and that interference with PKA activity may lead mice glioblastoma cells to apoptotic death.	('interference', 'Var', (99, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('glioblastoma', 'Disease', (144, 156))	('lead', 'Reg', (134, 138))	('murine', 'Species', '10090', (13, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('apoptotic death', 'CPA', (166, 181))	('mice', 'Species', '10090', (139, 143))	('PKA', 'Gene', (117, 120))	('rat', 'Species', '10116', (65, 68))
41138	29267253	It was also suggested that alterations of the cAMP pathway may initiate the immortalization phase of carcinogenesis.	('carcinogenesis', 'Disease', (101, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('rat', 'Species', '10116', (31, 34))	('cAMP', 'Gene', (46, 50))	('initiate', 'PosReg', (63, 71))	('cAMP', 'Gene', '820', (46, 50))	('alterations', 'Var', (27, 38))
41202	29211022	After treatment, chromosome instability may restore intra-tumoral heterogeneity in the surviving population and enable the continued evolution of the tumor, leading to recurrence.	('restore', 'PosReg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('evolution', 'MPA', (133, 142))	('enable', 'Reg', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('chromosome instability', 'Phenotype', 'HP:0040012', (17, 39))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('chromosome instability', 'Var', (17, 39))	('tumor', 'Disease', (150, 155))
41205	29211022	This pathway dictates many aspects of embryonic and post-embryonic development in multicellular organisms, and re-activation of this signaling pathway has been associated with cancer.	('re-activation', 'Var', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('dictates', 'Reg', (13, 21))	('associated', 'Reg', (160, 170))
41207	29211022	EGFR is commonly overexpressed or activated via gene amplified and/or gain of function mutations in a variety of cancers.	('EGFR', 'Gene', (0, 4))	('overexpressed', 'PosReg', (17, 30))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('activated', 'PosReg', (34, 43))	('gain of function', 'PosReg', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('mutations', 'Var', (87, 96))
41209	29211022	In GBM, nearly 60% of patients have abnormalities on EGFR, rendering EGFR as a compelling drug target.	('EGFR', 'Gene', (53, 57))	('abnormalities', 'Var', (36, 49))	('patients', 'Species', '9606', (22, 30))
41242	29211022	The variation in Chr7 copy number defined the TMC and STIC phenotype in the U251 GBM cell line, and the mis-segregation of Chr7 led to inter-conversion between subpopulations, demonstrating the dynamics of tumor heterogeneity in a changing environment, as shown in Figure 1B,E.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('inter-conversion', 'MPA', (135, 151))	('mis', 'Gene', '268', (104, 107))	('mis', 'Gene', (104, 107))	('variation', 'Var', (4, 13))	('led to', 'Reg', (128, 134))	('tumor', 'Disease', (206, 211))	('TMC', 'Chemical', '-', (46, 49))	('STIC', 'Chemical', '-', (54, 58))	('Chr7', 'Gene', (17, 21))	('Chr7', 'Gene', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
41273	29211022	Spearman correlation analysis found significant positive correlations between passage numbers of U251-NS in SA-conditions (between passages 4 to 16) and cell growth speed (rs = 0.93, p < 0.0001), TMC fraction (rs = 0.88, p < 0.01) and free-NADH fraction (rs = 0.79, p = 0.04), but not with EGFR protein (rs = 0.31, p > 0.05).	('SA', 'Chemical', '-', (108, 110))	('cell growth speed', 'CPA', (153, 170))	('U251-NS', 'Var', (97, 104))	('TMC', 'Chemical', '-', (196, 199))	('free-NADH', 'Chemical', '-', (235, 244))
41280	29211022	When imaged in vitro, FLIM identified a higher fraction of bound NADH in both of the STIC-enriched cultures, U251-NS and 51A, relative to their TMC-enriched cultures, U251 and 51B (Figure 2).	('higher', 'PosReg', (40, 46))	('bound', 'Interaction', (59, 64))	('NADH', 'Protein', (65, 69))	('NADH', 'Chemical', 'MESH:D009243', (65, 69))	('STIC', 'Chemical', '-', (85, 89))	('U251-NS', 'Var', (109, 116))	('TMC', 'Chemical', '-', (144, 147))
41306	29211022	Prior to the study, monolayer cultures of U251-NS, U251NS-RFP and 51A were achieved by culture in fibronectin-coated dishes (1 mug/cm2).	('fibronectin', 'Gene', (98, 109))	('U251NS-RFP', 'Var', (51, 61))	('fibronectin', 'Gene', '2335', (98, 109))	('U251-NS', 'Var', (42, 49))
41322	29211022	For single-cell analysis of the in vivo images, individual cells were identified and masked by their fluorescent protein label of either GFP (505-540 nm emission) or RFP (575-620 nm emission).	('505-540 nm', 'Var', (142, 152))	('mis', 'Gene', '268', (183, 186))	('mis', 'Gene', (183, 186))	('mis', 'Gene', '268', (154, 157))	('mis', 'Gene', (154, 157))
41325	29211022	The excitation was separated from the emission light by a 690-nm dichroic mirror, and the NADH emission was collected by a 460/80 bandpass filter and a photomultiplier tube (H7422P-40, Hamamatsu Photonics, Hamamatsu, Japan).	('H7422P', 'SUBSTITUTION', 'None', (174, 180))	('mis', 'Gene', (96, 99))	('NADH', 'Chemical', 'MESH:D009243', (90, 94))	('mis', 'Gene', '268', (39, 42))	('mis', 'Gene', (39, 42))	('H7422P', 'Var', (174, 180))	('mis', 'Gene', '268', (96, 99))
41344	28797031	ATG9A was consistently induced by hypoxia, and silencing of ATG9A led to decreased proliferation in vitro and delayed tumour growth in vivo.	('proliferation', 'CPA', (83, 96))	('decreased', 'NegReg', (73, 82))	('ATG9A', 'Gene', (60, 65))	('delayed', 'NegReg', (110, 117))	('silencing', 'Var', (47, 56))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('hypoxia', 'Disease', (34, 41))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('tumour growth', 'Disease', (118, 131))	('tumour growth', 'Disease', 'MESH:D006130', (118, 131))	('rat', 'Species', '10116', (90, 93))
41345	28797031	Hypoxia-induced activation of autophagy was compromised upon ATG9A depletion.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('ATG9A', 'Protein', (61, 66))	('depletion', 'Var', (67, 76))	('Hypoxia', 'Disease', (0, 7))
41346	28797031	This work shows that inhibition of autophagy is a promising strategy against GBM and identifies ATG9 as a novel target in hypoxia-induced autophagy.	('autophagy', 'CPA', (35, 44))	('hypoxia', 'Disease', (122, 129))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('ATG9', 'Gene', (96, 100))	('inhibition', 'Var', (21, 31))	('GBM', 'Disease', (77, 80))	('rat', 'Species', '10116', (62, 65))
41368	28797031	NCH421k and NCH644 harbouring Scramble or ATG9A shRNA were stereotactically implanted in NOD/SCID mice (13 7500 NCH421k cells or 50 000 NCH644 cells per animal; 6-7 per group).	('NCH644', 'Chemical', '-', (12, 18))	('NCH644', 'Var', (12, 18))	('NCH644', 'Chemical', '-', (136, 142))	('SCID', 'Disease', 'MESH:D053632', (93, 97))	('SCID', 'Disease', (93, 97))	('mice', 'Species', '10090', (98, 102))
41383	28797031	GBM stem-like cultures (NCH421k, NCH660h, NCH465, NCH601 and NCH644) were kindly provided by Christel Herold-Mende (University of Heidelberg, Germany) and were cultured as previously described.	('NCH644', 'Chemical', '-', (61, 67))	('NCH644', 'Var', (61, 67))	('NCH421k', 'Var', (24, 31))	('NCH601', 'Var', (50, 56))
41392	28797031	Supernatant containing viral particles was used to transduce 100 000 cells and puromycine selection permitted to obtain 100% of stably transduced GFP-positive cells (0.5 mug ml-1 for NCH421k and U87, 1 mug ml-1 for NCH644 for at least 2 weeks).	('U87', 'Gene', '641648', (195, 198))	('NCH421k', 'Var', (183, 190))	('NCH644', 'Chemical', '-', (215, 221))	('U87', 'Gene', (195, 198))	('puromycine', 'Chemical', 'MESH:D011691', (79, 89))
41397	28797031	shScramble and shATG9A transfected NCH421k, NCH644 (10 000 cells) and U87 (5000 cells) were plated in 6 well plates.	('U87', 'Gene', '641648', (70, 73))	('NCH644', 'Chemical', '-', (44, 50))	('U87', 'Gene', (70, 73))	('NCH421k', 'Var', (35, 42))
41421	28797031	Out of six cultures tested NCH644, U87 and T98G exhibited increased sensitivity to chloroquine in hypoxia (Figure 1G).	('T98G', 'CellLine', 'CVCL:0556', (43, 47))	('increased', 'PosReg', (58, 67))	('U87', 'Gene', '641648', (35, 38))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('chloroquine', 'Chemical', 'MESH:D002738', (83, 94))	('T98G', 'Var', (43, 47))	('NCH644', 'Chemical', '-', (27, 33))	('NCH644', 'Var', (27, 33))	('U87', 'Gene', (35, 38))
41423	28797031	Again, mefloquine was generally more potent in normoxia, and increased sensitivity in hypoxia was observed only for NCH644, which displayed highest IC50 at normal oxygen levels (Figure 1G).	('mefloquine', 'Chemical', 'MESH:D015767', (7, 17))	('NCH644', 'Chemical', '-', (116, 122))	('NCH644', 'Var', (116, 122))	('IC50', 'MPA', (148, 152))	('oxygen', 'Chemical', 'MESH:D010100', (163, 169))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))
41444	28797031	The upregulation of ATG9A was confirmed by qPCR in GBM stem-like cells (NCH644, NCH421k, NCH660h, NCH601, NCH465) and adherent cultures (U87, U251) (Figure 3C).	('NCH644', 'Var', (72, 78))	('ATG9A', 'Gene', (20, 25))	('upregulation', 'PosReg', (4, 16))	('NCH601', 'Var', (98, 104))	('U87', 'Gene', (137, 140))	('NCH660h', 'Var', (89, 96))	('NCH465', 'Var', (106, 112))	('U87', 'Gene', '641648', (137, 140))	('NCH644', 'Chemical', '-', (72, 78))
41447	28797031	To study the involvement of ATG9 in autophagy, we generated an efficient long-term ATG9A knockdown (75-98%, Figure 4A) in three GBM cultures, resulting in reduced proliferation both in normoxia and hypoxia (Figure 4B).	('reduced', 'NegReg', (155, 162))	('rat', 'Species', '10116', (170, 173))	('rat', 'Species', '10116', (54, 57))	('proliferation', 'CPA', (163, 176))	('normoxia and hypoxia', 'Disease', 'MESH:D000860', (185, 205))	('ATG9A', 'Gene', (83, 88))	('knockdown', 'Var', (89, 98))
41450	28797031	ATG9A knockdown led to a significant increase in mouse survival (+12-18% Figure 4D).	('ATG9A', 'Gene', (0, 5))	('mouse survival', 'CPA', (49, 63))	('mouse', 'Species', '10090', (49, 54))	('increase', 'PosReg', (37, 45))	('knockdown', 'Var', (6, 15))
41456	28797031	Inhibiting autophagy was shown to potentiate various anti-cancer therapies in vitro, including gliomas, where cells were subjected to external stress.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('autophagy', 'CPA', (11, 20))	('potentiate', 'PosReg', (34, 44))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
41461	28797031	This heterogeneous response suggests that the genetic background, for example, PTEN deletion, p53 mutation or EGFR amplification, may differentially affect the extent of basal level of autophagy and of treatment response in GBM and that appropriate biomarkers may be required to efficiently stratify patients.	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('deletion', 'Var', (84, 92))	('EGFR', 'Gene', (110, 114))	('affect', 'Reg', (149, 155))	('amplification', 'Var', (115, 128))	('EGFR', 'Gene', '1956', (110, 114))	('p53', 'Gene', '7157', (94, 97))	('rat', 'Species', '10116', (293, 296))	('treatment response', 'CPA', (202, 220))	('basal', 'MPA', (170, 175))	('PTEN', 'Gene', (79, 83))	('patients', 'Species', '9606', (300, 308))	('PTEN', 'Gene', '5728', (79, 83))
41476	28797031	Here we show that ATG9A also represents an important pro-survival molecule, with ATG9A depletion leading to a strong reduction of tumour growth, thus confirming the relevance of autophagy as a promising target for GBM treatment.	('reduction', 'NegReg', (117, 126))	('tumour growth', 'Disease', 'MESH:D006130', (130, 143))	('ATG9A', 'Gene', (81, 86))	('depletion', 'Var', (87, 96))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumour growth', 'Disease', (130, 143))
41477	28797031	Of note, ATG7 knockdown displayed a therapeutic outcome only during anti-angiogenic treatment.	('ATG7', 'Gene', '10533', (9, 13))	('ATG7', 'Gene', (9, 13))	('knockdown', 'Var', (14, 23))
41480	28797031	Here we show that upon ATG9A depletion, GBM cells were not able to activate autophagy upon hypoxia.	('depletion', 'Var', (29, 38))	('autophagy', 'CPA', (76, 85))	('hypoxia', 'Disease', (91, 98))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
41483	28797031	In conclusion, our data support the notion that inhibiting autophagy represents an effective therapy in primary GBM, although it may be concentration and patient dependent.	('autophagy', 'CPA', (59, 68))	('patient', 'Species', '9606', (154, 161))	('inhibiting', 'Var', (48, 58))	('primary GBM', 'Disease', (104, 115))	('rat', 'Species', '10116', (143, 146))
41488	25609694	Aberrant expression of NF-kappaB has been linked to cancer, inflammatory diseases and improper development.	('Aberrant expression', 'Var', (0, 19))	('inflammatory diseases', 'Disease', 'MESH:D007249', (60, 81))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inflammatory diseases', 'Disease', (60, 81))	('NF-kappaB', 'Gene', (23, 32))	('expression', 'Species', '29278', (9, 19))	('improper development', 'Disease', (86, 106))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('NF-kappaB', 'Gene', '4790', (23, 32))	('linked', 'Reg', (42, 48))
41494	25609694	Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle.	('glucose metabolism flux', 'Disease', (148, 171))	('higher', 'PosReg', (91, 97))	('lactate', 'Chemical', 'MESH:D019344', (78, 85))	('glucose metabolism flux', 'Disease', 'MESH:D044882', (148, 171))	('changes', 'Reg', (137, 144))	('ZBTB2', 'Gene', (36, 41))	('pyruvate', 'Chemical', 'MESH:D019289', (65, 73))	('ectopic', 'Var', (28, 35))	('lactate', 'MPA', (78, 85))	('glycolysis', 'MPA', (181, 191))	('TCA', 'Chemical', 'MESH:D014238', (201, 204))
41499	25609694	Moreover, targeting of ZBTB2 in human gastric cancer by microRNA-149 inhibits proliferation and cell cycle progression, and a genome-wide association study identified ZBTB2 in a gene cluster associated with susceptibility to chronic myeloid leukemia.	('ZBTB2', 'Gene', (23, 28))	('myeloid leukemia', 'Disease', (233, 249))	('gastric cancer', 'Phenotype', 'HP:0012126', (38, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (38, 52))	('inhibits', 'NegReg', (69, 77))	('ZBTB2', 'Gene', (167, 172))	('myeloid leukemia', 'Disease', 'MESH:D007951', (233, 249))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (233, 249))	('leukemia', 'Phenotype', 'HP:0001909', (241, 249))	('gastric cancer', 'Disease', (38, 52))	('targeting', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (32, 37))	('microRNA-149', 'Var', (56, 68))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (225, 249))
41501	25609694	Interestingly, ZBTB2 was also found to associate with the transcription cofactor CBP, and ZBTB2 has also been identified as a candidate oncoprotein having an R261W polymorphism that potentiates its mitogenic activity in human colorectal cancers with microsatellite instability.	('CBP', 'Gene', (81, 84))	('R261W', 'Var', (158, 163))	('human', 'Species', '9606', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('colorectal cancers', 'Disease', (226, 244))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('R261W', 'Mutation', 'rs1036759710', (158, 163))	('potentiates', 'PosReg', (182, 193))	('mitogenic activity', 'CPA', (198, 216))	('CBP', 'Gene', '1387', (81, 84))	('ZBTB2', 'Gene', (90, 95))	('colorectal cancers', 'Disease', 'MESH:D015179', (226, 244))
41503	25609694	In particular, NF-kappaB regulates the expression of genes controlling apoptosis, cell adhesion, proliferation, inflammation and tissue remodeling, and dysregulation of NF-kappaB activity has been linked to inflammatory disorders, autoimmune and metabolic diseases, as well as cancer.	('activity', 'MPA', (179, 187))	('NF-kappaB', 'Gene', (15, 24))	('NF-kappaB', 'Gene', (169, 178))	('metabolic diseases', 'Disease', 'MESH:D008659', (246, 264))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('inflammatory disorders', 'Disease', (207, 229))	('expression', 'Species', '29278', (39, 49))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('NF-kappaB', 'Gene', '4790', (169, 178))	('metabolic diseases', 'Disease', (246, 264))	('inflammation', 'Disease', (112, 124))	('linked', 'Reg', (197, 203))	('expression', 'MPA', (39, 49))	('dysregulation', 'Var', (152, 165))	('inflammatory disorders', 'Disease', 'MESH:D015212', (207, 229))	('NF-kappaB', 'Gene', '4790', (15, 24))
41525	25609694	The pGL2-RelA/p65-Luc -47-bp construct with mutation at GC-box #3 (bp, -30 to -20) was prepared by site-directed mutagenesis.	('RelA', 'Gene', (9, 13))	('p65', 'Gene', '5970', (14, 17))	('mutation', 'Var', (44, 52))	('RelA', 'Gene', '5970', (9, 13))	('pGL2', 'Gene', (4, 8))	('p65', 'Gene', (14, 17))	('pGL2', 'Gene', '54949', (4, 8))
41555	25609694	HEK293 cells were transfected with pcDNA3 or pcDNA3-ZBTB2, grown for an additional 48 h and treated with formaldehyde (final concentration 1%) to cross-link proteins to DNA, followed by cell lysis in RIPA buffer.	('pcDNA3-ZBTB2', 'Gene', (45, 57))	('pcDNA3', 'Var', (35, 41))	('RIPA buffer', 'Chemical', '-', (200, 211))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('cross-link', 'Interaction', (146, 156))	('formaldehyde', 'Chemical', 'MESH:D005557', (105, 117))	('proteins', 'Protein', (157, 165))
41564	25609694	The probes were labeled by the addition of Klenow enzyme and 32P-alpha-[dATP], followed by purification using Sephadex G-25 columns.	('Sephadex', 'Chemical', 'MESH:C025614', (110, 118))	('Klenow enzyme', 'Protein', (43, 56))	('32P-alpha-', 'Var', (61, 71))	('32P', 'Chemical', 'MESH:C000615311', (61, 64))	('dATP', 'Chemical', 'MESH:C026600', (72, 76))
41585	25609694	Once tumors had reached 100-120 mm3 in volume, mice were injected intra-tumorally five times at 2-day intervals with either control dl324 or dl324-shRNA ZBTB2 viruses (2 x 108 PFU).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('dl324-shRNA', 'Var', (141, 152))	('intra-tumoral', 'Disease', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mice', 'Species', '10090', (47, 51))	('intra-tumoral', 'Disease', 'MESH:D009369', (66, 79))
41588	25609694	DAB immunohistochemical (IHC) staining was done according to the manufacturer's instructions (VECTASTAIN ABC Kit, Vector Laboratories) after incubating with anti-ZBTB2, anti-RelA/p65 and anti-PDK4 antibodies overnight at 4 C. Student's t-test was used for the statistical analyses.	('PDK4', 'Gene', '5166', (192, 196))	('PDK4', 'Gene', (192, 196))	('DAB', 'Chemical', 'MESH:C000469', (0, 3))	('RelA', 'Gene', (174, 178))	('p65', 'Gene', (179, 182))	('RelA', 'Gene', '5970', (174, 178))	('anti-ZBTB2', 'Var', (157, 167))	('p65', 'Gene', '5970', (179, 182))
41598	25609694	Alternatively, knockdown of Sp1 expression potently decreased transcription of the RelA/p65 promoter in most of the constructs, but not in the pRelA/p65-Luc +1 construct (Supplementary Figure S2B).	('p65', 'Gene', '5970', (149, 152))	('p65', 'Gene', (88, 91))	('knockdown', 'Var', (15, 24))	('RelA', 'Gene', '5970', (83, 87))	('Sp1', 'Gene', (28, 31))	('RelA', 'Gene', (144, 148))	('decreased', 'NegReg', (52, 61))	('transcription', 'MPA', (62, 75))	('RelA', 'Gene', (83, 87))	('p65', 'Gene', '5970', (88, 91))	('expression', 'Species', '29278', (32, 42))	('RelA', 'Gene', '5970', (144, 148))	('p65', 'Gene', (149, 152))
41601	25609694	To that end, we found that the pGL2-RelA/p65-Luc (-47 bp) construct was activated by Sp1; deletion of further downstream regions resulted in no transcriptional activation by Sp1.	('deletion', 'Var', (90, 98))	('RelA', 'Gene', '5970', (36, 40))	('p65', 'Gene', (41, 44))	('Sp1', 'Gene', (85, 88))	('pGL2', 'Gene', '54949', (31, 35))	('transcriptional activation', 'MPA', (144, 170))	('p65', 'Gene', '5970', (41, 44))	('pGL2', 'Gene', (31, 35))	('RelA', 'Gene', (36, 40))
41604	25609694	Using RT-qPCR and western blot analysis, we investigated whether ectopic ZBTB2 overexpression or knockdown affected transcription of the endogenous RelA/p65 gene.	('RelA', 'Gene', '5970', (148, 152))	('p65', 'Gene', (153, 156))	('ZBTB2', 'Gene', (73, 78))	('knockdown', 'Var', (97, 106))	('transcription', 'MPA', (116, 129))	('p65', 'Gene', '5970', (153, 156))	('expression', 'Species', '29278', (83, 93))	('affected', 'Reg', (107, 115))	('RelA', 'Gene', (148, 152))
41605	25609694	In human HEK293 cells, ectopic ZBTB2 significantly downregulated RelA/p65, while ZBTB2 knockdown enhanced RelA/p65 expression at the protein level (Figure 2B).	('p65', 'Gene', (111, 114))	('ZBTB2', 'Gene', (81, 86))	('RelA', 'Gene', (106, 110))	('ectopic', 'Var', (23, 30))	('p65', 'Gene', '5970', (70, 73))	('HEK293', 'CellLine', 'CVCL:0045', (9, 15))	('human', 'Species', '9606', (3, 8))	('expression', 'Species', '29278', (115, 125))	('p65', 'Gene', '5970', (111, 114))	('enhanced', 'PosReg', (97, 105))	('expression', 'MPA', (115, 125))	('downregulated', 'NegReg', (51, 64))	('RelA', 'Gene', (65, 69))	('RelA', 'Gene', '5970', (106, 110))	('ZBTB2', 'Gene', (31, 36))	('RelA', 'Gene', '5970', (65, 69))	('p65', 'Gene', (70, 73))	('knockdown', 'Var', (87, 96))
41606	25609694	Ectopic ZBTB2 expression repressed RelA/p65 transcription by 0.4- to 0.5-fold, and knockdown of ZBTB2 increased transcription of the RelA/p65 gene by 2.5-fold (Figure 2C).	('RelA', 'Gene', '5970', (35, 39))	('p65', 'Gene', (40, 43))	('ZBTB2', 'Gene', (8, 13))	('RelA', 'Gene', (133, 137))	('p65', 'Gene', '5970', (138, 141))	('RelA', 'Gene', '5970', (133, 137))	('expression', 'Species', '29278', (14, 24))	('p65', 'Gene', '5970', (40, 43))	('ZBTB2', 'Gene', (96, 101))	('increased', 'PosReg', (102, 111))	('p65', 'Gene', (138, 141))	('knockdown', 'Var', (83, 92))	('RelA', 'Gene', (35, 39))	('transcription', 'MPA', (112, 125))
41615	25609694	Alternatively, we also used ChIP to investigate whether knockdown of ZBTB2 expression could increase Sp1 binding to the region flanking GC-box #3 (Figure 4D and E).	('knockdown', 'Var', (56, 65))	('increase', 'PosReg', (92, 100))	('expression', 'Species', '29278', (75, 85))	('ZBTB2', 'Gene', (69, 74))	('Sp1', 'Protein', (101, 104))	('binding', 'Interaction', (105, 112))
41616	25609694	Furthermore, to even more firmly establish the importance of GC-box #3 in RelA/p65 transcriptional initiation and activation by Sp1 and repression by ZBTB2, we made a reporter construct with a mutation introduced at the core of GC-box #3 (CCCGGCCCC to TTTAATTTT).	('RelA', 'Gene', (74, 78))	('p65', 'Gene', '5970', (79, 82))	('RelA', 'Gene', '5970', (74, 78))	('3 (CCCGGCCCC to TTTAATTTT', 'Mutation', 'c.3CCCGGCCCC>TTTAATTTT', (236, 261))	('p65', 'Gene', (79, 82))	('mutation', 'Var', (193, 201))
41628	25609694	Ectopic ZBTB2 expression repressed interleukin genes, while knockdown of ZBTB2 derepressed interleukin genes, particularly IL-1alpha (Supplementary Figure S4A and B).	('IL-1alpha', 'Gene', (123, 132))	('ZBTB2', 'Gene', (73, 78))	('ZBTB2', 'Gene', (8, 13))	('expression', 'Species', '29278', (14, 24))	('interleukin genes', 'MPA', (91, 108))	('knockdown', 'Var', (60, 69))	('derepressed', 'NegReg', (79, 90))	('repressed interleukin genes', 'MPA', (25, 52))
41630	25609694	While ZBTB2 potently repressed reporter expression, ZBTB2DeltaPOZ (lacking the POZ domain) very weakly repressed reporter expression, suggesting the importance of the POZ domain in transcriptional repression (Figure 6D).	('ZBTB2DeltaPOZ', 'Var', (52, 65))	('expression', 'Species', '29278', (40, 50))	('expression', 'Species', '29278', (122, 132))	('reporter expression', 'MPA', (31, 50))
41637	25609694	While ectopic Sp1 increases cytoplasmic and nuclear RelA/p65, ectopic ZBTB2 decreases cytoplasmic and nuclear RelA/p65.	('increases', 'PosReg', (18, 27))	('p65', 'Gene', '5970', (115, 118))	('p65', 'Gene', (57, 60))	('decreases', 'NegReg', (76, 85))	('RelA', 'Gene', (110, 114))	('p65', 'Gene', '5970', (57, 60))	('ectopic', 'Var', (62, 69))	('RelA', 'Gene', (52, 56))	('ZBTB2', 'Gene', (70, 75))	('RelA', 'Gene', '5970', (52, 56))	('RelA', 'Gene', '5970', (110, 114))	('p65', 'Gene', (115, 118))
41638	25609694	Moreover, we tested whether ectopic ZBTB2 changes RelA/p65 associated with IkappaB-alpha by co-immunoprecipitation with an anti-RelA/p65 antibody and western blot analysis with an anti-IkappaB-alpha antibody.	('RelA', 'Gene', '5970', (50, 54))	('p65', 'Gene', (133, 136))	('ZBTB2', 'Gene', (36, 41))	('RelA', 'Gene', '5970', (128, 132))	('tested', 'Reg', (13, 19))	('p65', 'Gene', (55, 58))	('associated', 'Interaction', (59, 69))	('ectopic', 'Var', (28, 35))	('p65', 'Gene', '5970', (133, 136))	('p65', 'Gene', '5970', (55, 58))	('RelA', 'Gene', (128, 132))	('IkappaB-alpha', 'Protein', (75, 88))	('RelA', 'Gene', (50, 54))
41639	25609694	When ZBTB2 was overexpressed, more IkappaB-alpha interacted with RelA/p65, suggesting that ZBTB2 may decrease nuclear RelA/p65 by increasing cytosolic RelA/p65-IkappaB-alpha interactions (Supplementary Figure S5A and B).	('p65', 'Gene', (156, 159))	('RelA', 'Gene', (118, 122))	('interactions', 'Interaction', (174, 186))	('p65', 'Gene', '5970', (156, 159))	('RelA', 'Gene', '5970', (118, 122))	('p65', 'Gene', (123, 126))	('increasing', 'PosReg', (130, 140))	('ZBTB2', 'Var', (91, 96))	('p65', 'Gene', '5970', (70, 73))	('RelA', 'Gene', (151, 155))	('nuclear', 'MPA', (110, 117))	('RelA', 'Gene', '5970', (65, 69))	('RelA', 'Gene', '5970', (151, 155))	('RelA', 'Gene', (65, 69))	('p65', 'Gene', '5970', (123, 126))	('decrease', 'NegReg', (101, 109))	('p65', 'Gene', (70, 73))
41653	25609694	Ectopic expression of ZBTB2 in HEK293 cells decreased PDH activity (Figure 7C).	('PDH', 'Gene', (54, 57))	('ZBTB2', 'Gene', (22, 27))	('Ectopic expression', 'Var', (0, 18))	('expression', 'Species', '29278', (8, 18))	('PDH', 'Gene', '54704', (54, 57))	('HEK293', 'CellLine', 'CVCL:0045', (31, 37))	('decreased PDH activity', 'Phenotype', 'HP:0002928', (44, 66))	('decreased', 'NegReg', (44, 53))
41654	25609694	Furthermore, we investigated whether decreased PDH activity in cells with ectopic ZBTB2 expression affected lactate production.	('activity', 'MPA', (51, 59))	('lactate production', 'MPA', (108, 126))	('ZBTB2', 'Gene', (82, 87))	('ectopic', 'Var', (74, 81))	('PDH', 'Gene', (47, 50))	('decreased PDH activity', 'Phenotype', 'HP:0002928', (37, 59))	('PDH', 'Gene', '54704', (47, 50))	('lactate', 'Chemical', 'MESH:D019344', (108, 115))	('expression', 'Species', '29278', (88, 98))	('decreased', 'NegReg', (37, 46))
41655	25609694	Lactate assays showed that the concentration of lactate was increased by ectopic ZBTB2 (Figure 7D).	('ZBTB2', 'Gene', (81, 86))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('ectopic', 'Var', (73, 80))	('increased', 'PosReg', (60, 69))	('lactate', 'Chemical', 'MESH:D019344', (48, 55))	('concentration of lactate', 'MPA', (31, 55))
41656	25609694	We also examined whether PDK4 upregulation by ZBTB2 was through repression of RelA/p65 expression by a 'loss of function' approach in which ZBTB2 siRNA and/or RelA/p65 siRNA were transfected into HEK293 cells.	('p65', 'Gene', '5970', (164, 167))	('PDK4', 'Gene', '5166', (25, 29))	('RelA', 'Gene', (78, 82))	('RelA', 'Gene', '5970', (159, 163))	('p65', 'Gene', '5970', (83, 86))	('PDK4', 'Gene', (25, 29))	('expression', 'Species', '29278', (87, 97))	('RelA', 'Gene', '5970', (78, 82))	('p65', 'Gene', (164, 167))	('ZBTB2', 'Var', (140, 145))	('HEK293', 'CellLine', 'CVCL:0045', (196, 202))	('upregulation', 'PosReg', (30, 42))	('RelA', 'Gene', (159, 163))	('p65', 'Gene', (83, 86))	('ZBTB2', 'Gene', (46, 51))
41657	25609694	Those results showed PDK4 expression decreased by ZBTB2 knockdown and increased by RelA/p65 knockdown (Figure 7E).	('expression', 'MPA', (26, 36))	('p65', 'Gene', (88, 91))	('increased', 'PosReg', (70, 79))	('PDK4', 'Gene', '5166', (21, 25))	('ZBTB2', 'Gene', (50, 55))	('PDK4', 'Gene', (21, 25))	('RelA', 'Gene', (83, 87))	('p65', 'Gene', '5970', (88, 91))	('RelA', 'Gene', '5970', (83, 87))	('expression', 'Species', '29278', (26, 36))	('decreased', 'NegReg', (37, 46))	('knockdown', 'Var', (56, 65))
41658	25609694	Moreover, ZBTB2 knockdown could not decrease PDK4 expression in the absence of RelA/p65, eventually resulting in increased PDH activity and decreased lactate production, which was not observed in the cells with RelA/p65 knockdown (Figure 7F and G).	('p65', 'Gene', (84, 87))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('PDH', 'Gene', '54704', (123, 126))	('activity', 'MPA', (127, 135))	('expression', 'MPA', (50, 60))	('RelA', 'Gene', '5970', (211, 215))	('p65', 'Gene', '5970', (84, 87))	('ZBTB2', 'Gene', (10, 15))	('p65', 'Gene', (216, 219))	('PDH', 'Gene', (123, 126))	('RelA', 'Gene', (79, 83))	('increased', 'PosReg', (113, 122))	('expression', 'Species', '29278', (50, 60))	('lactate production', 'MPA', (150, 168))	('p65', 'Gene', '5970', (216, 219))	('decreased', 'NegReg', (140, 149))	('PDK4', 'Gene', '5166', (45, 49))	('PDK4', 'Gene', (45, 49))	('knockdown', 'Var', (16, 25))	('RelA', 'Gene', '5970', (79, 83))	('RelA', 'Gene', (211, 215))
41660	25609694	It has been previously shown that microRNA-149 downregulates ZBTB2 expression.	('downregulates', 'NegReg', (47, 60))	('ZBTB2', 'Gene', (61, 66))	('expression', 'Species', '29278', (67, 77))	('microRNA-149', 'Var', (34, 46))	('expression', 'MPA', (67, 77))
41673	25609694	These changes suggest that a metabolic shift to glycolysis in cells with ectopic ZBTB2 may also be applicable to glioblastoma.	('glioblastoma', 'Disease', (113, 125))	('ZBTB2', 'Gene', (81, 86))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('ectopic', 'Var', (73, 80))
41679	25609694	The presence of ZBTB2 potently blocks the DNA-binding activity of Sp1 and also nearly completely blocks transcription of a RelA/p65 reporter by Sp1 through the key regulatory element, GC-box #3 (Figures 2-4).	('DNA-binding', 'Interaction', (42, 53))	('ZBTB2', 'Gene', (16, 21))	('Sp1', 'Gene', (66, 69))	('Sp1', 'Gene', (144, 147))	('RelA', 'Gene', (123, 127))	('p65', 'Gene', '5970', (128, 131))	('RelA', 'Gene', '5970', (123, 127))	('transcription', 'MPA', (104, 117))	('blocks', 'NegReg', (31, 37))	('blocks', 'NegReg', (97, 103))	('presence', 'Var', (4, 12))	('p65', 'Gene', (128, 131))
41695	25609694	Additionally, acetylation of RelA/p65 has been demonstrated to decrease its DNA-binding affinity, and post-translational modifications of RelA/p65 by HATs or HDACs influence termination of the NF-kappaB response.	('acetylation', 'Var', (14, 25))	('DNA-binding affinity', 'Interaction', (76, 96))	('NF-kappaB', 'Gene', (193, 202))	('RelA', 'Gene', '5970', (29, 33))	('NF-kappaB', 'Gene', '4790', (193, 202))	('p65', 'Gene', (34, 37))	('decrease', 'NegReg', (63, 71))	('p65', 'Gene', (143, 146))	('influence', 'Reg', (164, 173))	('p65', 'Gene', '5970', (34, 37))	('RelA', 'Gene', (138, 142))	('p65', 'Gene', '5970', (143, 146))	('RelA', 'Gene', (29, 33))	('RelA', 'Gene', '5970', (138, 142))
41707	25609694	The molecular events triggered by overexpressed ZBTB2 may cause metabolic switching to favor glycolysis over the TCA cycle, a metabolic feature of cancer cells.	('overexpressed', 'Var', (34, 47))	('favor', 'PosReg', (87, 92))	('TCA cycle', 'MPA', (113, 122))	('glycolysis', 'MPA', (93, 103))	('metabolic switching', 'MPA', (64, 83))	('TCA', 'Chemical', 'MESH:D014238', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cause', 'Reg', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('ZBTB2', 'Gene', (48, 53))	('cancer', 'Disease', (147, 153))
41753	24662935	Plants, which are not endangered or protected, were identified by Dr. Jeanne Millogo-Rasolodimby (Plant Biology and Ecology Laboratory, Ouagadougou University) and a voucher specimen was deposited under numbers 15941, 15939, 15942, 15938, 13162, 15943 and 15944 for O. basilicum, O. americanum, H. spicigera, L. multiflora, A. conyzoides, E. camaldulensis and Z. officinale respectively in the herbarium of the Plant Biology and Ecology Laboratory.	('men', 'Species', '9606', (179, 182))	('E. camaldulensis', 'Species', '34316', (339, 355))	('15939', 'Var', (218, 223))	('15941', 'Var', (211, 216))	('L. multiflora', 'Species', '74761', (309, 322))	('Z. officinale', 'Species', '94328', (360, 373))	('15938', 'Var', (232, 237))	('A. conyzoides', 'Species', '68299', (324, 337))	('15944', 'Var', (256, 261))	('O. basilicum', 'Species', '39350', (266, 278))	('O. americanum', 'Species', '204141', (280, 293))	('15943', 'Var', (246, 251))	('15942', 'Var', (225, 230))	('13162', 'Var', (239, 244))
41849	24662935	SF-767 and SF-763 cell lines are radiotherapy resistant; in SF-767 cells, STAT3 pathway is activated while in SF-763, both STAT3 and AKT pathways are constitutively activated.	('STAT3', 'Gene', (123, 128))	('SF-763', 'CellLine', 'CVCL:6949', (110, 116))	('STAT3', 'Gene', '6774', (74, 79))	('AKT', 'Gene', '207', (133, 136))	('STAT3', 'Gene', (74, 79))	('SF-767', 'Var', (60, 66))	('activated', 'PosReg', (91, 100))	('SF-763', 'CellLine', 'CVCL:6949', (11, 17))	('AKT', 'Gene', (133, 136))	('STAT3', 'Gene', '6774', (123, 128))
41878	24662935	The main difference between these two cell lines regards the survival pathways: indeed STAT3 pathway is activated in SF-767 cells, while both Akt and STAT3 pathways are induced in SF-763 cells.	('Akt', 'Gene', (142, 145))	('STAT3', 'Gene', (87, 92))	('SF-763', 'CellLine', 'CVCL:6949', (180, 186))	('STAT3', 'Gene', '6774', (150, 155))	('Akt', 'Gene', '207', (142, 145))	('STAT3', 'Gene', (150, 155))	('STAT3', 'Gene', '6774', (87, 92))	('SF-767', 'Var', (117, 123))	('activated', 'PosReg', (104, 113))
41896	24705102	It has been well established that aberrant CYR61 expression and signaling can lead to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('CYR61', 'Gene', (43, 48))	('lead to', 'Reg', (78, 85))	('signaling', 'MPA', (64, 73))	('aberrant', 'Var', (34, 42))	('expression', 'MPA', (49, 59))	('CYR61', 'Gene', '3491', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
41947	24705102	Therefore, we examined the activation of AKT, ERK1/2, and p70S6 kinase in response to miRNA overexpression in LN229 cells.	('ERK1/2', 'Gene', (46, 52))	('miR', 'Gene', (86, 89))	('p70S6', 'Var', (58, 63))	('AKT', 'Gene', '207', (41, 44))	('LN229', 'CellLine', 'CVCL:0393', (110, 115))	('ERK1/2', 'Gene', '5595;5594', (46, 52))	('activation', 'PosReg', (27, 37))	('miR', 'Gene', '29116', (86, 89))	('AKT', 'Gene', (41, 44))
41949	24705102	The Western blot in Figure 3A shows that all three miRNAs significantly increased the phosphorylation of ERK1/2 (T202/Y204), and p70S6 kinase (T389), as compared to empty vector control.	('increased', 'PosReg', (72, 81))	('T389', 'Var', (143, 147))	('T202/Y204', 'Var', (113, 122))	('phosphorylation', 'MPA', (86, 101))	('miR', 'Gene', (51, 54))	('ERK1/2', 'Gene', (105, 111))	('ERK1/2', 'Gene', '5595;5594', (105, 111))	('p70S6 kinase', 'MPA', (129, 141))	('miR', 'Gene', '29116', (51, 54))
41952	24705102	Therefore, we next sought to determine the contribution of PI3-kinase, ERK1/2, and mTOR Complex 1 (mTORC1) signaling to the activation of p70S6 kinase, which is phosphorylated in response to mTOR pathway activation.	('mTORC1', 'Gene', '382056', (99, 105))	('mTOR', 'Gene', (83, 87))	('mTOR', 'Gene', (191, 195))	('mTOR', 'Gene', '2475', (191, 195))	('ERK1/2', 'Gene', (71, 77))	('mTORC1', 'Gene', (99, 105))	('p70S6', 'Var', (138, 143))	('ERK1/2', 'Gene', '5595;5594', (71, 77))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))	('mTOR', 'Gene', '2475', (83, 87))
41953	24705102	LN229 cells stably expressing our miRNAs of interest were serum-starved for 24 h, pretreated with PI3-kinase inhibitor LY294002 (50 microM), MEK1 inhibitor U0126 (15 microM), or mTORC1 inhibitor rapamycin (10 nM) for 1 h, followed by 1 h treatment with 10% FBS.	('MEK1', 'Gene', (141, 145))	('LN229', 'CellLine', 'CVCL:0393', (0, 5))	('LY294002', 'Chemical', 'MESH:C085911', (119, 127))	('mTORC1', 'Gene', '382056', (178, 184))	('FBS', 'Disease', 'MESH:D005198', (257, 260))	('miR', 'Gene', (34, 37))	('mTORC1', 'Gene', (178, 184))	('rapamycin', 'Chemical', 'MESH:D020123', (195, 204))	('MEK1', 'Gene', '5604', (141, 145))	('U0126', 'Chemical', 'MESH:C113580', (156, 161))	('miR', 'Gene', '29116', (34, 37))	('LY294002', 'Var', (119, 127))	('FBS', 'Disease', (257, 260))
41957	24705102	A Western blot for phospho-AKT (S473) was conducted using lysates incubated with LY294002 and rapamycin (Figure 3C).	('AKT', 'Gene', (27, 30))	('LY294002', 'Chemical', 'MESH:C085911', (81, 89))	('AKT', 'Gene', '207', (27, 30))	('LY294002', 'Var', (81, 89))	('rapamycin', 'Chemical', 'MESH:D020123', (94, 103))
41958	24705102	As expected, LY294002 blocked AKT phosphorylation at S473 (Figure 3C, top panel) and rapamycin had no effect on AKT phosphorylation (Figure 3C, middle panel).	('blocked', 'NegReg', (22, 29))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('AKT', 'Gene', '207', (30, 33))	('AKT', 'Gene', '207', (112, 115))	('rapamycin', 'Chemical', 'MESH:D020123', (85, 94))	('LY294002', 'Var', (13, 21))	('AKT', 'Gene', (30, 33))	('AKT', 'Gene', (112, 115))
41959	24705102	MiRNA expression did not result in a significant increase of AKT phosphorylation, as compared to vector control.	('AKT', 'Gene', (61, 64))	('AKT', 'Gene', '207', (61, 64))	('MiRNA', 'Var', (0, 5))
41981	24705102	Expression levels of CYR61-targeting miRNAs (136, 155, and 634) in LN229 cells treated with fenofibrate were measured by quantitative real-time PCR (qRT-PCR) as described in the Experimental Section.	('CYR61', 'Gene', '3491', (21, 26))	('miR', 'Gene', (37, 40))	('136', 'Var', (45, 48))	('miR', 'Gene', '29116', (37, 40))	('LN229', 'CellLine', 'CVCL:0393', (67, 72))	('CYR61', 'Gene', (21, 26))	('fenofibrate', 'Chemical', 'MESH:D011345', (92, 103))
41994	24705102	LY294002 and U0126 were from Enzo Life Sciences (Farmingdale, NY, USA).	('LY294002', 'Var', (0, 8))	('U0126', 'Var', (13, 18))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))
42005	24705102	Phospho-p70S6 kinase (T389) (#9234), total p70S6 kinase (#2708), phospho-ERK1/2 (T202/Y204) (#9106), total ERK1/2 (#9102), phospho-AKT (S473) (#4060), total AKT (9272) and TSC2 (#4308) antibodies were purchased from Cell Signaling Technology (Beverly, MA, USA).	('T389) (#9234', 'Var', (22, 34))	('AKT', 'Gene', '207', (131, 134))	('ERK1/2', 'Gene', (107, 113))	('TSC2', 'Gene', '7249', (172, 176))	('TSC2', 'Gene', (172, 176))	('#4060', 'Var', (143, 148))	('#9234', 'Var', (29, 34))	('ERK1/2', 'Gene', '5595;5594', (107, 113))	('T202/Y204) (#9106', 'Var', (81, 98))	('AKT', 'Gene', (131, 134))	('ERK1/2', 'Gene', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (73, 79))	('AKT', 'Gene', '207', (157, 160))	('#9102', 'Var', (115, 120))	('#2708', 'Var', (57, 62))	('AKT', 'Gene', (157, 160))	('#4308', 'Var', (178, 183))
42007	24705102	Monoclonal antibodies specific to PP2A catalytic alpha subunit (610555) and GRB2 (610112) were from BD Transduction Laboratories (San Jose, CA, USA).	('GRB2', 'Gene', (76, 80))	('PP2A', 'Gene', '5524', (34, 38))	('GRB2', 'Gene', '2885', (76, 80))	('PP2A', 'Gene', (34, 38))	('610555', 'Var', (64, 70))	('610112', 'Var', (82, 88))
42069	24705102	Another recent report demonstrated that inhibition of clusterin-dependent ERK1/2 activation sensitized pancreatic cancer cells to gemcitabine treatment.	('inhibition', 'Var', (40, 50))	('pancreatic cancer', 'Disease', (103, 120))	('activation', 'PosReg', (81, 91))	('clusterin-dependent', 'Protein', (54, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('sensitized', 'Reg', (92, 102))	('ERK1/2', 'Gene', (74, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('gemcitabine', 'Chemical', 'MESH:C056507', (130, 141))	('ERK1/2', 'Gene', '5595;5594', (74, 80))
42170	33923028	Likewise, melatonin mediates the anti-angiogenic property in hypoxic PC-3 Prostate Cancer cells by upregulation of microRNA3195 and microRNA374b.	('hypoxic PC-3 Prostate Cancer', 'Disease', (61, 89))	('upregulation', 'PosReg', (99, 111))	('PC', 'Phenotype', 'HP:0012125', (69, 71))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('melatonin', 'Chemical', 'MESH:D008550', (10, 19))	('microRNA374b', 'Var', (132, 144))	('microRNA3195', 'Var', (115, 127))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (74, 89))	('hypoxic PC-3 Prostate Cancer', 'Disease', 'MESH:D011471', (61, 89))	('anti-angiogenic property', 'CPA', (33, 57))
42296	33923028	However, an increase in the survival rate in poor prognosis group has been demonstrated in melatonin-treated patients as compared to untreated patients.	('survival', 'MPA', (28, 36))	('patients', 'Species', '9606', (109, 117))	('melatonin-treated', 'Var', (91, 108))	('melatonin', 'Chemical', 'MESH:D008550', (91, 100))	('increase', 'PosReg', (12, 20))	('patients', 'Species', '9606', (143, 151))
42313	33923028	The results showed that co-administration of melatonin with gefitinib reduced the viability of H1975 cells with harbored T790M somatic mutation, as compared to HCC827 cells with an active epidermal growth factor receptor (EGFR) mutation.	('epidermal growth factor receptor', 'Gene', (188, 220))	('T790M', 'Var', (121, 126))	('reduced', 'NegReg', (70, 77))	('HCC827', 'CellLine', 'CVCL:2063', (160, 166))	('HCC', 'Phenotype', 'HP:0001402', (160, 163))	('epidermal growth factor receptor', 'Gene', '1956', (188, 220))	('EGFR', 'Gene', '1956', (222, 226))	('T790M', 'Mutation', 'rs121434569', (121, 126))	('melatonin', 'Chemical', 'MESH:D008550', (45, 54))	('viability', 'CPA', (82, 91))	('H1975', 'CellLine', 'CVCL:1511', (95, 100))	('EGFR', 'Gene', (222, 226))	('gefitinib', 'Chemical', 'MESH:D000077156', (60, 69))
42432	33923028	In studies combining melatonin with chemotherapy, adjuvant melatonin decreased one-year mortality (RR = 0.60; 95% CI = 0.54-0.67) and improved outcomes of stable disease, partial response, and complete response; statistically significant pooled RRs were 1.15, 1.70, and 2.53, respectively.	('improved', 'PosReg', (134, 142))	('mortality', 'Disease', 'MESH:D003643', (88, 97))	('complete', 'Disease', (193, 201))	('mortality', 'Disease', (88, 97))	('decreased', 'NegReg', (69, 78))	('melatonin', 'Chemical', 'MESH:D008550', (59, 68))	('one-year', 'CPA', (79, 87))	('adjuvant', 'Var', (50, 58))	('melatonin', 'Chemical', 'MESH:D008550', (21, 30))	('stable disease', 'Disease', (155, 169))	('partial', 'Disease', (171, 178))
42467	33923028	In those individuals taking melatonin, the overall tumor regression rate and the 5-year survival were elevated, together with an improved clinical tolerance to the pharmaceutical agents.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('5-year survival', 'CPA', (81, 96))	('elevated', 'PosReg', (102, 110))	('tumor', 'Disease', (51, 56))	('melatonin', 'Chemical', 'MESH:D008550', (28, 37))	('clinical', 'MPA', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('improved', 'PosReg', (129, 137))	('melatonin', 'Var', (28, 37))
42480	33923028	In a double-blind placebo-controlled randomized study, a reduced likelihood of presenting with symptoms suggestive of an affective disorder was reported in individuals administered 6 mg oral melatonin compared with those given a placebo.	('reduced', 'NegReg', (57, 64))	('6 mg', 'Var', (181, 185))	('affective disorder', 'Disease', (121, 139))	('melatonin', 'Chemical', 'MESH:D008550', (191, 200))
42680	32469935	IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment.	('tumor', 'Disease', (79, 84))	('IDO', 'Var', (0, 3))	('breakdown', 'MPA', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tryptophan', 'Chemical', 'MESH:D014364', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
42806	32469935	Other new IDO1 inhibitors have emerged, such as BMS-985205, PF-06850003, and navoximod, being investigated in preclinical and clinical research for different tumor types.	('tumor', 'Disease', (158, 163))	('PF-06850003', 'Var', (60, 71))	('IDO1', 'Gene', (10, 14))	('BMS-985205', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
42808	31552420	RNA binding candidates for human ADAR3 from substrates of a gain of function mutant expressed in neuronal cells Human ADAR3 is a catalytically inactive member of the Adenosine Deaminase Acting on RNA (ADAR) protein family, whose active members catalyze A-to-I RNA editing in metazoans.	('gain of function', 'PosReg', (60, 76))	('N', 'Chemical', 'MESH:D009584', (197, 198))	('human', 'Species', '9606', (27, 32))	('Human', 'Species', '9606', (112, 117))	('ADAR', 'Gene', (201, 205))	('ADAR3', 'Gene', (118, 123))	('ADAR', 'Gene', '103', (118, 122))	('Adenosine Deaminase Acting on RNA', 'Gene', (166, 199))	('ADAR3', 'Gene', '105', (33, 38))	('ADAR', 'Gene', (33, 37))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('ADAR', 'Gene', '103', (201, 205))	('mutant', 'Var', (77, 83))	('ADAR3', 'Gene', (33, 38))	('ADAR', 'Gene', '103', (33, 37))	('ADAR3', 'Gene', '105', (118, 123))	('N', 'Chemical', 'MESH:D009584', (261, 262))	('ADAR', 'Gene', (118, 122))	('Adenosine Deaminase Acting on RNA', 'Gene', '103', (166, 199))
42809	31552420	Five mutations (A389V, V485I, E527Q, Q549R and Q733D) engender RNA deaminase in human ADAR3.	('RNA', 'MPA', (63, 66))	('E527Q', 'Mutation', 'rs775206655', (30, 35))	('A389V', 'Mutation', 'rs538700330', (16, 21))	('Q549R', 'Mutation', 'rs199642258', (37, 42))	('Q733D', 'Mutation', 'p.Q733D', (47, 52))	('Q733D', 'Var', (47, 52))	('Q549R', 'Var', (37, 42))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('engender', 'Reg', (54, 62))	('V485I', 'Var', (23, 28))	('human', 'Species', '9606', (80, 85))	('E527Q', 'Var', (30, 35))	('V485I', 'Mutation', 'p.V485I', (23, 28))	('A389V', 'Var', (16, 21))
42813	31552420	Malfunctions in ADARs are associated with human diseases, including Aicardi-Goutieres Syndrome (AGS), Dyschromatosis symmetrica hereditaria (DSH) and cancers.	('Dyschromatosis symmetrica hereditaria', 'Disease', 'MESH:C535729', (102, 139))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('Aicardi-Goutieres Syndrome', 'Disease', 'MESH:C535607', (68, 94))	('Malfunctions', 'Var', (0, 12))	('Dyschromatosis symmetrica hereditaria', 'Disease', (102, 139))	('cancers', 'Disease', (150, 157))	('human', 'Species', '9606', (42, 47))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('AGS', 'Disease', 'MESH:C535607', (96, 99))	('AGS', 'Disease', (96, 99))	('ADAR', 'Gene', '103', (16, 20))	('Aicardi-Goutieres Syndrome', 'Disease', (68, 94))	('ADAR', 'Gene', (16, 20))	('associated', 'Reg', (26, 36))
42817	31552420	ADARs deaminate adenosines within duplex RNAs using a base-flipping mechanism.	('deaminate', 'Var', (6, 15))	('ADAR', 'Gene', (0, 4))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('adenosines', 'Chemical', 'MESH:D000241', (16, 26))	('ADAR', 'Gene', '103', (0, 4))
42821	31552420	There is also the intriguing possibility that ADAR3 targets and edits (or simply binds to) yet unidentified RNA substrates in the brain.	('edits', 'Var', (64, 69))	('ADAR3', 'Gene', (46, 51))	('binds', 'Interaction', (81, 86))	('N', 'Chemical', 'MESH:D009584', (109, 110))
42826	31552420	For instance, in vitro studies have shown that ADAR3 can inhibit editing on the 5-HT2cR RNA by ADAR1 and ADAR2.	('ADAR2', 'Gene', (105, 110))	('editing on the 5-HT2cR RNA', 'MPA', (65, 91))	('ADAR1', 'Gene', '103', (95, 100))	('inhibit', 'NegReg', (57, 64))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('ADAR1', 'Gene', (95, 100))	('ADAR3', 'Var', (47, 52))	('ADAR2', 'Gene', '104', (105, 110))
42830	31552420	On the other hand, ADAR3 may have a direct effect on the fate of cellular RNAs as an RNA binding protein, independent of RNA-editing.	('N', 'Chemical', 'MESH:D009584', (75, 76))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('effect', 'Reg', (43, 49))	('ADAR3', 'Var', (19, 24))	('N', 'Chemical', 'MESH:D009584', (86, 87))	('RNAs', 'Protein', (74, 78))
42834	31552420	Combining computational design using the Janus program and functional screening of ADAR2/ADAR3 chimeras, we enabled human ADAR3 as an active deaminase by introducing five point mutations in its deaminase domain.	('ADAR2', 'Gene', '104', (83, 88))	('mutations', 'Var', (177, 186))	('ADAR2', 'Gene', (83, 88))	('ADAR3', 'Gene', (122, 127))	('human', 'Species', '9606', (116, 121))
42838	31552420	Two particularly interesting novel targets are 3' UTRs of mRNAs of EGR1 and DUSP1, which are known to be activity-dependent immediate early genes that respond to stimuli in the brain.	('EGR1', 'Gene', (67, 71))	('DUSP1', 'Gene', (76, 81))	('mRNAs', 'Var', (58, 63))	('N', 'Chemical', 'MESH:D009584', (60, 61))
42862	31552420	To introduce mutations to hADAR3-D, QuikChange II XL site-directed mutagenesis kit (Agilent) was used.	('mutations', 'Var', (13, 22))	('hADAR3', 'Gene', (26, 32))	('hADAR3', 'Gene', '105', (26, 32))
42865	31552420	Point mutations were introduced into hADAR3 gene using QuikChange II XL site-directed mutagenesis kit.	('Point mutations', 'Var', (0, 15))	('hADAR3', 'Gene', (37, 43))	('hADAR3', 'Gene', '105', (37, 43))
42888	31552420	Following 48 h of induction, total RNAs were isolated from yeast cells (S. cerevisiae INVSc1 strain) overexpressing ADAR proteins using RiboPure-Yeast kit (Ambion).	('ADAR', 'Gene', (116, 120))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('overexpressing', 'Var', (101, 115))	('S. cerevisiae', 'Species', '4932', (72, 85))	('yeast', 'Species', '4932', (59, 64))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('ADAR', 'Gene', '103', (116, 120))	('Yeast', 'Species', '4932', (145, 150))
42903	31552420	Nested RT-PCR was performed on total RNA samples isolated from U87 cells transfected with hADAR3 M3 or hADAR3 M3 E434A plasmid DNA as described above for RNA-seq using Access RT-PCR kit (Promega) for 15 cycles and then followed by Phusion Hot Start DNA Polymerase (ThermoScientific) for the second PCR of 25 cycles.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('hADAR3', 'Gene', (103, 109))	('hADAR3', 'Gene', (90, 96))	('N', 'Chemical', 'MESH:D009584', (250, 251))	('hADAR3', 'Gene', '105', (103, 109))	('E434A', 'Mutation', 'p.E434A', (113, 118))	('E434A', 'Var', (113, 118))	('hADAR3', 'Gene', '105', (90, 96))	('Hot Start', 'Phenotype', 'HP:0031217', (239, 248))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('U87', 'Gene', '677775', (63, 66))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('U87', 'Gene', (63, 66))	('N', 'Chemical', 'MESH:D009584', (155, 156))
42919	31552420	For RT-qPCR, total RNA was used from cells overexpressing ADAR3 wild type or control (human ADAR2 deaminase domain mutant, ADAR2-D E396A).	('ADAR2', 'Gene', '104', (92, 97))	('ADAR2', 'Gene', (92, 97))	('ADAR2', 'Gene', '104', (123, 128))	('ADAR2', 'Gene', (123, 128))	('human', 'Species', '9606', (86, 91))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('ADAR3', 'Gene', (58, 63))	('E396A', 'Var', (131, 136))	('E396A', 'Mutation', 'p.E396A', (131, 136))
42924	31552420	Janus mutation scores were weighted by the distance of the residue to a reference site, which was the side chain OE2 atom of E434 in the ADAR3 homology model, the presumed proton transfer residue in the active site of ADAR3 (Figure 1A).	('OE2', 'Gene', '253738', (113, 116))	('OE2', 'Gene', (113, 116))	('E434', 'Var', (125, 129))
42927	31552420	This involved generating chimeric ADAR2/ADAR3 proteins.	('ADAR2', 'Gene', '104', (34, 39))	('ADAR2', 'Gene', (34, 39))	('chimeric', 'Var', (25, 33))
42928	31552420	ADAR2-D and ADAR3-D share high sequence similarity and are therefore likely to generate stable chimeras.	('ADAR2', 'Gene', (0, 5))	('ADAR3-D', 'Var', (12, 19))	('ADAR2', 'Gene', '104', (0, 5))
42931	31552420	Among the top eleven mutations, six (H387R, A389V, S411T, V435I, V436I, V485I) are located in the ADAR3 sequence in Chi322.	('V436I', 'Var', (65, 70))	('S411T', 'Var', (51, 56))	('V436I', 'Mutation', 'p.V436I', (65, 70))	('A389V', 'Var', (44, 49))	('V435I', 'Var', (58, 63))	('V485I', 'Var', (72, 77))	('A389V', 'Mutation', 'rs538700330', (44, 49))	('H387R', 'Var', (37, 42))	('V485I', 'Mutation', 'p.V485I', (72, 77))	('V435I', 'Mutation', 'rs763776977', (58, 63))	('H387R', 'Mutation', 'p.H387R', (37, 42))	('S411T', 'Mutation', 'p.S411T', (51, 56))
42932	31552420	Thus, to generate quantifiable fluorescence signal, an E to Q mutation at the base flipping residue (E527Q in hADAR3) known to enhance ADAR editing activity was introduced in Chi322.	('hADAR3', 'Gene', (110, 116))	('enhance', 'PosReg', (127, 134))	('ADAR', 'Gene', '103', (111, 115))	('activity', 'MPA', (148, 156))	('E527Q', 'Var', (101, 106))	('ADAR', 'Gene', '103', (135, 139))	('ADAR', 'Gene', (111, 115))	('hADAR3', 'Gene', '105', (110, 116))	('E527Q', 'Mutation', 'rs775206655', (101, 106))	('ADAR', 'Gene', (135, 139))
42935	31552420	Importantly, we found that mutation A389V increased the fluorescence signal by more than 20-fold, suggesting a substantial increase in the activity of the chimeric protein.	('increased', 'PosReg', (42, 51))	('A389V', 'Var', (36, 41))	('A389V', 'Mutation', 'rs538700330', (36, 41))	('increase', 'PosReg', (123, 131))	('activity', 'MPA', (139, 147))	('fluorescence signal', 'MPA', (56, 75))
42936	31552420	Another mutation, V485I, increased the fluorescence intensity by ~3-fold, suggesting that this mutation is also beneficial for activating the ADAR3 deaminase, albeit to a lesser extent.	('increased', 'PosReg', (25, 34))	('activating', 'MPA', (127, 137))	('ADAR3 deaminase', 'Enzyme', (142, 157))	('V485I', 'Mutation', 'p.V485I', (18, 23))	('fluorescence intensity', 'MPA', (39, 61))	('V485I', 'Var', (18, 23))
42937	31552420	Consistent with results from the fluorescent reporter assay, the colorimetric reporter assay showed that A389V mutation had the largest effect on editing activity of Chi322 and V485I had a beneficial but lesser effect whereas other mutations tested showed no effect (Supplementary Figure S3A-C).	('editing activity', 'MPA', (146, 162))	('A389V', 'Mutation', 'rs538700330', (105, 110))	('V485I', 'Mutation', 'p.V485I', (177, 182))	('V485I', 'Var', (177, 182))	('Chi322', 'Gene', (166, 172))	('A389V', 'Var', (105, 110))
42938	31552420	The other active chimeric protein that was identified, Chi223, contains hADAR3 sequence spanning aa667- aa739.	('hADAR3', 'Gene', (72, 78))	('aa667-', 'Var', (97, 103))	('hADAR3', 'Gene', '105', (72, 78))
42941	31552420	We carried out a second Janus prediction using NZ of K700 near the IHP molecule as the reference site, generating a new list of candidate mutations shown in Table 2.	('IHP', 'Chemical', 'MESH:C057613', (67, 70))	('K700', 'Var', (53, 57))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('mutations', 'Var', (138, 147))
42943	31552420	Importantly, introducing this mutation to Chi223 clearly increased signal in the colorimetric reporter assay to a level comparable to that of wild type ADAR2 (Figure 1D, Supplementary Figure S3D), indicating this mutation is beneficial for activating ADAR3.	('signal', 'MPA', (67, 73))	('colorimetric reporter assay', 'MPA', (81, 108))	('mutation', 'Var', (30, 38))	('ADAR3', 'Gene', (251, 256))	('ADAR2', 'Gene', '104', (152, 157))	('ADAR2', 'Gene', (152, 157))	('increased', 'PosReg', (57, 66))
42944	31552420	It is known that an E to Q mutation at the base flipping residue of either ADAR1 or ADAR2 increases activities of both enzymes substantially.	('ADAR1', 'Gene', '103', (75, 80))	('E to Q mutation', 'Var', (20, 35))	('activities', 'MPA', (100, 110))	('increases', 'PosReg', (90, 99))	('ADAR1', 'Gene', (75, 80))	('ADAR2', 'Gene', '104', (84, 89))	('ADAR2', 'Gene', (84, 89))
42945	31552420	We converted the putative base flipping residue of human ADAR3 (E527) to a Q, giving rise to a single point mutant hADAR3-D protein (M1) with no detectable editing activity, indicating that the E527Q mutation alone is not sufficient to activate the deaminase (Figure 2A).	('hADAR3', 'Gene', (115, 121))	('hADAR3', 'Gene', '105', (115, 121))	('E527Q', 'Var', (194, 199))	('human', 'Species', '9606', (51, 56))	('E527Q', 'Mutation', 'rs775206655', (194, 199))	('E527', 'Var', (64, 68))
42946	31552420	We then introduced the three activity-improving mutations identified above (A389V, V485I and Q733D), giving rise to mutant hADAR3-D M2.	('V485I', 'Var', (83, 88))	('hADAR3', 'Gene', '105', (123, 129))	('A389V', 'Mutation', 'rs538700330', (76, 81))	('V485I', 'Mutation', 'p.V485I', (83, 88))	('hADAR3', 'Gene', (123, 129))	('A389V', 'Var', (76, 81))	('Q733D', 'Mutation', 'p.Q733D', (93, 98))	('Q733D', 'Var', (93, 98))	('mutant', 'Var', (116, 122))
42949	31552420	the orphan base), when mutated to the corresponding residue in ADAR3 (glutamine at position 549), led to a substantial decrease in the deamination efficiency of ADAR2.	('decrease', 'NegReg', (119, 127))	('ADAR2', 'Gene', '104', (161, 166))	('ADAR2', 'Gene', (161, 166))	('mutated', 'Var', (23, 30))	('deamination efficiency', 'MPA', (135, 157))	('glutamine', 'Chemical', 'MESH:C578860', (70, 79))
42950	31552420	This suggests that Q549 in ADAR3 may be activity inhibiting.	('Q549', 'Var', (19, 23))	('Q549', 'CellLine', 'CVCL:0023', (19, 23))	('ADAR3', 'Gene', (27, 32))	('activity', 'MPA', (40, 48))
42951	31552420	Importantly, Q549R is one of the top ranked mutations predicted by Janus for activating ADAR3 using either reference site (Table 1, Table 2).	('Q549R', 'Mutation', 'rs199642258', (13, 18))	('Q549R', 'Var', (13, 18))	('activating', 'MPA', (77, 87))	('ADAR3', 'Gene', (88, 93))
42952	31552420	We thus further introduced the Q549R mutation into hADAR3-D M2, giving rise to mutant hADAR3-D M3.	('hADAR3', 'Gene', (86, 92))	('hADAR3', 'Gene', (51, 57))	('Q549R', 'Var', (31, 36))	('hADAR3', 'Gene', '105', (51, 57))	('mutant', 'Var', (79, 85))	('hADAR3', 'Gene', '105', (86, 92))	('Q549R', 'Mutation', 'rs199642258', (31, 36))
42955	31552420	The mutant protein showed clear editing activity on a segment of the yeast bromodomain factor 2 mRNA, the same type of substrate used in the reporter assays (Figure 1B), with a kobs of 0.076 +- 0.0045 min-1 (Figure 2B, C).	('mutant', 'Var', (4, 10))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('editing', 'MPA', (32, 39))	('kobs', 'Species', '59530', (177, 181))	('yeast', 'Species', '4932', (69, 74))
42961	31552420	On these RNAs, we further tested whether the full length hADAR3 bearing the M3 mutations could also perform editing in yeast cells.	('tested', 'Reg', (26, 32))	('hADAR3', 'Gene', (57, 63))	('yeast', 'Species', '4932', (119, 124))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('hADAR3', 'Gene', '105', (57, 63))	('mutations', 'Var', (79, 88))
42965	31552420	These simulations suggest that the distance between the zinc-coordinated hydroxyl group and the C6 position of the reactive purine in the complex with wild type ADAR3-D is longer than those in complexes of ADAR2-D and ADAR3-D M3 (Supplementary Figure S7).	('ADAR2', 'Gene', '104', (206, 211))	('ADAR2', 'Gene', (206, 211))	('hydroxyl', 'Chemical', 'MESH:D017665', (73, 81))	('ADAR3-D', 'Var', (161, 168))	('purine', 'Chemical', 'MESH:D011687', (124, 130))
42966	31552420	Having shown that the mutant hADAR3-D M3 could efficiently catalyze deamination on various RNAs both in vitro and in yeast cells, we turned our attention to identifying RNA substrates in human cells.	('RNAs', 'Protein', (91, 95))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('hADAR3', 'Gene', (29, 35))	('hADAR3', 'Gene', '105', (29, 35))	('yeast', 'Species', '4932', (117, 122))	('mutant', 'Var', (22, 28))	('human', 'Species', '9606', (187, 192))	('deamination', 'MPA', (68, 79))	('N', 'Chemical', 'MESH:D009584', (170, 171))
42970	31552420	Inspired by this method, we envisioned a similar approach that would use full length hADAR3 M3 bearing the five mutations to identify the binding targets of wild type human ADAR3.	('mutations', 'Var', (112, 121))	('hADAR3', 'Gene', (85, 91))	('hADAR3', 'Gene', '105', (85, 91))	('human', 'Species', '9606', (167, 172))
42973	31552420	5' or 3' binding loop), although two mutations (E527Q and Q549R) are expected to enhance contacts important for stabilizing the base-flipped RNA conformation necessary for deamination (see below).	('E527Q', 'Var', (48, 53))	('deamination', 'MPA', (172, 183))	('E527Q', 'Mutation', 'rs775206655', (48, 53))	('Q549R', 'Mutation', 'rs199642258', (58, 63))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('base-flipped RNA conformation', 'MPA', (128, 157))	('contacts', 'MPA', (89, 97))	('enhance', 'PosReg', (81, 88))	('Q549R', 'Var', (58, 63))
42974	31552420	Therefore, RNA binding selectivity by hADAR3 is expected to be minimally altered by the mutations introduced, and the editing targets of the active full length hADAR3 M3 mutant should represent binding targets of the wild type hADAR3.	('M3 mutant', 'Var', (167, 176))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('hADAR3', 'Gene', '105', (227, 233))	('hADAR3', 'Gene', '105', (38, 44))	('hADAR3', 'Gene', (160, 166))	('mutant', 'Var', (170, 176))	('hADAR3', 'Gene', '105', (160, 166))	('hADAR3', 'Gene', (38, 44))	('RNA', 'MPA', (11, 14))	('hADAR3', 'Gene', (227, 233))
42975	31552420	As a control, an inactivated mutant of hADAR3 M3 generated by mutating the proton transfer residue E434 to an alanine was used to account for competitive binding by hADAR3.	('hADAR3', 'Gene', '105', (165, 171))	('binding', 'Interaction', (154, 161))	('mutating', 'Var', (62, 70))	('alanine', 'Chemical', 'MESH:D000409', (110, 117))	('hADAR3', 'Gene', (39, 45))	('hADAR3', 'Gene', '105', (39, 45))	('E434', 'Var', (99, 103))	('hADAR3', 'Gene', (165, 171))
42978	31552420	The full-length hADAR3 M3 and its inactive mutant E434A were similarly expressed in U87 cells (Supplementary Figure S8).	('E434A', 'Mutation', 'p.E434A', (50, 55))	('E434A', 'Var', (50, 55))	('U87', 'Gene', (84, 87))	('hADAR3', 'Gene', (16, 22))	('U87', 'Gene', '677775', (84, 87))	('hADAR3', 'Gene', '105', (16, 22))
42979	31552420	Before identifying potential transcriptome-wide editing targets of hADAR3 M3, we performed reverse transcription followed by PCR to amplify regions surrounding the editing site in glioma factor 1 (GLI1) mRNA on total RNA isolated from cells to evaluate the method.	('N', 'Chemical', 'MESH:D009584', (218, 219))	('N', 'Chemical', 'MESH:D009584', (205, 206))	('glioma factor 1', 'Gene', (180, 195))	('hADAR3', 'Gene', (67, 73))	('GLI1', 'Gene', '2735', (197, 201))	('editing', 'Var', (164, 171))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('hADAR3', 'Gene', '105', (67, 73))	('GLI1', 'Gene', (197, 201))	('glioma factor 1', 'Gene', '2735', (180, 195))
43007	31552420	Importantly, hADAR3 expression caused an increase in measured transcript levels for both DUSP1 (2.1 +- 0.3-fold) and EGR1 (5 +- 1-fold), whereas beta-actin and GAPDH transcripts are unaffected (Figure 4E).	('EGR1', 'Gene', (117, 121))	('increase', 'PosReg', (41, 49))	('measured transcript levels', 'MPA', (53, 79))	('expression', 'Var', (20, 30))	('GAPDH', 'Gene', '2597', (160, 165))	('hADAR3', 'Gene', (13, 19))	('DUSP1', 'Gene', (89, 94))	('GAPDH', 'Gene', (160, 165))	('hADAR3', 'Gene', '105', (13, 19))
43008	31552420	For comparison, we also expressed an RNA-binding and deaminase deficient mutant of human ADAR2 (ADAR2-D E396A) and this had no effect on DUSP1 or EGR1 transcript levels (Figure 4E).	('E396A', 'Mutation', 'p.E396A', (104, 109))	('ADAR2', 'Gene', '104', (89, 94))	('ADAR2', 'Gene', (89, 94))	('human', 'Species', '9606', (83, 88))	('ADAR2', 'Gene', '104', (96, 101))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('ADAR2', 'Gene', (96, 101))	('RNA-binding', 'Interaction', (37, 48))	('DUSP1', 'MPA', (137, 142))	('EGR1 transcript levels', 'MPA', (146, 168))	('E396A', 'Var', (104, 109))
43011	31552420	However, CLIP-seq requires large amounts of RNA as starting materials, suffers from high level of non-specific crosslinking, exhibits low cross-linking efficiency for dsRNA binding proteins as well as prevents downstream analysis of binding sites due to the introduction of sequencing errors at the sites of crosslinking.	('binding', 'Interaction', (233, 240))	('cross-linking', 'MPA', (138, 151))	('low', 'NegReg', (134, 137))	('sequencing', 'Var', (274, 284))	('N', 'Chemical', 'MESH:D009584', (170, 171))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('dsRNA binding', 'Protein', (167, 180))	('prevents', 'NegReg', (201, 209))
43019	31552420	Using this approach, we identified candidate mutations to convert ADAR3 into an active RNA deaminase.	('mutations', 'Var', (45, 54))	('ADAR3', 'Gene', (66, 71))	('convert', 'Reg', (58, 65))	('N', 'Chemical', 'MESH:D009584', (88, 89))
43020	31552420	A subset of these mutations were then tested in ADAR2/ADAR3 chimeric proteins to determine their effect on activity.	('activity', 'MPA', (107, 115))	('ADAR2', 'Gene', '104', (48, 53))	('ADAR2', 'Gene', (48, 53))	('tested', 'Reg', (38, 44))	('mutations', 'Var', (18, 27))
43021	31552420	With this strategy we identified four relatively conservative mutations (A389V, V485I, Q549R and Q733D) that, along with the known deaminase-activating mutation E527Q, activated the ADAR3 deaminase.	('Q549R', 'Var', (87, 92))	('E527Q', 'Mutation', 'rs775206655', (161, 166))	('ADAR3 deaminase', 'Enzyme', (182, 197))	('Q733D', 'Mutation', 'p.Q733D', (97, 102))	('V485I', 'Var', (80, 85))	('V485I', 'Mutation', 'p.V485I', (80, 85))	('A389V', 'Var', (73, 78))	('activated', 'PosReg', (168, 177))	('E527Q', 'Var', (161, 166))	('Q549R', 'Mutation', 'rs199642258', (87, 92))	('A389V', 'Mutation', 'rs538700330', (73, 78))	('Q733D', 'Var', (97, 102))
43023	31552420	The A389V mutation is at a location in ADAR3 corresponding to V351 in human ADAR2.	('A389V', 'Var', (4, 9))	('A389V', 'Mutation', 'rs538700330', (4, 9))	('human', 'Species', '9606', (70, 75))	('ADAR2', 'Gene', '104', (76, 81))	('ADAR2', 'Gene', (76, 81))	('V351', 'Var', (62, 66))
43024	31552420	In crystal structures of the ADAR2 deaminase domain bound to RNA bearing a transition state analog (8-azaN hydrate) at the editing site, the side chain of V351 provides a hydrophobic surface that anchors the edited base in position for catalysis (Figure 5A).	('N', 'Chemical', 'MESH:D009584', (105, 106))	('ADAR2', 'Gene', (29, 34))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('8-azaN hydrate', 'Chemical', 'MESH:C034930', (100, 114))	('ADAR2', 'Gene', '104', (29, 34))	('V351', 'Var', (155, 159))
43026	31552420	The V485I mutation corresponds to I446 in ADAR2.	('V485I', 'Mutation', 'p.V485I', (4, 9))	('I446', 'Var', (34, 38))	('ADAR2', 'Gene', '104', (42, 47))	('ADAR2', 'Gene', (42, 47))	('V485I', 'Var', (4, 9))
43028	31552420	The Q549R and E527Q mutations alter residues involved in stabilizing the base-flipped conformation of the nucleotide opposite the editing site (i.e.	('E527Q', 'Var', (14, 19))	('base-flipped conformation of the nucleotide', 'MPA', (73, 116))	('alter', 'Reg', (30, 35))	('E527Q', 'Mutation', 'rs775206655', (14, 19))	('Q549R', 'Mutation', 'rs199642258', (4, 9))	('stabilizing', 'MPA', (57, 68))	('Q549R', 'Var', (4, 9))
43029	31552420	Finally, the Q733D mutation (corresponding to D695 in ADAR2) is located at the IHP binding site.	('ADAR2', 'Gene', '104', (54, 59))	('ADAR2', 'Gene', (54, 59))	('D695', 'Var', (46, 50))	('Q733D', 'Var', (13, 18))	('Q733D', 'Mutation', 'p.Q733D', (13, 18))	('IHP', 'Chemical', 'MESH:C057613', (79, 82))
43030	31552420	The side chain of D695 is involved in water-mediated hydrogen bonding to an IHP phosphate, and a glutamine at this location is likely to disrupt this interaction (Figure 5D).	('IHP phosphate', 'Chemical', 'MESH:C057613', (76, 89))	('glutamine', 'Chemical', 'MESH:C578860', (97, 106))	('IHP phosphate', 'MPA', (76, 89))	('involved', 'Reg', (26, 34))	('D695', 'Var', (18, 22))	('hydrogen', 'Chemical', 'MESH:D006859', (53, 61))	('interaction', 'Interaction', (150, 161))	('disrupt', 'NegReg', (137, 144))
43031	31552420	Results from a molecular dynamics simulation were consistent with the notion that the five mutations stabilize a conformation of the protein-RNA complex involving close approach of the reactive zinc-hydroxide to adenine C6 (Supplementary Figure S5).	('stabilize', 'Reg', (101, 110))	('zinc-hydroxide', 'Chemical', 'MESH:C052745', (194, 208))	('adenine C6', 'Chemical', 'MESH:D000225', (212, 222))	('mutations', 'Var', (91, 100))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('conformation', 'MPA', (113, 125))
43037	31552420	We believe that expression of ADAR3 along with knocking down ADAR1 and/or ADAR2 to decrease RNA editing background would significantly expand the ADAR3-editing list reported in this study.	('ADAR2', 'Gene', (74, 79))	('ADAR1', 'Gene', '103', (61, 66))	('ADAR3', 'Gene', (30, 35))	('RNA editing', 'MPA', (92, 103))	('ADAR2', 'Gene', '104', (74, 79))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('knocking down', 'Var', (47, 60))	('ADAR1', 'Gene', (61, 66))
43038	31552420	Besides, prior to performing RNA-seq, we found that editing on the Gli1 RNA, which is also edited by both ADAR1 and ADAR2, was improved from ~10% upon overexpression of inactive hADAR3 M3 E434A to around 17% with overexpressed hADAR3 M3 (Supplementary Figure S8).	('N', 'Chemical', 'MESH:D009584', (73, 74))	('hADAR3', 'Gene', '105', (227, 233))	('hADAR3', 'Gene', '105', (178, 184))	('editing', 'MPA', (52, 59))	('ADAR2', 'Gene', '104', (116, 121))	('ADAR2', 'Gene', (116, 121))	('ADAR1', 'Gene', (106, 111))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('E434A', 'Mutation', 'p.E434A', (188, 193))	('E434A', 'Var', (188, 193))	('ADAR1', 'Gene', '103', (106, 111))	('Gli1', 'Gene', (67, 71))	('hADAR3', 'Gene', (178, 184))	('Gli1', 'Gene', '2735', (67, 71))	('improved', 'PosReg', (127, 135))	('hADAR3', 'Gene', (227, 233))
43057	31552420	Further improvement of the mutant will be possible, with potential application in site-directed RNA editing, given the efficient editing activity and distinct deamination specificity exhibited by the ADAR3 mutant compared to ADAR1 and ADAR2.	('deamination', 'MPA', (159, 170))	('mutant', 'Var', (206, 212))	('ADAR1', 'Gene', (225, 230))	('editing', 'MPA', (129, 136))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('ADAR3', 'Gene', (200, 205))	('ADAR1', 'Gene', '103', (225, 230))	('ADAR2', 'Gene', '104', (235, 240))	('ADAR2', 'Gene', (235, 240))
43065	31576243	Furthermore, the co-expressed networks of dysregulated RBPs with transcriptional factors and lncRNAs also require further investigation.	('ncRNA', 'Gene', '220202', (94, 99))	('dysregulated', 'Var', (42, 54))	('RBP', 'Gene', (55, 58))	('RBP', 'Gene', '57794', (55, 58))	('ncRNA', 'Gene', (94, 99))
43076	31576243	Furthermore, dysregulated expression of some RBPs can lead to disease, including neurological disorders and cancers.	('disease', 'Disease', (62, 69))	('expression', 'MPA', (26, 36))	('lead to', 'Reg', (54, 61))	('neurological disorders', 'Disease', 'MESH:D009422', (81, 103))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('RBP', 'Gene', (45, 48))	('RBP', 'Gene', '57794', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('neurological disorders', 'Disease', (81, 103))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('dysregulated', 'Var', (13, 25))	('cancers', 'Disease', (108, 115))
43082	31576243	Silencing RPL34 plays a blocking role in cell proliferation and metastasis, but promoting cell apoptosis of oral squamous cell carcinomas (OSCCs).	('RPL34', 'Gene', '6164', (10, 15))	('OSCCs', 'Disease', (139, 144))	('OSCCs', 'Disease', 'MESH:D002294', (139, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('promoting', 'PosReg', (80, 89))	('cell apoptosis', 'CPA', (90, 104))	('RPL34', 'Gene', (10, 15))	('metastasis', 'CPA', (64, 74))	('Silencing', 'Var', (0, 9))	('oral squamous cell carcinomas', 'Disease', (108, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 137))
43086	31576243	In addition, the silencing of SRSF7 affects the expression of osteopontin splice variants and decreases the proliferation rate of renal cancer cells.	('renal cancer', 'Disease', (130, 142))	('affects', 'Reg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('SRSF7', 'Gene', (30, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (130, 142))	('SRSF7', 'Gene', '6432', (30, 35))	('expression', 'MPA', (48, 58))	('renal cancer', 'Disease', 'MESH:D007680', (130, 142))	('decreases', 'NegReg', (94, 103))	('silencing', 'Var', (17, 26))	('osteopontin', 'Gene', '6696', (62, 73))	('osteopontin', 'Gene', (62, 73))
43098	31576243	An accumulating genome-wide association study (GWAS) shows that the mutations of TFs or TF-binding sites are closely related to many human cancers (reviewed in), such as gastric cancer, liver cancer, prostate cancer, colorectal cancer and breast cancer.	('breast cancer', 'Disease', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('cancers', 'Disease', (139, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('colorectal cancer', 'Disease', (217, 234))	('liver cancer', 'Disease', 'MESH:D006528', (186, 198))	('prostate cancer', 'Disease', (200, 215))	('related', 'Reg', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('liver cancer', 'Phenotype', 'HP:0002896', (186, 198))	('human', 'Species', '9606', (133, 138))	('liver cancer', 'Disease', (186, 198))	('TFs', 'Gene', (81, 84))	('gastric cancer', 'Disease', (170, 184))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (68, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
43136	31576243	Generally, in the TNM system, 'T' refers to a primary tumor, 'T1 ~ T4' represents the severity of primary cancer according to the increase in tumor volume and the extent of involvement of adjacent tissues, and 'T0' indicates no primary tumor.	("'T1 ~ T4'", 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('TNM', 'Disease', 'MESH:D009362', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('increase', 'PosReg', (130, 138))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (236, 241))	('TNM', 'Disease', (18, 21))
43197	31576243	These results suggest that dysregulated RBPs play a key role in the regulation of the development of the CHOL and KICH M-stage, which may provide a new perspective for potential prognostic biomarkers and therapeutic targets for patients with cancers at M stages in two cancer types CHOL and KICH.	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('patients', 'Species', '9606', (228, 236))	('CHOL', 'Phenotype', 'HP:0030153', (282, 286))	('RBP', 'Gene', '57794', (40, 43))	('dysregulated', 'Var', (27, 39))	('CHOL', 'Phenotype', 'HP:0030153', (105, 109))	('RBP', 'Gene', (40, 43))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
43202	31576243	Functional enrichment analyzing demonstrated that cluster 1 and cluster 3 had similar functions and mainly enriched in functional categories involved in gene silencing and negative regulation of translation, such as post transcriptional gene silencing, negative regulation of translation and cellular amide metabolic process, cellular response to dsRNA, miRNA metabolic process.	('negative regulation', 'NegReg', (253, 272))	('translation', 'MPA', (276, 287))	('negative regulation', 'NegReg', (172, 191))	('amide', 'Chemical', 'MESH:D000577', (301, 306))	('miRNA', 'CPA', (354, 359))	('gene silencing', 'Var', (237, 251))	('cellular', 'CPA', (326, 334))	('translation', 'MPA', (195, 206))	('cellular amide metabolic process', 'MPA', (292, 324))	('involved', 'Reg', (141, 149))	('gene silencing', 'Var', (153, 167))
43213	31576243	First, we found the five largest transcription factor families, they are C2H2-ZF, Homeodomain, Nuclear receptor, bHLH and bZIP, and the corresponding proportion is 37%, 17%, 9%, 9% and 9% (Figs.	('C2H2-ZF', 'Var', (73, 80))	('C2H2', 'Chemical', 'MESH:C543495', (73, 77))	('bHLH', 'Gene', (113, 117))
43260	31326657	Overall, there was a significant increase in survival of mice co-treated with T7-polyGIONs loaded with miR-100/antimiR-21 plus systemic TMZ, compared to the untreated control group, or the animals receiving non-targeted polyGIONs-miR-100/antimiR-21, or TMZ alone.	('mice', 'Species', '10090', (57, 61))	('polyGIONs', 'Chemical', '-', (220, 229))	('T7-polyGIONs', 'Var', (78, 90))	('T7-polyGIONs', 'Chemical', '-', (78, 90))	('TMZ', 'Chemical', 'MESH:D000077204', (253, 256))	('increase', 'PosReg', (33, 41))	('survival', 'CPA', (45, 53))	('polyGIONs', 'Chemical', '-', (81, 90))	('miR-100/antimiR-21', 'Var', (103, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (136, 139))
43274	31326657	Thus, it would be advantageous to investigate the combined therapeutic effect of miR-100 and antimiR-21 in improving TMZ therapy, which is the present fist line standard clinical therapeutic drug for GBM patients, especially on p53 wildtype and mutant GBM cells.	('TMZ', 'MPA', (117, 120))	('patients', 'Species', '9606', (204, 212))	('TMZ', 'Chemical', 'MESH:D000077204', (117, 120))	('mutant', 'Var', (245, 251))	('miR-100', 'Gene', (81, 88))	('GBM', 'Phenotype', 'HP:0012174', (252, 255))	('GBM', 'Phenotype', 'HP:0012174', (200, 203))	('p53', 'Var', (228, 231))
43276	31326657	To improve the delivery of synthetic miRNA mimics and antisense miRNAs in patients, and to reduce their degradation in the systemic circulation, various delivery systems have been proposed for clinical translation.	('reduce', 'NegReg', (91, 97))	('miR', 'Gene', (37, 40))	('antisense', 'Var', (54, 63))	('delivery', 'MPA', (15, 23))	('improve', 'PosReg', (3, 10))	('miR', 'Gene', (64, 67))	('patients', 'Species', '9606', (74, 82))	('miR', 'Gene', '751557', (37, 40))	('miR', 'Gene', '751557', (64, 67))	('degradation in the systemic circulation', 'MPA', (104, 143))
43294	31326657	Comparing the FTIR spectra of chitin and 6-OTs-chitin shows that the 1602 cm-1 absorption peak resulted from stretching vibration of the benzene ring, while the C-H bending vibration of the benzene ring were assigned at 811 cm-1 and 677 cm-1.	('benzene', 'Chemical', 'MESH:D001554', (190, 197))	('6-OTs-chitin', 'Chemical', '-', (41, 53))	('1602 cm-1', 'Var', (69, 78))	('benzene', 'Chemical', 'MESH:D001554', (137, 144))	('chitin', 'Chemical', 'MESH:D002686', (30, 36))	('chitin', 'Chemical', 'MESH:D002686', (47, 53))	('resulted from', 'Reg', (95, 108))	('C-H bending', 'MPA', (161, 172))	('stretching vibration', 'MPA', (109, 129))
43296	31326657	After nucleophilic substitution with CDen, the absorption peaks at 1347 cm-1 and 1175 cm-1 from the tosyl group disappeared.	('absorption', 'MPA', (47, 57))	('CDen', 'Chemical', '-', (37, 41))	('nucleophilic substitution', 'Var', (6, 31))
43299	31326657	All of these observations indicated that p-toluene sulfonyl ester on the C6 position of chitin was displaced by nucleophilic substitution with CDen.	('chitin', 'Chemical', 'MESH:D002686', (88, 94))	('CDen', 'Chemical', '-', (143, 147))	('p-toluene sulfonyl ester', 'MPA', (41, 65))	('nucleophilic substitution', 'Var', (112, 137))	('p-toluene sulfonyl ester', 'Chemical', '-', (41, 65))
43352	31326657	At every time point of analysis, the cellular uptake level of Cy5-miRNAs was higher in the case of T7 functionalized nanoparticles.	('T7 functionalized', 'Var', (99, 116))	('higher', 'PosReg', (77, 83))	('miR', 'Gene', (66, 69))	('Cy5', 'Chemical', 'MESH:C085321', (62, 65))	('T7', 'Chemical', '-', (99, 101))	('miR', 'Gene', '751557', (66, 69))
43353	31326657	For instance, at 4 h, mean Cy5 fluorescence of internalized miRNA was 1120 au in case of non-targeted nanoparticles, whereas in the case of T7 targeted nanoparticles, mean Cy5 fluorescence intensity of cells was 2045 au.	('non-targeted nanoparticles', 'Var', (89, 115))	('miR', 'Gene', (60, 63))	('Cy5 fluorescence', 'MPA', (27, 43))	('miR', 'Gene', '751557', (60, 63))	('Cy5', 'Chemical', 'MESH:C085321', (27, 30))	('Cy5', 'Chemical', 'MESH:C085321', (172, 175))	('T7', 'Chemical', '-', (140, 142))
43354	31326657	Thus, with significance of p<0.0001 T7-mediated targeting increased cellular uptake in U87-MG cells by 1.82 fold higher at 4 h of incubation.	('cellular uptake', 'CPA', (68, 83))	('increased', 'PosReg', (58, 67))	('higher', 'PosReg', (113, 119))	('U87-MG', 'CellLine', 'CVCL:0022', (87, 93))	('T7', 'Chemical', '-', (36, 38))	('T7-mediated', 'Var', (36, 47))
43360	31326657	The surface modification of these nanoparticles with T7 peptide further improved the nanoparticle internalization by targeting the transferrin receptor-mediated endocytosis in cancer cells.	('improved', 'PosReg', (72, 80))	('nanoparticle internalization', 'MPA', (85, 113))	('transferrin receptor', 'Gene', (131, 151))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('T7', 'Chemical', '-', (53, 55))	('peptide', 'Chemical', 'MESH:D010455', (56, 63))	('targeting', 'Reg', (117, 126))	('T7 peptide', 'Var', (53, 63))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('transferrin receptor', 'Gene', '22042', (131, 151))
43364	31326657	We observed in cell populations treated with T7 peptide functionalized polyGIONs that there were significantly (P < 0.05) higher levels of fluorescence signal compared to cells treated with non-targeted CD-CS-polyGIONs.	('polyGIONs', 'Var', (71, 80))	('peptide', 'Chemical', 'MESH:D010455', (48, 55))	('polyGIONs', 'Chemical', '-', (209, 218))	('levels of fluorescence signal', 'MPA', (129, 158))	('T7', 'Chemical', '-', (45, 47))	('higher', 'PosReg', (122, 128))	('polyGIONs', 'Chemical', '-', (71, 80))	('CD-CS-polyGIONs', 'Chemical', '-', (203, 218))
43366	31326657	The cells treated with non-targeted polyGIONs showed a clear increase in miRNA levels compared to bare miRNA treated cells, but much lower than with use of targeted nanoparticles.	('miR', 'Gene', '751557', (73, 76))	('polyGIONs', 'Var', (36, 45))	('miR', 'Gene', '751557', (103, 106))	('miR', 'Gene', (103, 106))	('increase', 'PosReg', (61, 69))	('miR', 'Gene', (73, 76))	('lower', 'NegReg', (133, 138))	('polyGIONs', 'Chemical', '-', (36, 45))
43373	31326657	Further analysis of size and charge of these nanoparticles revealed that the higher extent of T7 functionalization led to an increase in size of the nanoparticles from 53 nm to 65 nm owing to higher instance of CD-adamantine interaction.	('CD-adamantine', 'MPA', (211, 224))	('T7', 'Chemical', '-', (94, 96))	('increase', 'PosReg', (125, 133))	('CD-adamantine', 'Chemical', '-', (211, 224))	('higher', 'PosReg', (192, 198))	('size', 'MPA', (137, 141))	('T7 functionalization', 'Var', (94, 114))	('interaction', 'Interaction', (225, 236))
43377	31326657	We showed in the miRNA uptake results that we achieved the highest labeling in cells treated with T7 functionalized CD-CS-polyGIONs, followed by marginally lower levels in non-targeted polyGIONs.	('polyGIONs', 'Chemical', '-', (122, 131))	('T7 functionalized', 'Var', (98, 115))	('polyGIONs', 'Chemical', '-', (185, 194))	('miR', 'Gene', (17, 20))	('labeling', 'MPA', (67, 75))	('CD-CS-polyGIONs', 'Chemical', '-', (116, 131))	('T7', 'Chemical', '-', (98, 100))	('miR', 'Gene', '751557', (17, 20))
43380	31326657	We subsequently used the optimized formulation of T7 functionalized CD-CS-polyGIONs for co-delivery of antimiR-21 and miR-100 in U87-MG cells.	('U87-MG', 'CellLine', 'CVCL:0022', (129, 135))	('miR-100', 'Gene', (118, 125))	('T7', 'Chemical', '-', (50, 52))	('antimiR-21', 'Var', (103, 113))	('mul', 'Gene', (38, 41))	('CD-CS-polyGIONs', 'Chemical', '-', (68, 83))	('mul', 'Gene', '68729', (38, 41))
43389	31326657	We tested the functional effects of antimiR-21 and miR-100 combinations (delivered using CD-CS-polyGIONs) in improving sensitivity of GBM cells to TMZ chemotherapy.	('miR-100', 'Gene', (51, 58))	('combinations', 'Var', (59, 71))	('improving', 'PosReg', (109, 118))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('tested', 'Reg', (3, 9))	('antimiR-21', 'Gene', (36, 46))	('CD-CS-polyGIONs', 'Chemical', '-', (89, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (147, 150))	('sensitivity', 'MPA', (119, 130))
43390	31326657	We investigated in U87-MG cells the antiproliferative and cytotoxic effects of T7-targeted and non-targeted CD-CS-polyGIONs co-delivering antimiR-21 (50 pmol) and miR-100 (50 pmol), with or without TMZ (100 muM or 250 muM) treatment (Figure 3E).	('CD-CS-polyGIONs', 'Chemical', '-', (108, 123))	('T7', 'Chemical', '-', (79, 81))	('cytotoxic', 'CPA', (58, 67))	('miR-100', 'Gene', (163, 170))	('antimiR-21', 'Var', (138, 148))	('TMZ', 'Chemical', 'MESH:D000077204', (198, 201))	('U87-MG', 'CellLine', 'CVCL:0022', (19, 25))	('antiproliferative', 'CPA', (36, 53))
43395	31326657	Co-treatment with 100 muM TMZ in combination with antimiR-21 or miR-100 independently resulted in 43.8% and 54.7% decline in cell viability compared to 31.2% by TMZ alone, which clearly indicated that both antimiR-21 and miR-100 independently augment the anticancer potential of TMZ against U87-MG cells.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('augment', 'PosReg', (243, 250))	('U87-MG', 'CellLine', 'CVCL:0022', (291, 297))	('decline', 'NegReg', (114, 121))	('cell viability', 'CPA', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('TMZ', 'Chemical', 'MESH:D000077204', (26, 29))	('miR-100', 'Var', (221, 228))	('miR-100', 'Gene', (64, 71))	('TMZ', 'Chemical', 'MESH:D000077204', (161, 164))	('TMZ', 'Chemical', 'MESH:D000077204', (279, 282))	('cancer', 'Disease', (259, 265))
43397	31326657	Of note, at the higher concentrations of TMZ (250 muM), we found that co-treatment with antimiR-21 and miR-100 brought about a decline in cell viability from 30.2% to 15.2%.	('antimiR-21', 'Gene', (88, 98))	('miR-100', 'Var', (103, 110))	('cell viability', 'CPA', (138, 152))	('decline', 'NegReg', (127, 134))	('TMZ', 'Chemical', 'MESH:D000077204', (41, 44))
43400	31326657	Although an increase in TMZ dosage alone from 100 muM to 250 muM brought about a decline in cell viability from 69.8% to 59%, co-treatment using antimiR-21 and miR-100 plus 100 muM TMZ reduced the cell viability to 39.2%.	('TMZ', 'Chemical', 'MESH:D000077204', (24, 27))	('miR-100', 'Var', (160, 167))	('cell viability', 'CPA', (197, 211))	('decline', 'NegReg', (81, 88))	('cell viability', 'CPA', (92, 106))	('TMZ', 'Chemical', 'MESH:D000077204', (181, 184))	('reduced', 'NegReg', (185, 192))
43403	31326657	Of note, in live/dead analysis of cells treated with combinations of TMZ plus antimiR-21 and/or miR-100, we found two distinct cell population subsets clearly distinguished by their nuclear content in the apoptotic region, pointing to the fact that miRNA pre-sensitization occurred by sequential induction of cell death through early and late apoptotic processes (Figure 3E).	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('miR', 'Gene', (249, 252))	('miR', 'Gene', (82, 85))	('miR', 'Gene', '751557', (249, 252))	('miR', 'Gene', (96, 99))	('miR', 'Gene', '751557', (82, 85))	('combinations', 'Var', (53, 65))	('miR', 'Gene', '751557', (96, 99))
43406	31326657	PTEN is a direct target of miR-21, and loss of PTEN by mutation, methylation, or deletion leads to decreased apoptosis.	('decreased', 'NegReg', (99, 108))	('apoptosis', 'CPA', (109, 118))	('deletion', 'Var', (81, 89))	('PTEN', 'Gene', '19211', (47, 51))	('loss', 'NegReg', (39, 43))	('PTEN', 'Gene', (47, 51))	('methylation', 'Var', (65, 76))	('mutation', 'Var', (55, 63))	('PTEN', 'Gene', '19211', (0, 4))	('PTEN', 'Gene', (0, 4))
43416	31326657	TMZ alone mediates cytotoxicity by introducing a methyl group to the O-6 position of guanine (G) in genomic DNA, and subsequent futile cycles of DNA mismatch repair (MMR) system in removing GT mismatches leads to G2/M cell cycle arrest, cellular senescence and apoptosis; this is always preceded by accumulation of p53 and p21 proteins.	('mul', 'Gene', '68729', (303, 306))	('p21 proteins', 'Protein', (323, 335))	('cytotoxicity', 'Disease', (19, 31))	('cellular senescence', 'CPA', (237, 256))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (218, 235))	('mismatches', 'Var', (193, 203))	('p53', 'Protein', (315, 318))	('mul', 'Gene', (303, 306))	('arrest', 'Disease', 'MESH:D006323', (229, 235))	('cytotoxicity', 'Disease', 'MESH:D064420', (19, 31))	('apoptosis', 'CPA', (261, 270))	('guanine', 'Chemical', 'MESH:D006147', (85, 92))	('methyl', 'Var', (49, 55))	('arrest', 'Disease', (229, 235))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
43417	31326657	We observed that the levels of p53 and p21 had increased approximately 2.2-fold and 1.8-fold, respectively, in U87-MG cells after 72 h exposure to a level of TMZ (i.e.	('U87-MG', 'CellLine', 'CVCL:0022', (111, 117))	('p21', 'Var', (39, 42))	('increased', 'PosReg', (47, 56))	('p53', 'Var', (31, 34))	('TMZ', 'Chemical', 'MESH:D000077204', (158, 161))
43419	31326657	The crucial role of p53 in driving the TMZ therapeutic response converges with miR-100 mediated upregulation of p53 and caspase-3 through the mTOR pathway (miR-100 directly targets 3'UTR of mTOR in a post-transcriptional manner).	('mTOR', 'Gene', (142, 146))	('miR-100', 'Gene', (79, 86))	('caspase-3', 'Gene', '12367', (120, 129))	('mTOR', 'Gene', '56717', (142, 146))	('mTOR', 'Gene', (190, 194))	('p53', 'Protein', (112, 115))	('TMZ', 'Chemical', 'MESH:D000077204', (39, 42))	('caspase-3', 'Gene', (120, 129))	('miR-100', 'Var', (156, 163))	('mTOR', 'Gene', '56717', (190, 194))	('upregulation', 'PosReg', (96, 108))
43420	31326657	As a direct manifestation of this convergence in signalling pathways, miR-100 improves the TMZ cytotoxicity by harnessing the combined outcome of caspase-3 and p53 mediated apoptotic signaling.	('caspase-3', 'Gene', (146, 155))	('miR-100', 'Var', (70, 77))	('cytotoxicity', 'Disease', (95, 107))	('improves', 'PosReg', (78, 86))	('TMZ', 'Chemical', 'MESH:D000077204', (91, 94))	('caspase-3', 'Gene', '12367', (146, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (95, 107))
43442	31326657	The weight loss was significantly delayed in the case of CD-CS-polyGIONs-miRNA and T7 targeted CD-CS-polyGIONs-miRNA treated mice, which also correlated well with the health status of these mice indicating tumor growth suppression (Figure 5D).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('weight loss', 'Disease', 'MESH:D015431', (4, 15))	('T7', 'Chemical', '-', (83, 85))	('tumor growth suppression', 'Disease', (206, 230))	('weight loss', 'Disease', (4, 15))	('delayed', 'NegReg', (34, 41))	('tumor growth suppression', 'Disease', 'MESH:D006130', (206, 230))	('mice', 'Species', '10090', (125, 129))	('CD-CS-polyGIONs-miRNA', 'Chemical', '-', (57, 78))	('CD-CS-polyGIONs-miRNA', 'Chemical', '-', (95, 116))	('weight loss', 'Phenotype', 'HP:0001824', (4, 15))	('mice', 'Species', '10090', (190, 194))	('CD-CS-polyGIONs-miRNA', 'Var', (57, 78))
43447	31326657	At the early stage of intranasal administration of nanoparticles, both targeted and non-targeted nanoparticles home into the brain but over the course of time only T7-functionalized nanoparticles were predominantly retained in the brain in comparison to non-targeted nanoparticles, which also show progressive accumulation in the lungs and kidney.	('T7-functionalized', 'Var', (164, 181))	('T7', 'Chemical', '-', (164, 166))	('mul', 'Gene', '68729', (314, 317))	('mul', 'Gene', (314, 317))
43450	31326657	The T7-targeted polyGIONs were able to achieve ~42% reduction in tumor volume when compared to use of the non-targeted counterpart showing only a ~7.8% reduction in tumor volume over the course of 24 days' treatment.	('reduction', 'NegReg', (52, 61))	('tumor', 'Disease', (65, 70))	('T7', 'Chemical', '-', (4, 6))	('T7-targeted', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('polyGIONs', 'Chemical', '-', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (165, 170))
43455	31326657	This accumulation was much more pronounced for T7-targeted CD-CS-polyGIONs as compared to the non-targeted nanoparticles.	('mul', 'Gene', '68729', (9, 12))	('T7-targeted', 'Var', (47, 58))	('mul', 'Gene', (9, 12))	('CD-CS-polyGIONs', 'Chemical', '-', (59, 74))	('T7', 'Chemical', '-', (47, 49))
43485	31326657	Subsequent evaluation of these regions under a Cy5 filter of a fluorescence microscope showed the presence of Cy5 labelled miRNA specifically co- localized to this region of dead cells.	('Cy5', 'Chemical', 'MESH:C085321', (110, 113))	('miR', 'Gene', (123, 126))	('Cy5', 'Chemical', 'MESH:C085321', (47, 50))	('miR', 'Gene', '751557', (123, 126))	('Cy5', 'Var', (110, 113))
43487	31326657	These observations are in close agreement with those of the in vivo fluorescence imaging and the T1-weighted MRI intracranial imaging, denoting the selective accumulation of Cy5 labelled miRNAs and GION nanostars in the brain.	('mul', 'Gene', '68729', (162, 165))	('miR', 'Gene', '751557', (187, 190))	('Cy5', 'Var', (174, 177))	('Cy5', 'Chemical', 'MESH:C085321', (174, 177))	('mul', 'Gene', (162, 165))	('miR', 'Gene', (187, 190))	('GION nanostars', 'Protein', (198, 212))
43490	31326657	The H&E stained sections of nasal mucosal epithelium from T7-CD-CS polyGIONs administered mice did not show any instance of toxicity or nasal congestion (Figure S8).	('T7', 'Chemical', '-', (58, 60))	('toxicity', 'Disease', 'MESH:D064420', (124, 132))	('H&E', 'Chemical', '-', (4, 7))	('CD-CS', 'Chemical', '-', (61, 66))	('mice', 'Species', '10090', (90, 94))	('nasal congestion', 'Phenotype', 'HP:0001742', (136, 152))	('polyGIONs', 'Chemical', '-', (67, 76))	('toxicity', 'Disease', (124, 132))	('from', 'Var', (53, 57))
43491	31326657	The TUNEL staining of tumor tissues collected from controls and the animals treated with polyGION delivered Cy5-antimiR-21-miR-100 plus TMZ revealed significant enhancement in apoptosis in the tumors of animals treated with combination therapy compared to controls (Figure 7C).	('Cy5', 'Chemical', 'MESH:C085321', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('polyGION', 'Chemical', '-', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (22, 27))	('tumors', 'Disease', (193, 199))	('apoptosis', 'CPA', (176, 185))	('Cy5-antimiR-21-miR-100', 'Var', (108, 130))	('TMZ', 'Chemical', 'MESH:D000077204', (136, 139))	('enhancement', 'PosReg', (161, 172))
43492	31326657	Overall, our results show efficient delivery of antimiR-21 and miR-100 corresponding to the intratumoral regions of cell death in GBM mouse models.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('miR-100', 'Gene', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('tumor', 'Disease', (97, 102))	('antimiR-21', 'Var', (48, 58))	('mouse', 'Species', '10090', (134, 139))
43493	31326657	There was a significant increase in survival of mice co-treated with T7-polyGIONs loaded with miR-100-antimiR-21 plus systemic TMZ, compared to the untreated control group, or the animals receiving polyGIONs-miR-100-antimiR-21, or TMZ alone.	('increase', 'PosReg', (24, 32))	('miR-100-antimiR-21', 'Var', (94, 112))	('mice', 'Species', '10090', (48, 52))	('polyGIONs', 'Chemical', '-', (72, 81))	('T7-polyGIONs', 'Var', (69, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (231, 234))	('survival', 'CPA', (36, 44))	('polyGIONs', 'Chemical', '-', (198, 207))	('TMZ', 'Chemical', 'MESH:D000077204', (127, 130))	('T7-polyGIONs', 'Chemical', '-', (69, 81))
43573	31326657	We seeded 50,000 U87-MG cells in 12-well plates and treated with equivalent amounts of T7 targeted polyGIONs loaded with either antimiR-21 or miR-100 or with both in the presence or absence of TMZ.	('U87-MG', 'CellLine', 'CVCL:0022', (17, 23))	('TMZ', 'Chemical', 'MESH:D000077204', (193, 196))	('miR-100', 'Var', (142, 149))	('T7', 'Chemical', '-', (87, 89))	('antimiR-21', 'Var', (128, 138))	('polyGIONs', 'Chemical', '-', (99, 108))
43610	30942445	In the present study, using a tetracycline-inducible system in PTEN-null U87 cells, we demonstrate that MARCKS overexpression suppresses growth and enhances radiation sensitivity in vivo.	('suppresses', 'NegReg', (126, 136))	('radiation sensitivity', 'CPA', (157, 178))	('overexpression', 'Var', (111, 125))	('growth', 'CPA', (137, 143))	('MARCKS', 'Gene', (104, 110))	('tetracycline', 'Chemical', 'MESH:D013752', (30, 42))	('enhances', 'PosReg', (148, 156))
43612	30942445	The overexpression of the non-phosphorylatable ED mutant exerted growth-suppressive and radiation-sensitizing effects, while the pseudo-phosphorylated ED mutant exhibited an enhanced colony formation and clonogenic survival ability.	('clonogenic survival ability', 'CPA', (204, 231))	('enhanced', 'PosReg', (174, 182))	('ED', 'Chemical', '-', (151, 153))	('growth-suppressive', 'CPA', (65, 83))	('mutant', 'Var', (50, 56))	('overexpression', 'PosReg', (4, 18))	('colony formation', 'CPA', (183, 199))	('ED', 'Chemical', '-', (47, 49))
43617	30942445	GBM is well characterized as a pathway-driven disease with alterations in receptor tyrosine kinases (RTKs), activating mutations in PI3CA (p110) and PIK3R1 (p85) or the loss of phosphatase and tensin homolog (PTEN) occurring in up to 88% of GBM cases, which promotes the conversion of phosphatidylinositol -bisphosphate [PtdlnsP2] into phosphatidylinositol -trisphosphate [PtdlnsP3].	('GBM', 'Disease', (0, 3))	('conversion of phosphatidylinositol -bisphosphate', 'MPA', (271, 319))	('phosphatase', 'Gene', (177, 188))	('p85', 'Gene', (157, 160))	('PIK3R1', 'Gene', '18708', (149, 155))	('PI3CA', 'Gene', (132, 137))	('PIK3R1', 'Gene', (149, 155))	('p85', 'Gene', '21981', (157, 160))	('phosphatidylinositol -trisphosphate', 'Chemical', '-', (336, 371))	('GBM', 'Gene', (241, 244))	('mutations', 'Var', (119, 128))	('PTEN', 'Gene', (209, 213))	('alterations', 'Reg', (59, 70))	('phosphatidylinositol -bisphosphate', 'Chemical', '-', (285, 319))
43618	30942445	The accumulation of PtdlnsP3 promotes the localization of proteins containing pleckstrin homology (PH) domains to the plasma membrane, enhancing downstream signaling, such as the activation of AKT and mammalian target of rapamycin complex (mTORC), promoting cancer growth and therapeutic resistance, as well as oncogenic transformation.	('AKT', 'Pathway', (193, 196))	('oncogenic transformation', 'CPA', (311, 335))	('proteins', 'Protein', (58, 66))	('accumulation', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('promoting', 'PosReg', (248, 257))	('localization', 'MPA', (42, 54))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('therapeutic resistance', 'CPA', (276, 298))	('activation', 'PosReg', (179, 189))	('downstream signaling', 'MPA', (145, 165))	('enhancing', 'PosReg', (135, 144))	('PtdlnsP3', 'Gene', (20, 28))	('mammalian target of rapamycin', 'Gene', '2475', (201, 230))	('mammalian target of rapamycin', 'Gene', (201, 230))	('promotes', 'PosReg', (29, 37))
43632	30942445	Additionally, Jarboe et al demonstrated that the knockdown of MARCKS in GBM promoted cell proliferation and radiation resistance through upregulations in non-homologous end joining (NHEJ) DNA repair mechanisms, and that patients with a high MARCKS expression, particularly in MGMT unmethylated GBM tumors, had substantial survival benefits.	('knockdown', 'Var', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('cell proliferation', 'CPA', (85, 103))	('survival benefits', 'CPA', (322, 339))	('upregulations', 'PosReg', (137, 150))	('expression', 'MPA', (248, 258))	('patients', 'Species', '9606', (220, 228))	('GBM tumors', 'Disease', (294, 304))	('MARCKS', 'Gene', (241, 247))	('GBM tumors', 'Disease', 'MESH:D005910', (294, 304))	('promoted', 'PosReg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('radiation resistance', 'CPA', (108, 128))
43633	30942445	Since MARCKS itself is not mutated in GBM, it is suggested that primarily epigenetic, post-transcriptional or post-translational modifications will overcome the MARCKS tumor-suppressing effects.	('tumor', 'Disease', (168, 173))	('epigenetic', 'Var', (74, 84))	('overcome', 'PosReg', (148, 156))	('post-translational modifications', 'Var', (110, 142))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('post-transcriptional', 'Var', (86, 106))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
43639	30942445	U87 cells were engineered to overexpress MARCKS or the MARCKS ED mutants in a tetracycline-dependent manner as previously described.	('tetracycline', 'Chemical', 'MESH:D013752', (78, 90))	('ED', 'Chemical', '-', (62, 64))	('overexpress', 'PosReg', (29, 40))	('mutants', 'Var', (65, 72))
43642	30942445	Fragments from these plasmids with the mutations were cloned into the pLenti6.3/TO/V5-MARCKS-WT using restriction sites and standard protocols to generate MARCKS mutant lentiviral plasmids containing blasticidin resistance and a V-5 epitope tag.	('mutant', 'Var', (162, 168))	('blasticidin', 'Chemical', 'MESH:C004500', (200, 211))	('mutations', 'Var', (39, 48))
43652	30942445	The blots were blocked in 5% BSA for 1 h and probed with the following antibodies at 4 C overnight with gentle rocking using manufacturer recommended dilutions: V5-HRP (P/N 46-0708; Invitrogen/Thermo Fisher Scientific), MARCKS anti-rabbit (ab52616), MARCKS anti-mouse (ab55451) (both from Abcam, Cambridge, MA, USA), phosphorylated (p-)histone H2AX S139 (9718S), p-Akt (Ser473; D9E; #4060), p-Akt (Thr308; C31E5E; #2965), Akt (C67E7; #4691), PKCalpha (#2056) (all from Cell Signaling Technology, Danvers, MA, USA), rabbit IgG control (20304E; Imgenex/Novus Biologicals, Centennial, CO, USA) and Actin (sc-1616-R), lamin A/C (sc-7292), alpha-tubulin (sc-53646) (all from Santa Cruz Biotechnology, Santa Cruz, CA, USA).	('Akt', 'Gene', '11651', (365, 368))	('Akt', 'Gene', (365, 368))	('Akt', 'Gene', (393, 396))	('Akt', 'Gene', '11651', (422, 425))	('mouse', 'Species', '10090', (262, 267))	('PKCalpha', 'Gene', '18750', (442, 450))	('rabbit', 'Species', '9986', (232, 238))	('P/N 46', 'SUBSTITUTION', 'None', (169, 175))	('PKCalpha', 'Gene', (442, 450))	('lamin A/C', 'Gene', '16905', (614, 623))	('alpha-tubulin', 'Protein', (635, 648))	('lamin A/C', 'Gene', (614, 623))	('Akt', 'Gene', (422, 425))	('Akt', 'Gene', '11651', (393, 396))	('P/N 46', 'Var', (169, 175))	('rabbit', 'Species', '9986', (515, 521))
43658	30942445	A total of 5,000 cells per well (n=12) were counted using a hemocytometer and plated for each of the validated MARCKS mutant lines into black 96-well plates containing 100 microl of DMEM with 10% FBS and 2 microg/ml of the doxycycline (doxycycline medium).	('FBS', 'Disease', (196, 199))	('DMEM', 'Chemical', '-', (182, 186))	('doxycycline', 'Chemical', 'MESH:D004318', (236, 247))	('FBS', 'Disease', 'MESH:D005198', (196, 199))	('mutant', 'Var', (118, 124))	('MARCKS', 'Gene', (111, 117))	('doxycycline', 'Chemical', 'MESH:D004318', (223, 234))
43673	30942445	Slides were analyzed on the image cytometer Xcyto10 (ChemoMetec) at x20 magnification with excitation/filter sets AF546 (LED535; 582-636), AF488 (LED488; 513-555), MASK (LED405; 430-475) DAPI (LED405; 573-613) for high-resolution images and the quantification of fluorescent intensities and localization.	('LED405;', 'Var', (193, 200))	('ED', 'Chemical', '-', (171, 173))	('ED', 'Chemical', '-', (147, 149))	('LED488; 513-555', 'Var', (146, 161))	('MASK', 'Gene', '108857', (164, 168))	('LED535; 582-636', 'Var', (121, 136))	('DAPI', 'Chemical', 'MESH:C007293', (187, 191))	('LED405; 430-475', 'Var', (170, 185))	('MASK', 'Gene', (164, 168))	('AF488', 'Var', (139, 144))	('ED', 'Chemical', '-', (194, 196))	('ED', 'Chemical', '-', (122, 124))
43680	30942445	1 and S1: MARCKS-AF546 (400 msec, LED535; 582-636), phal-loidin-AF488 (400 msec, LED488; 513-555), DAPI (400 msec, LED405; 573-613); Fig.	('ED', 'Chemical', '-', (82, 84))	('ED', 'Chemical', '-', (35, 37))	('LED535', 'Var', (34, 40))	('LED405', 'Var', (115, 121))	('DAPI', 'Chemical', 'MESH:C007293', (99, 103))	('ED', 'Chemical', '-', (116, 118))
43702	30942445	We have previously shown that MARCKS protein expression is inversely associated with GBM proliferation and intracranial xenograft growth rates, with the knockdown of MARCKS in the PTEN-null line, U251, resulting in an enhanced radiation resistance.	('enhanced', 'PosReg', (218, 226))	('knockdown', 'Var', (153, 162))	('MARCKS', 'Gene', (30, 36))	('U251', 'CellLine', 'CVCL:0021', (196, 200))	('radiation resistance', 'CPA', (227, 247))	('GBM proliferation', 'CPA', (85, 102))
43707	30942445	We then investigated the mechanisms through which the phosphorylation of the 4 serine residues present in MARCKS ED affect the ability of MARCKS to suppress GBM growth and radiation resistance by generating additional ED mutants: i) A non-phosphorylatable ED mutant (NP) replaced the serine residues with alanine, to prevent the loss of plasma membrane binding by phosphorylation; ii) a pseudo-phosphorylated ED mutant (PP) substituted the serine residues with aspartic acid, which prevented membrane binding by mimicking negatively charged phosphorylation groups; and iii) a deleted effector domain mutant (DeltaED) that lacks an ED (Fig.	('serine', 'Chemical', 'MESH:D012694', (284, 290))	('ED', 'Chemical', '-', (631, 633))	('ED', 'Chemical', '-', (409, 411))	('suppress', 'NegReg', (148, 156))	('plasma membrane', 'MPA', (337, 352))	('serine', 'Chemical', 'MESH:D012694', (440, 446))	('GBM growth', 'CPA', (157, 167))	('serine', 'Chemical', 'MESH:D012694', (79, 85))	('radiation resistance', 'CPA', (172, 192))	('mutants', 'Var', (221, 228))	('ED', 'Chemical', '-', (613, 615))	('ED', 'Chemical', '-', (218, 220))	('ED', 'Chemical', '-', (256, 258))	('ED', 'Chemical', '-', (113, 115))
43708	30942445	To evaluate the cellular localization of the MARCKS mutants, immunofluorescent imaging, and the analysis of the mutants 72 h following doxycycline induction were performed using the image cytometer Xcyto10.	('doxycycline', 'Chemical', 'MESH:D004318', (135, 146))	('MARCKS', 'Gene', (45, 51))	('mutants', 'Var', (52, 59))
43715	30942445	These data indicate that the localization of WT+ and NP MARCKS mutants is consistent with an ED that is unphosphorylated and membrane-bound, while the PP mutant mimics the cytoplasmic localization of phosphorylated MARCKS.	('localization', 'MPA', (29, 41))	('MARCKS', 'Gene', (56, 62))	('ED', 'Chemical', '-', (93, 95))	('mutants', 'Var', (63, 70))
43716	30942445	To identify differences in GBM growth with MARCKS overexpression and the potential effects of ED phosphorylation, we measured the growth of our MARCKS mutants 7 days following doxycycline induction.	('mutants', 'Var', (151, 158))	('doxycycline', 'Chemical', 'MESH:D004318', (176, 187))	('growth', 'MPA', (130, 136))	('ED', 'Chemical', '-', (94, 96))	('MARCKS', 'Gene', (144, 150))
43717	30942445	Statistically significant (P<0.0001) decreases in growth were observed in the WT+ and NP mutants, and no decrease in growth in PP or DeltaED compared to the CTL line (Fig.	('decreases', 'NegReg', (37, 46))	('growth', 'MPA', (50, 56))	('NP mutants', 'Var', (86, 96))	('ED', 'Chemical', '-', (138, 140))
43723	30942445	3E), although we lacked NP and PP ED mutants in U373 for additional validation.	('U373', 'Gene', (48, 52))	('ED', 'Chemical', '-', (34, 36))	('U373', 'CellLine', 'CVCL:2219', (48, 52))	('mutants', 'Var', (37, 44))
43724	30942445	Both AKT activation and PKCalpha protein expression are associated with enhanced cancer growth, proliferation and survival signaling, and the knockdown of MARCKS in GBM has been previously shown to enhance AKT phosphorylation and decrease PKCalpha levels.	('PKCalpha', 'Gene', '18750', (24, 32))	('activation', 'PosReg', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('expression', 'MPA', (41, 51))	('proliferation', 'CPA', (96, 109))	('knockdown', 'Var', (142, 151))	('cancer', 'Disease', (81, 87))	('PKCalpha', 'Gene', '18750', (239, 247))	('decrease', 'NegReg', (230, 238))	('AKT', 'Pathway', (206, 209))	('PKCalpha', 'Gene', (239, 247))	('enhanced', 'PosReg', (72, 80))	('survival signaling', 'CPA', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('enhance', 'PosReg', (198, 205))	('PKCalpha', 'Gene', (24, 32))	('MARCKS', 'Gene', (155, 161))	('AKT', 'Enzyme', (5, 8))
43725	30942445	In this study, we examined the mechanisms through which the overexpression of MARCKS ED mutants affect these features and found that WT+ and NP MARCKS overexpression decreased the activation of AKT (T308 and S473 phosphorylation) by 45 and 32%, respectively compared to the PBS-treated cells, while CTL and PP exhibited negligible suppression.	('PBS', 'Chemical', 'MESH:D007854', (274, 277))	('MARCKS ED', 'Gene', (78, 87))	('S473', 'Var', (208, 212))	('decreased', 'NegReg', (166, 175))	('mutants', 'Var', (88, 95))	('ED', 'Chemical', '-', (85, 87))	('activation', 'PosReg', (180, 190))
43726	30942445	No effects were observed on PKCalpha expression with the overexpression of our MARCKS mutants (Fig.	('PKCalpha', 'Gene', (28, 36))	('mutants', 'Var', (86, 93))	('overexpression', 'PosReg', (57, 71))	('MARCKS', 'Gene', (79, 85))	('PKCalpha', 'Gene', '18750', (28, 36))
43742	30942445	MARCKS ED also serves as an NLS, and differences in its phosphorylation are also likely to regulate nuclear import.	('regulate', 'Reg', (91, 99))	('ED', 'Chemical', '-', (7, 9))	('phosphorylation', 'MPA', (56, 71))	('differences', 'Var', (37, 48))	('nuclear import', 'MPA', (100, 114))
43743	30942445	Indeed, we detected differences in the nuclear localization of our PP ED mutant from WT+ and NP ED mutant that needs additional future validation in a model system with endogenous MARCKS expression (Fig.	('PP ED', 'Gene', (67, 72))	('ED', 'Chemical', '-', (96, 98))	('ED', 'Chemical', '-', (70, 72))	('mutant', 'Var', (73, 79))	('differences', 'Reg', (20, 31))	('nuclear localization', 'MPA', (39, 59))
43744	30942445	Due to the important role of PtdlnsP2 in oncogenic signaling, the frequent mutations of GBM altering PtdlnsP2 signaling, and the role of MARCKS in regulating PtdlnsP2 availability, in this study, we evaluated the effects of MARCKS expression and ED phosphorylation on GBM growth and therapeutic resistance.	('altering', 'Reg', (92, 100))	('PtdlnsP2', 'Gene', (101, 109))	('GBM', 'Gene', (88, 91))	('mutations', 'Var', (75, 84))	('ED', 'Chemical', '-', (246, 248))
43746	30942445	To determine the mechanisms through which the phosphorylation of MARCKS ED may alter these tumor-suppressing effects, we mimicked ED phosphorylation or prevented phosphorylation through substitution of the 4 ED serine residues.	('substitution', 'Var', (186, 198))	('ED', 'Chemical', '-', (72, 74))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('prevented', 'NegReg', (152, 161))	('ED', 'Chemical', '-', (208, 210))	('alter', 'Reg', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('phosphorylation', 'MPA', (162, 177))	('tumor', 'Disease', (91, 96))	('ED', 'Chemical', '-', (130, 132))	('serine', 'Chemical', 'MESH:D012694', (211, 217))
43750	30942445	Although slight decreases in filamentous actin staining were observed following the overexpression of MARCKS in all our mutant lines compared with control or uninduced group, no substantial differences existed between the ED mutants.	('overexpression', 'PosReg', (84, 98))	('filamentous actin staining', 'MPA', (29, 55))	('MARCKS', 'Gene', (102, 108))	('ED', 'Chemical', '-', (222, 224))	('decreases', 'NegReg', (16, 25))	('mutant', 'Var', (120, 126))
43754	30942445	The significant suppression of cell viability in WT+ and NP (P=0.004 and P=0.0093, respectively) was dependent on exposure of the mutants to doxyxcline, and its resulting expression of mutant MARCKS protein, with no significant decreases in viability seen in CTL or PP as observed in Fig.	('expression', 'MPA', (171, 181))	('protein', 'Protein', (199, 206))	('mutant', 'Var', (185, 191))	('cell viability', 'CPA', (31, 45))	('suppression', 'NegReg', (16, 27))	('MARCKS', 'Gene', (192, 198))	('mutants', 'Var', (130, 137))	('doxyxcline', 'Chemical', '-', (141, 151))
43770	30942445	Transportin-1 and MARCKS interactions are previously unreported, but are consistent with emerging data that MARCKS is selectively imported into the nucleus in specific cell types, and our findings that only the PP mutant was not enriched in the nucleus suggests ED phosphorylation may inhibit its translocation through the nuclear membrane.	('inhibit', 'NegReg', (285, 292))	('Transportin-1', 'Gene', (0, 13))	('Transportin-1', 'Gene', '238799', (0, 13))	('ED', 'Chemical', '-', (262, 264))	('translocation through the nuclear membrane', 'MPA', (297, 339))	('phosphorylation', 'Var', (265, 280))
43779	30942445	The limitations of this study include the use of a doxycycline-inducible model with overexpression of MARCKS ED mutants, as opposed to testing at endogenous MARCKS levels with true serine phosphorylation, and the lack of additional NP and PP ED mutants that could be tested in PTEN null cell lines.	('doxycycline', 'Chemical', 'MESH:D004318', (51, 62))	('MARCKS ED', 'Gene', (102, 111))	('serine', 'Chemical', 'MESH:D012694', (181, 187))	('ED', 'Chemical', '-', (242, 244))	('mutants', 'Var', (112, 119))	('ED', 'Chemical', '-', (109, 111))
43784	30942445	Prior to this study, MARCKS knockdown was associated with enhanced GBM growth and radiation resistance, and the phosphorylation of MARCKS ED was associated with enhanced invasion with an undetermined effect on growth and radiation sensitivity in GBM.	('GBM growth', 'CPA', (67, 77))	('MARCKS', 'Gene', (131, 137))	('enhanced', 'PosReg', (161, 169))	('MARCKS', 'Gene', (21, 27))	('enhanced', 'PosReg', (58, 66))	('radiation resistance', 'CPA', (82, 102))	('ED', 'Chemical', '-', (138, 140))	('phosphorylation', 'Var', (112, 127))	('knockdown', 'Var', (28, 37))	('invasion', 'CPA', (170, 178))
43787	30942445	This study was supported by funding from the National Institutes of Health (the UAB MSTP training grant: T32GM008361 and the UAB Training Program in Brain Tumor Biology: T32NS048039), the American Cancer Society through a Research Scholar Grant (Grant no.	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Cancer', 'Disease', (197, 203))	('Cancer', 'Disease', 'MESH:D009369', (197, 203))	('Brain Tumor', 'Disease', (149, 160))	('Tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Brain Tumor', 'Phenotype', 'HP:0030692', (149, 160))	('Brain Tumor', 'Disease', 'MESH:D001932', (149, 160))	('T32NS048039', 'Var', (170, 181))
43849	30819771	We found significant correlations for T1+C (r=0.36 p<0.001), rCBV (r=0.33 p<0.0001), and FA (r=-0.24 p<0.03), although only T1+C and rCBV remained significant after correcting for multiple comparisons (p = 0.01).	('T1+C', 'Var', (38, 42))	('rCBV', 'Chemical', '-', (133, 137))	('rCBV', 'Chemical', '-', (61, 65))	('correlations', 'Interaction', (21, 33))	('rCBV', 'Gene', (61, 65))
43852	30819771	Meanwhile, the same subgroup analysis showed more consistent rCBV correlations across enhancing and non-enhancing biopsy subgroups, suggesting the potential utility of rCBV as a biomarker for both tumor segments.	('correlations', 'Var', (66, 78))	('rCBV', 'Chemical', '-', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('rCBV', 'Chemical', '-', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('rCBV', 'Gene', (61, 65))	('tumor', 'Disease', (197, 202))
43904	30875963	We therefore postulate that AMPK/miR-451 negative reciprocal feedback loop allows GBM cells/GSCs to adapt to tumor "ecosystem" by metabolic and behavioral flexibility, and that disruption of such a loop reduces invasiveness and diminishes therapy resistance.	('disruption', 'Var', (177, 187))	('miR-451', 'Gene', '574411', (33, 40))	('reduces', 'NegReg', (203, 210))	('invasiveness', 'CPA', (211, 223))	('AMPK', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('miR-451', 'Gene', (33, 40))	('AMPK', 'Gene', '5562', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('diminishes', 'NegReg', (228, 238))	('therapy resistance', 'CPA', (239, 257))	('tumor', 'Disease', (109, 114))
43919	30875963	In the last several years, important developments in cancer biology include the discovery of deregulated microRNAs and their use for therapeutic intervention.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('microRNAs', 'Protein', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('deregulated', 'Var', (93, 104))
43960	30875963	Additionally, forced expression of miR-451 sensitizes GBM cells to conventional radio-/chemo-therapy.	('miR-451', 'Gene', (35, 42))	('sensitizes', 'Reg', (43, 53))	('miR-451', 'Gene', '574411', (35, 42))	('forced expression', 'Var', (14, 31))	('GBM cells', 'CPA', (54, 63))
43998	30875963	MiR-451-mediated knock-down of CAB-39 led to obliteration of the LKB1 complex and consequently reduced its activity several fold .	('CAB-39', 'Gene', (31, 37))	('CAB-39', 'Gene', '51719', (31, 37))	('activity', 'MPA', (107, 115))	('LKB1', 'Gene', (65, 69))	('MiR-451', 'Gene', '574411', (0, 7))	('knock-down', 'Var', (17, 27))	('LKB1', 'Gene', '6794', (65, 69))	('obliteration', 'NegReg', (45, 57))	('reduced', 'NegReg', (95, 102))	('MiR-451', 'Gene', (0, 7))
44004	30875963	On the other hand, when we reduced the amount of glucose in the medium (15-fold from 4.5 g/L to 0.3 g/L), we observed a significant reduction in miR-451 expression in all GBM cells tested, but not in HeLa cells, that are known for lack of functional LKB1 due to gene methylation suggesting that intact AMPK signaling is required for repression of miR-451 in low glucose.	('miR-451', 'Gene', (145, 152))	('reduced', 'NegReg', (27, 34))	('AMPK', 'Gene', (302, 306))	('miR-451', 'Gene', (347, 354))	('methylation', 'Var', (267, 278))	('HeLa', 'CellLine', 'CVCL:0030', (200, 204))	('glucose', 'Chemical', 'MESH:D005947', (49, 56))	('LKB1', 'Gene', '6794', (250, 254))	('glucose', 'Chemical', 'MESH:D005947', (362, 369))	('reduction', 'NegReg', (132, 141))	('miR-451', 'Gene', '574411', (145, 152))	('miR-451', 'Gene', '574411', (347, 354))	('expression', 'MPA', (153, 163))	('LKB1', 'Gene', (250, 254))	('AMPK', 'Gene', '5562', (302, 306))
44006	30875963	Additive effect of double knock-down of alpha1/alpha2 can be explained by known functional redundancy between AMPK alpha subunits.	('double knock-down', 'Var', (19, 36))	('alpha1/alpha2', 'Gene', '146', (40, 53))	('alpha1/alpha2', 'Gene', (40, 53))	('AMPK', 'Gene', '5562', (110, 114))	('AMPK', 'Gene', (110, 114))
44011	30875963	In fact, OCT1 knock-down in GBM cells led to significant, two-fold decrease in miR-451 levels.	('miR-451', 'Gene', (79, 86))	('decrease', 'NegReg', (67, 75))	('knock-down', 'Var', (14, 24))	('OCT1', 'Gene', (9, 13))	('miR-451', 'Gene', '574411', (79, 86))	('OCT1', 'Gene', '5451', (9, 13))
44015	30875963	Re-introduced wild type or S335A mutant OCT1 into Oct1-/- fibroblasts it rescued the expression of miR-451.	('OCT1', 'Gene', '5451', (40, 44))	('expression', 'MPA', (85, 95))	('miR-451', 'Gene', '574411', (99, 106))	('Oct1', 'Gene', (50, 54))	('Oct1', 'Gene', '5451', (50, 54))	('OCT1', 'Gene', (40, 44))	('miR-451', 'Gene', (99, 106))	('rescued', 'PosReg', (73, 80))	('S335A', 'Var', (27, 32))	('S335A', 'Mutation', 'p.S335A', (27, 32))
44017	30875963	Briefly, we demonstrated that expression of miR-451 inversely correlates with activated AMPK and that AMPK is sufficient for the phosphorylation of OCT1 at S335, thus establishing AMPK as the kinase responsible in shutting-off OCT1-mediated transcription of miR-451 in response to glucose availability.	('AMPK', 'Gene', (180, 184))	('miR-451', 'Gene', (258, 265))	('S335', 'Var', (156, 160))	('miR-451', 'Gene', '574411', (44, 51))	('AMPK', 'Gene', (88, 92))	('AMPK', 'Gene', '5562', (88, 92))	('AMPK', 'Gene', '5562', (102, 106))	('AMPK', 'Gene', (102, 106))	('OCT1', 'Gene', (148, 152))	('miR-451', 'Gene', '574411', (258, 265))	('OCT1', 'Gene', (227, 231))	('miR-451', 'Gene', (44, 51))	('OCT1', 'Gene', '5451', (227, 231))	('OCT1', 'Gene', '5451', (148, 152))	('glucose', 'Chemical', 'MESH:D005947', (281, 288))	('AMPK', 'Gene', '5562', (180, 184))
44022	30875963	The AMPK-dependent inactivation of transcriptional activator of miR-451 enables cancer cells with the ability to escape from metabolically stressful events/locations.	('miR-451', 'Gene', '574411', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('AMPK', 'Gene', '5562', (4, 8))	('miR-451', 'Gene', (64, 71))	('AMPK', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('inactivation', 'Var', (19, 31))	('cancer', 'Disease', (80, 86))
44044	29303449	When timing of repeat resection was ignored, repeat resection was associated with a lower risk of death (HR:0.62, 95%CI: 0.43-0.90,p=.01); however, when timing was taken into account, repeat resection was associated with a higher risk of death (HR:2.19, 95%CI: 1.47-3.28,p<.001).	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('repeat resection', 'Var', (184, 200))	('death', 'Disease', 'MESH:D003643', (238, 243))	('death', 'Disease', (238, 243))
44101	29303449	After accounting for the timing of re-resection in a time-dependent model, repeat resection was associated with a higher risk of death (HR: 2.02, 95%CI: 1.40-2.91,p<.001).	('death', 'Disease', 'MESH:D003643', (129, 134))	('repeat resection', 'Var', (75, 91))	('death', 'Disease', (129, 134))
44129	29303449	Additionally, many studies suggest underlying molecular variations, including methylation status and IDH-1 mutations, are associated with tumor aggressiveness and survival.	('associated', 'Reg', (122, 132))	('mutations', 'Var', (107, 116))	('tumor aggressiveness', 'Disease', (138, 158))	('IDH-1', 'Gene', '3417', (101, 106))	('IDH-1', 'Gene', (101, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (144, 158))	('survival', 'CPA', (163, 171))	('methylation status', 'Var', (78, 96))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (138, 158))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
44139	29844123	Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis.	('Trk', 'Gene', '18211', (15, 18))	('brain malignancy', 'Disease', (134, 150))	('Glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('Glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('inhibition', 'Var', (19, 29))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('brain malignancy', 'Phenotype', 'HP:0030692', (134, 150))	('c-Met', 'Gene', (9, 14))	('CDK4/6', 'Gene', (54, 60))	('Glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('Glioblastoma', 'Disease', (75, 87))	('CDK4/6', 'Gene', '12567;12571', (54, 60))	('Glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('c-Met', 'Gene', '17295', (9, 14))	('Glioblastoma', 'Disease', (88, 100))	('Trk', 'Gene', (15, 18))	('brain malignancy', 'Disease', 'MESH:D001932', (134, 150))
44144	29844123	Mechanistically, inhibition of CDK4/6 drove NF-kappaB-mediated upregulation of hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) that in turn activated both c-Met and TrkA-B pathways.	('brain-derived neurotrophic factor', 'Gene', '12064', (111, 144))	('c-Met', 'Gene', '17295', (211, 216))	('CDK4/6', 'Protein', (31, 37))	('hepatocyte growth factor', 'Gene', '15234', (79, 103))	('nerve growth factor', 'Gene', '18049', (157, 176))	('nerve growth factor', 'Gene', (157, 176))	('brain-derived neurotrophic factor', 'Gene', (111, 144))	('inhibition', 'Var', (17, 27))	('hepatocyte growth factor', 'Gene', (79, 103))	('NF-kappaB', 'Gene', (44, 53))	('TrkA', 'Gene', '18211', (221, 225))	('activated', 'PosReg', (196, 205))	('c-Met', 'Gene', (211, 216))	('NF-kappaB', 'Gene', '18033', (44, 53))	('upregulation', 'PosReg', (63, 75))	('TrkA', 'Gene', (221, 225))
44151	29844123	Analysis of The Cancer Genome Atlas (TCGA) database revealed that the CDK4/6-Rb-E2F axis is deregulated in about 80% of GBMs, with lesions including loss of p16INK4a, providing an opportunity for the development of effective therapies through targeting the cell cycle in GBM.	('GBMs', 'Disease', (120, 124))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (16, 35))	('Rb', 'Chemical', 'MESH:D012413', (77, 79))	('loss', 'Var', (149, 153))	('GBM', 'Phenotype', 'HP:0012174', (120, 123))	('p16INK4a', 'Gene', (157, 165))	('GBM', 'Phenotype', 'HP:0012174', (271, 274))	('CDK4/6-Rb-E2F axis', 'Gene', (70, 88))	('deregulated', 'Reg', (92, 103))	('p16INK4a', 'Gene', '12578', (157, 165))	('Cancer Genome Atlas', 'Disease', (16, 35))
44154	29844123	In addition to mutations/amplifications in epidermal growth factor receptor (EGFR), one of the most common genetic abnormalities in GBM, other RTKs such as vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor alpha (PDGFRA), and c-Met have been shown to be altered to promote growth, treatment resistance, and recurrence.	('promote', 'PosReg', (311, 318))	('vascular endothelial growth factor receptor 2', 'Gene', '16542', (156, 201))	('PDGFRA', 'Gene', (259, 265))	('platelet-derived growth factor receptor alpha', 'Gene', '18595', (212, 257))	('mutations/amplifications', 'Var', (15, 39))	('epidermal growth factor receptor', 'Gene', '13649', (43, 75))	('GBM', 'Phenotype', 'HP:0012174', (132, 135))	('treatment resistance', 'CPA', (327, 347))	('growth', 'CPA', (319, 325))	('altered', 'Reg', (300, 307))	('recurrence', 'CPA', (353, 363))	('RTK', 'Gene', (143, 146))	('c-Met', 'Gene', (272, 277))	('RTK', 'Gene', '13867', (143, 146))	('c-Met', 'Gene', '17295', (272, 277))	('genetic abnormalities', 'Disease', 'MESH:D030342', (107, 128))	('epidermal growth factor receptor', 'Gene', (43, 75))	('genetic abnormalities', 'Disease', (107, 128))	('platelet-derived growth factor receptor alpha', 'Gene', (212, 257))	('vascular endothelial growth factor receptor 2', 'Gene', (156, 201))	('VEGFR2', 'Gene', (203, 209))	('PDGFRA', 'Gene', '18595', (259, 265))	('EGFR', 'Gene', '13649', (204, 208))	('VEGFR2', 'Gene', '16542', (203, 209))	('EGFR', 'Gene', (204, 208))	('EGFR', 'Gene', (77, 81))	('EGFR', 'Gene', '13649', (77, 81))
44167	29844123	Abemaciclib (S7158), palbociclib (S1116) and SGX-523 (S1112) were purchased from Selleckchem.	('SGX-523', 'Chemical', 'MESH:C547925', (45, 52))	('S1116', 'Var', (34, 39))	('S7158', 'Var', (13, 18))	('S1112', 'Var', (54, 59))
44171	29844123	Either G88 (5,000 or 500) or G528 (400,000) GICs were stereotactically injected into the right striatum of six-to-eight-week-old female BALB/c SCID NCr mice.	('G88', 'Chemical', 'MESH:C053236', (7, 10))	('G528', 'Chemical', '-', (29, 33))	('SCID', 'Disease', 'MESH:D053632', (143, 147))	('SCID', 'Disease', (143, 147))	('mice', 'Species', '10090', (152, 156))	('G528 (400,000', 'Var', (29, 42))
44178	29844123	The following antibodies were used for immunoblotting: Cyclin A (sc-751), phospho-Trk (sc-8058), and Trk (sc-7268) antibodies were purchased from Santa Cruz, Actin (A5441) and GAPDH (G9545) were from Sigma-Aldrich, NGF (ab52918), BDNF (ab108319), and HGF (ab83760) were from Abcam and the remaining antibodies including phospho-Trk (4168), phospho-c-Met (3077), c-Met (8198), Cyclin D1 (2978), PARP (9542), and phospho-Rb (9308) were from Cell Signaling.	('c-Met', 'Gene', (348, 353))	('PARP', 'Gene', '11545', (394, 398))	('2978', 'Var', (387, 391))	('c-Met', 'Gene', '17295', (348, 353))	('Trk', 'Gene', '18211', (101, 104))	('Trk', 'Gene', (82, 85))	('Trk', 'Gene', (328, 331))	('GAPDH', 'Gene', (176, 181))	('c-Met', 'Gene', (362, 367))	('PARP', 'Gene', (394, 398))	('Cyclin D1', 'Gene', '12443', (376, 385))	('Rb', 'Chemical', 'MESH:D012413', (419, 421))	('Cyclin A', 'Gene', (55, 63))	('c-Met', 'Gene', '17295', (362, 367))	('GAPDH', 'Gene', '14433', (176, 181))	('Trk', 'Gene', '18211', (328, 331))	('Trk', 'Gene', '18211', (82, 85))	('Cyclin D1', 'Gene', (376, 385))	('Trk', 'Gene', (101, 104))	('Cyclin A', 'Gene', '12428', (55, 63))
44212	29844123	Combining either a c-Met inhibitor (SGX-523) or a pan-Trk inhibitor (PF-06273340) with abemaciclib provided additive to mild synergistic effect (Fig.	('PF-06273340', 'Chemical', 'MESH:C000620071', (69, 80))	('PF-06273340', 'Var', (69, 80))	('Trk', 'Gene', '18211', (54, 57))	('SGX-523', 'Chemical', 'MESH:C547925', (36, 43))	('abemaciclib', 'Chemical', 'MESH:C000590451', (87, 98))	('c-Met', 'Gene', (19, 24))	('Trk', 'Gene', (54, 57))	('c-Met', 'Gene', '17295', (19, 24))
44214	29844123	However, when we combined both SGX-523 and PF-06273340 with abemaciclib, we observed significant synergy, comparable to the altiratinib-based combination treatment (Fig.	('abemaciclib', 'Chemical', 'MESH:C000590451', (60, 71))	('synergy', 'MPA', (97, 104))	('PF-06273340', 'Chemical', 'MESH:C000620071', (43, 54))	('SGX-523', 'Chemical', 'MESH:C547925', (31, 38))	('PF-06273340', 'Var', (43, 54))	('altiratinib', 'Chemical', 'MESH:C000597309', (124, 135))	('combined', 'Interaction', (17, 25))
44216	29844123	Transactivation of RTKs is a well-known adaptive response in cancer cells, leading to more potent stimulation of shared downstream oncogenic mediators.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('RTK', 'Gene', '13867', (19, 22))	('stimulation', 'PosReg', (98, 109))	('cancer', 'Disease', (61, 67))	('RTK', 'Gene', (19, 22))	('Transactivation', 'Var', (0, 15))	('more', 'PosReg', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
44238	29844123	GICs (G88 or G528) were stereotactically injected into the right striatum of six-to-eight-week-old female BALB/c SCID NCr mice.	('SCID', 'Disease', (113, 117))	('mice', 'Species', '10090', (122, 126))	('G88', 'Chemical', 'MESH:C053236', (6, 9))	('SCID', 'Disease', 'MESH:D053632', (113, 117))	('G88', 'Var', (6, 9))	('G528', 'Var', (13, 17))	('G528', 'Chemical', '-', (13, 17))
44253	29844123	Early promising results from phase I/II trials in Ras-mutated melanoma and pancreatic cancer using the combination of CDK4/6 and MEK inhibitors prompted further clinical trials (NCT02022982, NCT02065063).	('melanoma', 'Disease', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('MEK', 'Gene', '17242', (129, 132))	('pancreatic cancer', 'Disease', (75, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))	('NCT02022982', 'Var', (178, 189))	('MEK', 'Gene', (129, 132))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
44270	29844123	On the other hand, CDK4/6 inhibitors may cause severe adverse effects such as thrombocytopenia, neutropenia, anemia, and fatigue.	('thrombocytopenia', 'Disease', (78, 94))	('fatigue', 'Disease', 'MESH:D005221', (121, 128))	('inhibitors', 'Var', (26, 36))	('anemia', 'Disease', 'MESH:D000740', (109, 115))	('fatigue', 'Disease', (121, 128))	('anemia', 'Disease', (109, 115))	('neutropenia', 'Disease', 'MESH:D009503', (96, 107))	('fatigue', 'Phenotype', 'HP:0012378', (121, 128))	('thrombocytopenia', 'Disease', 'MESH:D013921', (78, 94))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (78, 94))	('neutropenia', 'Phenotype', 'HP:0001875', (96, 107))	('CDK4/6', 'Protein', (19, 25))	('anemia', 'Phenotype', 'HP:0001903', (109, 115))	('neutropenia', 'Disease', (96, 107))
44279	29844123	CDK4/6 inhibition in glioblastoma activates the c-Met and TrkA-B pathways mediated by NF-kappaB and can be reversed by a dual c-Met/Trk inhibitor.	('Trk', 'Gene', '18211', (132, 135))	('CDK4/6', 'Protein', (0, 6))	('Trk', 'Gene', (58, 61))	('glioblastoma', 'Disease', (21, 33))	('c-Met', 'Gene', '17295', (126, 131))	('TrkA', 'Gene', '18211', (58, 62))	('NF-kappaB', 'Gene', '18033', (86, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('inhibition', 'Var', (7, 17))	('Trk', 'Gene', '18211', (58, 61))	('c-Met', 'Gene', '17295', (48, 53))	('Trk', 'Gene', (132, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('c-Met', 'Gene', (126, 131))	('TrkA', 'Gene', (58, 62))	('activates', 'PosReg', (34, 43))	('NF-kappaB', 'Gene', (86, 95))	('c-Met', 'Gene', (48, 53))
44280	28358914	Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data Human hemochromatosis protein (HFE) is involved in iron metabolism.	('hemochromatosis', 'Gene', '3077', (121, 136))	('HFE', 'Gene', (146, 149))	('HFE', 'Gene', '3077', (42, 45))	('Human', 'Species', '9606', (115, 120))	('single nucleotide variants', 'Var', (12, 38))	('iron', 'Chemical', 'MESH:D007501', (166, 170))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('HFE', 'Gene', '3077', (146, 149))	('HFE', 'Gene', (42, 45))	('hemochromatosis', 'Gene', (121, 136))
44281	28358914	Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers.	('H63D', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('H63D', 'SUBSTITUTION', 'None', (29, 33))	('associated', 'Reg', (55, 65))	('HFE', 'Gene', '3077', (10, 13))	('C282Y', 'Var', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('HFE', 'Gene', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('C282Y', 'Mutation', 'rs1800562', (38, 43))
44282	28358914	Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM).	('C282Y', 'Mutation', 'rs1800562', (86, 91))	('decreased', 'NegReg', (24, 33))	('HFE', 'Gene', '3077', (92, 95))	('H63D', 'Var', (78, 82))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (124, 147))	('HFE', 'Gene', (92, 95))	('H63D', 'SUBSTITUTION', 'None', (78, 82))	('C282Y', 'Var', (86, 91))	('glioblastoma multiforme', 'Disease', (124, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('patients', 'Species', '9606', (110, 118))
44283	28358914	However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied.	('HFE', 'Gene', (70, 73))	('single nucleotide variation', 'Var', (29, 56))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('HFE', 'Gene', '3077', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
44286	28358914	Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene.	('C282Y', 'Mutation', 'rs1800562', (72, 77))	('HFE', 'Gene', '3077', (94, 97))	('C282Y', 'Var', (72, 77))	('H63D', 'Var', (66, 70))	('HFE', 'Gene', (94, 97))	('H63D', 'SUBSTITUTION', 'None', (66, 70))
44287	28358914	The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119-0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474-0.1159) HFE polymorphisms than 1000Genome.	('H63D', 'SUBSTITUTION', 'None', (86, 90))	('HFE', 'Gene', '3077', (194, 197))	('H63D', 'Var', (86, 90))	('C282Y', 'Mutation', 'rs1800562', (152, 157))	('HFE', 'Gene', (194, 197))	('C282Y', 'Var', (152, 157))
44288	28358914	The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients.	('HFE', 'Gene', '3077', (123, 126))	('HFE', 'Gene', '3077', (102, 105))	('C282Y', 'Mutation', 'rs1800562', (131, 136))	('HFE', 'Gene', (123, 126))	('HFE', 'Gene', (102, 105))	('C282Y', 'Var', (131, 136))	('H63D', 'SUBSTITUTION', 'None', (110, 114))	('H63D', 'Var', (110, 114))	('patients', 'Species', '9606', (141, 149))
44291	28358914	In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients' survival in the TCGA data set of GBM.	('HFE', 'Gene', (56, 59))	('polymorphisms', 'Var', (60, 73))	('impact', 'Reg', (81, 87))	('patients', 'Species', '9606', (92, 100))	('HFE', 'Gene', '3077', (56, 59))
44294	28358914	There are two major mutation sites in the gene for HFE: a single mutation of C to G at nucleotide 187 results in substitution of aspartic acid for histidine at amino acid 63 (H63D), and a second of G to A at nucleotide 845, results in substitution of tyrosine for cysteine at amino acid 282 (C282Y).	('C282Y', 'Mutation', 'rs1800562', (292, 297))	('G to A at nucleotide 845', 'Mutation', 'rs1800562', (198, 222))	('C to G', 'Gene', (77, 83))	('aspartic acid for histidine at amino acid 63', 'Mutation', 'rs1799945', (129, 173))	('substitution', 'Reg', (235, 247))	('HFE', 'Gene', '3077', (51, 54))	('H63D', 'SUBSTITUTION', 'None', (175, 179))	('tyrosine for cysteine', 'MPA', (251, 272))	('H63D', 'Var', (175, 179))	('tyrosine for cysteine at amino acid 282', 'Mutation', 'rs1800562', (251, 290))	('HFE', 'Gene', (51, 54))	('C to G at nucleotide 187', 'Mutation', 'rs1799945', (77, 101))
44295	28358914	Polymorphisms in the HFE gene are relatively common in Caucasians with the frequency for H63D HFE heterozygote and homozygote around 22-28% (22-24% heterozygote and 2.4-4% homozygote) and for C282Y HFE heterozygote and homozygote about 9-10% (8-10% heterozygote and 0.4-1% homozygote).	('HFE', 'Gene', '3077', (198, 201))	('HFE', 'Gene', '3077', (21, 24))	('HFE', 'Gene', (198, 201))	('C282Y', 'Var', (192, 197))	('H63D', 'SUBSTITUTION', 'None', (89, 93))	('HFE', 'Gene', '3077', (94, 97))	('H63D', 'Var', (89, 93))	('HFE', 'Gene', (21, 24))	('C282Y', 'Mutation', 'rs1800562', (192, 197))	('HFE', 'Gene', (94, 97))
44296	28358914	Both HFE polymorphisms are associated with increased cellular iron uptake which may indicate an increased need for iron for cancer cell proliferation.	('HFE', 'Gene', '3077', (5, 8))	('cancer', 'Disease', (124, 130))	('iron', 'Chemical', 'MESH:D007501', (62, 66))	('HFE', 'Gene', (5, 8))	('iron', 'Chemical', 'MESH:D007501', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('increased', 'PosReg', (43, 52))	('cellular iron uptake', 'MPA', (53, 73))	('polymorphisms', 'Var', (9, 22))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
44298	28358914	Expression of H63D or C282Y is more frequent in patients in a number of cancers including malignant glioma compared to unaffected controls.	('glioma', 'Disease', (100, 106))	('C282Y', 'Var', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('C282Y', 'Mutation', 'rs1800562', (22, 27))	('patients', 'Species', '9606', (48, 56))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('H63D', 'Var', (14, 18))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('H63D', 'SUBSTITUTION', 'None', (14, 18))
44299	28358914	Results from a HFE and brain tumor study demonstrated a higher frequency of H63D HFE polymorphism in patients with malignant gliomas.	('patients', 'Species', '9606', (101, 109))	('H63D', 'SUBSTITUTION', 'None', (76, 80))	('brain tumor', 'Disease', 'MESH:D001932', (23, 34))	('H63D', 'Var', (76, 80))	('brain tumor', 'Disease', (23, 34))	('HFE', 'Gene', (15, 18))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('HFE', 'Gene', (81, 84))	('malignant gliomas', 'Disease', (115, 132))	('brain tumor', 'Phenotype', 'HP:0030692', (23, 34))	('malignant gliomas', 'Disease', 'MESH:D005910', (115, 132))	('HFE', 'Gene', '3077', (81, 84))	('HFE', 'Gene', '3077', (15, 18))
44300	28358914	Multiple lines of evidence also suggest that, in addition to being a risk factor for cancer, expression of C282Y HFE polymorphism may enhance its progression.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('HFE', 'Gene', (113, 116))	('cancer', 'Disease', (85, 91))	('C282Y', 'Var', (107, 112))	('HFE', 'Gene', '3077', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('enhance', 'PosReg', (134, 141))	('progression', 'CPA', (146, 157))	('C282Y', 'Mutation', 'rs1800562', (107, 112))
44305	28358914	H63D and C282Y HFE polymorphisms are associated with an increased risk of cancers.	('HFE', 'Gene', (15, 18))	('C282Y', 'Mutation', 'rs1800562', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('H63D', 'SUBSTITUTION', 'None', (0, 4))	('H63D', 'Var', (0, 4))	('C282Y', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('HFE', 'Gene', '3077', (15, 18))
44307	28358914	Previously, in human studies, we found that male GBM patients that expressed H63D HFE polymorphism had poorer survival rates than male GBM patients expressing wild type (WT) HFE.	('HFE', 'Gene', '3077', (82, 85))	('patients', 'Species', '9606', (53, 61))	('survival rates', 'CPA', (110, 124))	('HFE', 'Gene', '3077', (174, 177))	('patients', 'Species', '9606', (139, 147))	('poorer', 'NegReg', (103, 109))	('H63D', 'SUBSTITUTION', 'None', (77, 81))	('H63D', 'Var', (77, 81))	('HFE', 'Gene', (174, 177))	('HFE', 'Gene', (82, 85))	('human', 'Species', '9606', (15, 20))
44309	28358914	The effect of other single nucleotide variant (SNV) in the HFE gene on cancer development and progression has not been systematically studied.	('single nucleotide', 'Var', (20, 37))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('HFE', 'Gene', '3077', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HFE', 'Gene', (59, 62))
44313	28358914	However, due to lack of Variant Call Format (VCF) or Mutation Annotation Format (MAF) files of GBM in the portal (personal communication with TCGA), gene sequence data was obtained to identify SNVs in the HFE gene of the GBM patients.	('HFE', 'Gene', '3077', (205, 208))	('SNVs', 'Var', (193, 197))	('HFE', 'Gene', (205, 208))	('patients', 'Species', '9606', (225, 233))
44315	28358914	Variants in the HFE gene were then identified from these sequences using the Genome Analysis Toolkit (GATK) software based on the GATK best practices pipeline.	('HFE', 'Gene', '3077', (16, 19))	('Variants', 'Var', (0, 8))	('HFE', 'Gene', (16, 19))
44316	28358914	The University of California Santa Cruz (UCSC) table browser was used to download all of the variants of the HFE gene to determine allele frequency of the general population based on dbSNP Build 142.	('HFE', 'Gene', '3077', (109, 112))	('variants', 'Var', (93, 101))	('HFE', 'Gene', (109, 112))	('California Santa Cruz', 'Disease', (18, 39))	('California Santa Cruz', 'Disease', 'MESH:D004670', (18, 39))
44322	28358914	In this study, we focused on the role of SNVs in the HFE gene and its association with survival in Caucasian patient samples as HFE polymorphisms are most prevalent in the Caucasian population.	('HFE', 'Gene', '3077', (53, 56))	('patient', 'Species', '9606', (109, 116))	('HFE', 'Gene', (53, 56))	('HFE', 'Gene', '3077', (128, 131))	('polymorphisms', 'Var', (132, 145))	('HFE', 'Gene', (128, 131))
44323	28358914	We selected only Caucasian samples with both SNVs in the HFE gene and clinical information available for gender and survival analysis.	('SNVs', 'Var', (45, 49))	('HFE', 'Gene', '3077', (57, 60))	('HFE', 'Gene', (57, 60))
44325	28358914	Kaplan-Meier plots were used to illustrate the relationship between patient's overall survival and HFE polymorphisms; and, these relationships were tested by log-rank test.	('polymorphisms', 'Var', (103, 116))	('HFE', 'Gene', '3077', (99, 102))	('HFE', 'Gene', (99, 102))	('patient', 'Species', '9606', (68, 75))
44327	28358914	HFE polymorphisms are more prevalent in Caucasians than in other races, thus we only used Caucasians data for the frequency of SNVs including H63D and C282Y HFE polymorphisms in the HFE gene and its association with survival analysis.	('H63D', 'SUBSTITUTION', 'None', (142, 146))	('HFE', 'Gene', '3077', (157, 160))	('C282Y', 'Mutation', 'rs1800562', (151, 156))	('HFE', 'Gene', '3077', (182, 185))	('HFE', 'Gene', '3077', (0, 3))	('C282Y', 'Var', (151, 156))	('HFE', 'Gene', (182, 185))	('HFE', 'Gene', (157, 160))	('HFE', 'Gene', (0, 3))	('H63D', 'Var', (142, 146))
44334	28358914	One patient's NB sample had C282Y heterozygote, but its tumor tissue had no mutation at 282 amino acid in the HFE gene.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('patient', 'Species', '9606', (4, 11))	('C282Y', 'Var', (28, 33))	('HFE', 'Gene', '3077', (110, 113))	('HFE', 'Gene', (110, 113))	('C282Y', 'Mutation', 'rs1800562', (28, 33))
44335	28358914	The other NB sample also had C282Y heterozygote; while, the TP sample had C282Y homozygote.	('C282Y', 'Var', (29, 34))	('C282Y', 'Var', (74, 79))	('C282Y', 'Mutation', 'rs1800562', (29, 34))	('C282Y', 'Mutation', 'rs1800562', (74, 79))
44338	28358914	Among those 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) were in the exon of HFE gene.	('H63D', 'SUBSTITUTION', 'None', (72, 76))	('H63D', 'Var', (72, 76))	('C282Y', 'Var', (78, 83))	('HFE', 'Gene', (105, 108))	('C282Y', 'Mutation', 'rs1800562', (78, 83))	('HFE', 'Gene', '3077', (105, 108))
44339	28358914	The statistical analysis indicated that blood normal of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119-0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474-0.1159) HFE polymorphisms than 1000Genome (Table 2).	('HFE', 'Gene', (183, 186))	('C282Y', 'Mutation', 'rs1800562', (141, 146))	('H63D', 'SUBSTITUTION', 'None', (75, 79))	('H63D', 'Var', (75, 79))	('HFE', 'Gene', '3077', (183, 186))	('C282Y', 'Var', (141, 146))
44340	28358914	The H63D genotype was present in 26.4% (23.0% heterozygote + 2.3% homozygote + 1.1% compound mutation:a sample with both H63D and C282Y HFE polymorphisms); while, the C282Y genotype was present in 7.6% (6.1% heterozygote + 0.4% homozygote + 1.1% compound mutation) in blood normal samples (Table 3).	('C282Y', 'Var', (167, 172))	('HFE', 'Gene', '3077', (136, 139))	('C282Y', 'Var', (130, 135))	('C282Y', 'Mutation', 'rs1800562', (130, 135))	('C282Y', 'Mutation', 'rs1800562', (167, 172))	('H63D', 'SUBSTITUTION', 'None', (4, 8))	('HFE', 'Gene', (136, 139))	('H63D', 'Var', (4, 8))	('H63D', 'SUBSTITUTION', 'None', (121, 125))	('H63D', 'Var', (121, 125))
44341	28358914	When we stratified H63D and C282Y HFE genotype by gender (Table 4), we found 23.8% H63D heterozygote, 2.4% H63D homozygote, and 1.2% compound mutation in male.	('H63D', 'SUBSTITUTION', 'None', (19, 23))	('H63D', 'Var', (19, 23))	('HFE', 'Gene', '3077', (34, 37))	('compound mutation', 'Var', (133, 150))	('C282Y', 'Var', (28, 33))	('H63D', 'SUBSTITUTION', 'None', (107, 111))	('H63D', 'SUBSTITUTION', 'None', (83, 87))	('HFE', 'Gene', (34, 37))	('H63D', 'Var', (83, 87))	('C282Y', 'Mutation', 'rs1800562', (28, 33))	('H63D', 'Var', (107, 111))
44342	28358914	In female, there were 21.6% heterozygote, 2.1% homozygote, and 1% compound mutation for H63D HFE.	('compound mutation', 'Var', (66, 83))	('HFE', 'Gene', (93, 96))	('H63D', 'SUBSTITUTION', 'None', (88, 92))	('H63D', 'Var', (88, 92))	('HFE', 'Gene', '3077', (93, 96))
44343	28358914	For the C282Y genotype, there were 5.5% C282Y heterozygote, 1.0% C282Y homozygote, and 1.2% compound mutation in male.	('C282Y', 'Var', (40, 45))	('compound mutation', 'Var', (92, 109))	('C282Y', 'Mutation', 'rs1800562', (8, 13))	('C282Y', 'Mutation', 'rs1800562', (40, 45))	('C282Y', 'Var', (8, 13))	('C282Y', 'Mutation', 'rs1800562', (65, 70))
44345	28358914	When we analyzed gender effect on H63D and C282Y HFE genotype between our previous sample and TCGA GBM NB samples, there were no differences between male and female in the H63D genotype (p = 0.31 for male & p = 0.86 for female by Chi-Square test) or in the C282Y genotype (p = 0.68 for male & p = 0.98 for female by Chi-Square test).	('C282Y', 'Var', (43, 48))	('HFE', 'Gene', '3077', (49, 52))	('the', 'Var', (253, 256))	('C282Y', 'Mutation', 'rs1800562', (43, 48))	('H63D', 'SUBSTITUTION', 'None', (34, 38))	('H63D', 'Var', (34, 38))	('H63D', 'SUBSTITUTION', 'None', (172, 176))	('H63D', 'Var', (172, 176))	('HFE', 'Gene', (49, 52))	('C282Y', 'Mutation', 'rs1800562', (257, 262))
44347	28358914	S65C and Q277K, in NB was not different than the frequency in 1000Genome.	('S65C', 'Mutation', 'rs1800730', (0, 4))	('S65C', 'Var', (0, 4))	('Q277K', 'Mutation', 'p.Q277K', (9, 14))	('Q277K', 'Var', (9, 14))
44348	28358914	A small number of NB samples demonstrated variation at that position, corresponding to S65C and Q277K.	('Q277K', 'Var', (96, 101))	('S65C', 'Mutation', 'rs1800730', (87, 91))	('S65C', 'Var', (87, 91))	('Q277K', 'Mutation', 'p.Q277K', (96, 101))
44349	28358914	There were 6 samples with variations in S65C and only one sample had variation in Q277K in NB samples of TCGA GBM.	('S65C', 'Var', (40, 44))	('Q277K', 'Mutation', 'p.Q277K', (82, 87))	('variations', 'Var', (26, 36))	('S65C', 'Mutation', 'rs1800730', (40, 44))
44350	28358914	Interestingly, one intron position SNV (Position 26091336), a known benign risk factor for hemochromatosis and located near exon 2, has increased frequency in NB samples compared to the frequency of 1000Genome (p<0.0001, 95% CI: 0.4739-0.5981) (Table 2).	('increased', 'PosReg', (136, 145))	('hemochromatosis', 'Gene', (91, 106))	('Position 26091336', 'Var', (40, 57))	('hemochromatosis', 'Gene', '3077', (91, 106))
44353	28358914	The Kaplan-Meier survival curve for the 264 Caucasian GBM samples revealed no difference between wild type (WT) and H63D HFE polymorphism GBM samples in log-rank test (p = 0.27) (Fig 1A).	('H63D', 'SUBSTITUTION', 'None', (116, 120))	('HFE', 'Gene', '3077', (121, 124))	('HFE', 'Gene', (121, 124))	('H63D', 'Var', (116, 120))
44357	28358914	Previously, we reported that male H63D HFE polymorphism GBM patients had poorer survival than male WT HFE GBM patients; and, female C282Y HFE polymorphism demonstrated poorer survival than male C282Y HFE polymorphism patients.	('HFE', 'Gene', '3077', (39, 42))	('poorer', 'NegReg', (168, 174))	('HFE', 'Gene', '3077', (102, 105))	('patients', 'Species', '9606', (60, 68))	('HFE', 'Gene', (200, 203))	('HFE', 'Gene', (39, 42))	('C282Y', 'Mutation', 'rs1800562', (132, 137))	('C282Y', 'Mutation', 'rs1800562', (194, 199))	('HFE', 'Gene', (102, 105))	('poorer', 'NegReg', (73, 79))	('HFE', 'Gene', '3077', (138, 141))	('H63D', 'SUBSTITUTION', 'None', (34, 38))	('H63D', 'Var', (34, 38))	('patients', 'Species', '9606', (217, 225))	('HFE', 'Gene', '3077', (200, 203))	('survival', 'CPA', (80, 88))	('HFE', 'Gene', (138, 141))	('patients', 'Species', '9606', (110, 118))
44359	28358914	The Kaplan-Meier survival curve for the 167 male GBM patients revealed no difference between WT and H63D HFE polymorphism (p = 0.75 in log-rank test) (Fig 2A).	('patients', 'Species', '9606', (53, 61))	('HFE', 'Gene', (105, 108))	('HFE', 'Gene', '3077', (105, 108))	('H63D', 'SUBSTITUTION', 'None', (100, 104))	('H63D', 'Var', (100, 104))
44360	28358914	The Kaplan-Meier survival curve for the 97 female GBM patients revealed no difference between WT and H63D HFE polymorphism (p = 0.14 in log-rank test) (Fig 2B).	('H63D', 'SUBSTITUTION', 'None', (101, 105))	('H63D', 'Var', (101, 105))	('HFE', 'Gene', '3077', (106, 109))	('patients', 'Species', '9606', (54, 62))	('HFE', 'Gene', (106, 109))
44361	28358914	Furthermore, when examining C282Y HFE polymorphism and survival analysis, there were no differences between WT and C282Y HFE polymorphism in males (p = 0.61 in log-rank test) as well as in females (p = 0.93 in log-rank test) (Fig 2C & 2D).	('HFE', 'Gene', (121, 124))	('C282Y', 'Mutation', 'rs1800562', (115, 120))	('HFE', 'Gene', '3077', (34, 37))	('HFE', 'Gene', '3077', (121, 124))	('C282Y', 'Var', (115, 120))	('HFE', 'Gene', (34, 37))	('C282Y', 'Mutation', 'rs1800562', (28, 33))
44362	28358914	Next, we determined survival between males and females with H63D or C282Y HFE polymorphisms.	('HFE', 'Gene', (74, 77))	('H63D', 'SUBSTITUTION', 'None', (60, 64))	('H63D', 'Var', (60, 64))	('C282Y', 'Var', (68, 73))	('C282Y', 'Mutation', 'rs1800562', (68, 73))	('HFE', 'Gene', '3077', (74, 77))
44366	28358914	We found one year survival status was not affected by H63D mutation (p = 0.31) or C282Y mutation (p = 0.58) in Fisher's exact test.	('H63D', 'Var', (54, 58))	('C282Y', 'Mutation', 'rs1800562', (82, 87))	('C282Y mutation', 'Var', (82, 96))	('H63D', 'SUBSTITUTION', 'None', (54, 58))
44367	28358914	The Kaplan-Meier survival curve for the 100 Caucasian GBM patients who enrolled at Henry Ford Hospital revealed no difference between WT HFE GBM patients and H63D HFE polymorphism GBM patients in log-rank test (p = 0.63) (Fig 4A).	('patients', 'Species', '9606', (145, 153))	('HFE', 'Gene', (163, 166))	('HFE', 'Gene', '3077', (137, 140))	('patients', 'Species', '9606', (184, 192))	('H63D', 'SUBSTITUTION', 'None', (158, 162))	('HFE', 'Gene', '3077', (163, 166))	('HFE', 'Gene', (137, 140))	('H63D', 'Var', (158, 162))	('patients', 'Species', '9606', (58, 66))
44368	28358914	The survival between WT HFE GBM patients and C282Y HFE polymorphism GBM patients was also not different in log-rank test (p = 0.34) (Fig 4B).	('patients', 'Species', '9606', (32, 40))	('C282Y', 'Mutation', 'rs1800562', (45, 50))	('HFE', 'Gene', '3077', (24, 27))	('HFE', 'Gene', '3077', (51, 54))	('C282Y', 'Var', (45, 50))	('HFE', 'Gene', (51, 54))	('HFE', 'Gene', (24, 27))	('patients', 'Species', '9606', (72, 80))
44370	28358914	The Kaplan-Meier survival curve for the 63 male GBM patients revealed no difference between WT and H63D HFE polymorphism (p = 0.50 in log-rank test) (Fig 5A).	('H63D', 'SUBSTITUTION', 'None', (99, 103))	('HFE', 'Gene', '3077', (104, 107))	('H63D', 'Var', (99, 103))	('HFE', 'Gene', (104, 107))	('patients', 'Species', '9606', (52, 60))
44371	28358914	The Kaplan-Meier survive curve for the 37 female GBM patients also revealed no difference between WT and H63D HFE polymorphism (p = 0.84 in log-rank test) (Fig 5B).	('H63D', 'SUBSTITUTION', 'None', (105, 109))	('patients', 'Species', '9606', (53, 61))	('H63D', 'Var', (105, 109))	('HFE', 'Gene', '3077', (110, 113))	('HFE', 'Gene', (110, 113))
44372	28358914	For C282Y HFE polymorphism and survival analysis, there were no difference between WT and C282Y HFE polymorphism in male (p = 0.24 in log-rank test) (Fig 5C) as well as in female (p = 0.84 in log-rank test) (Fig 5D).	('C282Y', 'Mutation', 'rs1800562', (90, 95))	('HFE', 'Gene', '3077', (96, 99))	('HFE', 'Gene', '3077', (10, 13))	('HFE', 'Gene', (10, 13))	('C282Y', 'Var', (90, 95))	('HFE', 'Gene', (96, 99))	('C282Y', 'Mutation', 'rs1800562', (4, 9))
44373	28358914	The Kaplan-Meier survival curve for the 27 H63D GBM patients revealed no difference between male and female patients (p = 0.87 in log-rank test) (Fig 6A).	('H63D', 'SUBSTITUTION', 'None', (43, 47))	('H63D', 'Var', (43, 47))	('patients', 'Species', '9606', (108, 116))	('GBM', 'Gene', (48, 51))	('patients', 'Species', '9606', (52, 60))
44375	28358914	According to PROGgeneV2, high HFE gene expression in GBM patients in the TCGA database demonstrated poorer survival compared to low HFE gene expressed GBM patients (Fig 7A).	('low HFE', 'Phenotype', 'HP:0011905', (128, 135))	('HFE', 'Gene', '3077', (30, 33))	('HFE', 'Gene', (132, 135))	('survival', 'MPA', (107, 115))	('patients', 'Species', '9606', (57, 65))	('HFE', 'Gene', (30, 33))	('poorer', 'NegReg', (100, 106))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (155, 163))	('HFE', 'Gene', '3077', (132, 135))
44376	28358914	We hypothesized that H63D and/or C282Y HFE polymorphism GBM patients express higher levels of the HFE gene than those GBM patients with WT HFE gene; and, that this difference in expression levels results in poorer survival for the H63D and/or C282Y HFE polymorphism group.	('H63D', 'Var', (231, 235))	('HFE', 'Gene', (39, 42))	('H63D', 'SUBSTITUTION', 'None', (21, 25))	('HFE', 'Gene', '3077', (139, 142))	('HFE', 'Gene', '3077', (249, 252))	('HFE', 'Gene', '3077', (98, 101))	('higher', 'PosReg', (77, 83))	('patients', 'Species', '9606', (60, 68))	('C282Y', 'Var', (243, 248))	('levels', 'MPA', (84, 90))	('H63D', 'Var', (21, 25))	('C282Y', 'Var', (33, 38))	('HFE', 'Gene', (139, 142))	('survival', 'MPA', (214, 222))	('HFE', 'Gene', (249, 252))	('patients', 'Species', '9606', (122, 130))	('HFE', 'Gene', (98, 101))	('C282Y', 'Mutation', 'rs1800562', (243, 248))	('poorer', 'NegReg', (207, 213))	('HFE', 'Gene', '3077', (39, 42))	('H63D', 'SUBSTITUTION', 'None', (231, 235))	('C282Y', 'Mutation', 'rs1800562', (33, 38))
44379	28358914	Among them, there are 39 H63D HFE polymorphisms and 6 C282Y HFE polymorphisms (Fig 7B).	('HFE', 'Gene', '3077', (30, 33))	('C282Y', 'Var', (54, 59))	('HFE', 'Gene', (60, 63))	('HFE', 'Gene', (30, 33))	('C282Y', 'Mutation', 'rs1800562', (54, 59))	('H63D', 'SUBSTITUTION', 'None', (25, 29))	('H63D', 'Var', (25, 29))	('HFE', 'Gene', '3077', (60, 63))
44380	28358914	The level of HFE gene expression was not different between the H63D HFE polymorphism GBM patients and WT patients (p = 0.31 for heterozygote, p = 0.60 for homozygote) in two sample t-test (Fig 7C).	('patients', 'Species', '9606', (105, 113))	('HFE', 'Gene', '3077', (68, 71))	('HFE', 'Gene', '3077', (13, 16))	('HFE', 'Gene', (68, 71))	('HFE', 'Gene', (13, 16))	('patients', 'Species', '9606', (89, 97))	('H63D', 'SUBSTITUTION', 'None', (63, 67))	('H63D', 'Var', (63, 67))
44381	28358914	There were also no differences between C282Y HFE polymorphism and HFE gene expression level (p = 0.38 for heterozygote, p = 0.11 for homozygote) in two sample t-test (Fig 7D).	('HFE', 'Gene', '3077', (66, 69))	('C282Y', 'Mutation', 'rs1800562', (39, 44))	('HFE', 'Gene', '3077', (45, 48))	('HFE', 'Gene', (66, 69))	('HFE', 'Gene', (45, 48))	('C282Y', 'Var', (39, 44))
44382	28358914	In the present TCGA GBM database study, we found that the frequency of two common HFE polymorphisms (H63D, C282Y) and several SNVs in the intron of HFE is increased in blood normal of TCGA GBM compared to the frequency of SNV in1000Genome.	('H63D', 'SUBSTITUTION', 'None', (101, 105))	('H63D', 'Var', (101, 105))	('HFE', 'Gene', '3077', (82, 85))	('HFE', 'Gene', (148, 151))	('increased', 'PosReg', (155, 164))	('HFE', 'Gene', (82, 85))	('C282Y', 'Var', (107, 112))	('HFE', 'Gene', '3077', (148, 151))	('C282Y', 'Mutation', 'rs1800562', (107, 112))
44383	28358914	In addition, there was no difference in survival between WT HFE and H63D or C282Y HFE polymorphism TCGA GBM patients.	('HFE', 'Gene', '3077', (82, 85))	('C282Y', 'Mutation', 'rs1800562', (76, 81))	('HFE', 'Gene', (60, 63))	('H63D', 'SUBSTITUTION', 'None', (68, 72))	('H63D', 'Var', (68, 72))	('HFE', 'Gene', (82, 85))	('patients', 'Species', '9606', (108, 116))	('HFE', 'Gene', '3077', (60, 63))
44385	28358914	We used TCGA GBM data for this study because H63D HFE polymorphism information was not available in genome-wide association studies (GWAS) of GBM patients.	('HFE', 'Gene', (50, 53))	('H63D', 'SUBSTITUTION', 'None', (45, 49))	('H63D', 'Var', (45, 49))	('HFE', 'Gene', '3077', (50, 53))	('patients', 'Species', '9606', (146, 154))
44387	28358914	As in our previous study, we only used data from Caucasian samples for HFE genotype and survival analysis in TCGA GBM in this study because both HFE polymorphisms (H63D, C282Y) are more prevalent in Caucasians than in other races.	('HFE', 'Gene', (145, 148))	('HFE', 'Gene', (71, 74))	('C282Y', 'Mutation', 'rs1800562', (170, 175))	('HFE', 'Gene', '3077', (145, 148))	('H63D', 'SUBSTITUTION', 'None', (164, 168))	('H63D', 'Var', (164, 168))	('C282Y', 'Var', (170, 175))	('HFE', 'Gene', '3077', (71, 74))
44389	28358914	Compared to our previous study, the number of H63D or C282Y HFE polymorphism GBM patients was increased from 25 (19 H63D, 6 C282Y) to 90 (70 H63D, 20 C282Y -including 3 H63D/C282Y).	('H63D', 'Var', (141, 145))	('H63D', 'SUBSTITUTION', 'None', (46, 50))	('H63D', 'SUBSTITUTION', 'None', (169, 173))	('H63D', 'Var', (46, 50))	('H63D', 'Var', (169, 173))	('C282Y', 'Var', (54, 59))	('HFE', 'Gene', (60, 63))	('C282Y', 'Mutation', 'rs1800562', (124, 129))	('patients', 'Species', '9606', (81, 89))	('C282Y', 'Mutation', 'rs1800562', (54, 59))	('H63D', 'SUBSTITUTION', 'None', (116, 120))	('H63D', 'Var', (116, 120))	('C282Y', 'Mutation', 'rs1800562', (150, 155))	('C282Y', 'Mutation', 'rs1800562', (174, 179))	('C282Y', 'Var', (124, 129))	('H63D', 'SUBSTITUTION', 'None', (141, 145))	('HFE', 'Gene', '3077', (60, 63))
44390	28358914	The number of male or female HFE polymorphism GBM samples also increased: 46 male H63D GBM samples in the present study while there were only 9 male H63D GBM samples in the previous study.	('H63D', 'SUBSTITUTION', 'None', (149, 153))	('H63D', 'Var', (149, 153))	('HFE', 'Gene', (29, 32))	('H63D', 'SUBSTITUTION', 'None', (82, 86))	('H63D', 'Var', (82, 86))	('polymorphism', 'Var', (33, 45))	('HFE', 'Gene', '3077', (29, 32))
44392	28358914	The two exon position SNVs were H63D and C282Y HFE polymorphisms.	('C282Y', 'Mutation', 'rs1800562', (41, 46))	('H63D', 'SUBSTITUTION', 'None', (32, 36))	('H63D', 'Var', (32, 36))	('HFE', 'Gene', '3077', (47, 50))	('HFE', 'Gene', (47, 50))	('C282Y', 'Var', (41, 46))
44393	28358914	These data indicated H63D and C282Y HFE polymorphisms as risk factors for GBM.	('HFE', 'Gene', (36, 39))	('risk', 'Reg', (57, 61))	('C282Y', 'Var', (30, 35))	('H63D', 'Var', (21, 25))	('C282Y', 'Mutation', 'rs1800562', (30, 35))	('GBM', 'Disease', (74, 77))	('H63D', 'SUBSTITUTION', 'None', (21, 25))	('HFE', 'Gene', '3077', (36, 39))
44394	28358914	There was a decreased frequency of C282Y HFE polymorphism in a population of hepatocellular carcinoma patients from Spain compared to a control group, while an increased frequency of H63D HFE polymorphism is noted in a sample of high glioma patients from Italy.	('H63D', 'Var', (183, 187))	('HFE', 'Gene', '3077', (188, 191))	('HFE', 'Gene', '3077', (41, 44))	('C282Y', 'Mutation', 'rs1800562', (35, 40))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (77, 101))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('HFE', 'Gene', (188, 191))	('hepatocellular carcinoma', 'Disease', (77, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (77, 101))	('C282Y', 'Var', (35, 40))	('decreased', 'NegReg', (12, 21))	('HFE', 'Gene', (41, 44))	('glioma', 'Disease', (234, 240))	('patients', 'Species', '9606', (241, 249))	('H63D', 'SUBSTITUTION', 'None', (183, 187))
44396	28358914	The impact of HFE polymorphisms on patient survival in cancers has been reported in 4 studies.	('HFE', 'Gene', (14, 17))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient', 'Species', '9606', (35, 42))	('HFE', 'Gene', '3077', (14, 17))	('polymorphisms', 'Var', (18, 31))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
44399	28358914	found no association between H63D and C282Y HFE polymorphisms and WT HFE breast cancer patients' survival in Brazilian women.	('HFE', 'Gene', '3077', (44, 47))	('H63D', 'Var', (29, 33))	('H63D', 'SUBSTITUTION', 'None', (29, 33))	('HFE', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('HFE', 'Gene', '3077', (69, 72))	('C282Y', 'Var', (38, 43))	('WT HFE breast cancer', 'Disease', (66, 86))	('WT HFE breast cancer', 'Disease', 'MESH:D006432', (66, 86))	('women', 'Species', '9606', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('C282Y', 'Mutation', 'rs1800562', (38, 43))	('patients', 'Species', '9606', (87, 95))	('HFE', 'Gene', (69, 72))
44400	28358914	Recently, we reported that there was a statistically significant shorter survival for male GBM patients with the H63D HFE polymorphism compared to male GBM patients with WT HFE (p = 0.03 by log-rank test).	('HFE', 'Gene', (173, 176))	('patients', 'Species', '9606', (156, 164))	('HFE', 'Gene', (118, 121))	('survival', 'MPA', (73, 81))	('patients', 'Species', '9606', (95, 103))	('shorter', 'NegReg', (65, 72))	('H63D', 'SUBSTITUTION', 'None', (113, 117))	('H63D', 'Var', (113, 117))	('HFE', 'Gene', '3077', (173, 176))	('HFE', 'Gene', '3077', (118, 121))
44401	28358914	Moreover, we reported that female GBM patients with the C282Y HFE polymorphism had decreased survival compared to male GBM patients with C282Y HFE polymorphism (p = 0.05 by log-rank test).	('survival', 'MPA', (93, 101))	('C282Y', 'Mutation', 'rs1800562', (56, 61))	('HFE', 'Gene', '3077', (143, 146))	('HFE', 'Gene', '3077', (62, 65))	('decreased', 'NegReg', (83, 92))	('patients', 'Species', '9606', (123, 131))	('HFE', 'Gene', (62, 65))	('HFE', 'Gene', (143, 146))	('patients', 'Species', '9606', (38, 46))	('C282Y', 'Var', (56, 61))	('C282Y', 'Mutation', 'rs1800562', (137, 142))
44404	28358914	However, H63D or C282Y HFE polymorphism GBM patients' survival data of TCGA GBM database revealed no difference from WT, even when we consider gender status (Fig 3).	('H63D', 'Var', (9, 13))	('HFE', 'Gene', '3077', (23, 26))	('patients', 'Species', '9606', (44, 52))	('H63D', 'SUBSTITUTION', 'None', (9, 13))	('HFE', 'Gene', (23, 26))	('C282Y', 'Var', (17, 22))	('C282Y', 'Mutation', 'rs1800562', (17, 22))
44406	28358914	Furthermore, the relationship between 1 year survival status and HFE genotype indicated that the proportion of H63D or C282Y HFE polymorphism was not different from WT HFE GBM patients.	('H63D', 'SUBSTITUTION', 'None', (111, 115))	('patients', 'Species', '9606', (176, 184))	('H63D', 'Var', (111, 115))	('HFE', 'Gene', '3077', (168, 171))	('HFE', 'Gene', (125, 128))	('C282Y', 'Var', (119, 124))	('HFE', 'Gene', '3077', (65, 68))	('HFE', 'Gene', '3077', (125, 128))	('HFE', 'Gene', (168, 171))	('HFE', 'Gene', (65, 68))	('C282Y', 'Mutation', 'rs1800562', (119, 124))
44410	28358914	For example, our study patients and TCGA GBM patients were treated with radiation and/or multiple choice of therapies such as chemotherapy (e.g., temozolomide, irinotecan, paclitaxel, procarbazine, BCNU, CCNU, fenretinide, carboplatin, VP-16), immunotherapy (1L-13 with pseudomonas exotoxin, HSPPC-96 vaccine), targeted molecular therapy (e.g., bevacizumab, O6-benzylguanine), hormone therapy (dexamethasone).	('patients', 'Species', '9606', (23, 31))	('VP-16', 'Gene', (236, 241))	('patients', 'Species', '9606', (45, 53))	('O6-benzylguanine', 'Var', (358, 374))	('VP-16', 'Gene', '3054', (236, 241))
44416	28358914	In conclusion, our data demonstrated that two common H63D and C282Y HFE polymorphisms and several SNVs in the intron of the HFE gene were increased in TCGA GBM; and, require further investigation into the role of cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('increased', 'PosReg', (138, 147))	('C282Y', 'Mutation', 'rs1800562', (62, 67))	('HFE', 'Gene', '3077', (68, 71))	('TCGA', 'Disease', (151, 155))	('H63D', 'SUBSTITUTION', 'None', (53, 57))	('HFE', 'Gene', (68, 71))	('H63D', 'Var', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('C282Y', 'Var', (62, 67))	('HFE', 'Gene', '3077', (124, 127))	('cancer', 'Disease', (213, 219))	('HFE', 'Gene', (124, 127))
44417	28358914	Our results also demonstrated that H63D and C282Y HFE polymorphisms do not impact GBM patients' survival in the TCGA GBM database.	('H63D', 'SUBSTITUTION', 'None', (35, 39))	('impact', 'Reg', (75, 81))	('H63D', 'Var', (35, 39))	('C282Y', 'Var', (44, 49))	('HFE', 'Gene', (50, 53))	('C282Y', 'Mutation', 'rs1800562', (44, 49))	('HFE', 'Gene', '3077', (50, 53))	('patients', 'Species', '9606', (86, 94))
44418	28358914	Further collaborative studies are needed to determine whether the role of H63D and C282Y HFE polymorphisms on cancer patients' survival is region specific.	('C282Y', 'Mutation', 'rs1800562', (83, 88))	('cancer', 'Disease', (110, 116))	('HFE', 'Gene', '3077', (89, 92))	('H63D', 'SUBSTITUTION', 'None', (74, 78))	('H63D', 'Var', (74, 78))	('C282Y', 'Var', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HFE', 'Gene', (89, 92))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
44459	27998280	Care was taken to exclude blood vessels and areas of cystic change or necrosis, defined as abnormal areas with hyperintense signal on T2-weighted and hypointense signal on T1-weighted without discernible enhancement after GBCA injection.	('cystic change', 'Disease', (53, 66))	('necrosis', 'Disease', (70, 78))	('necrosis', 'Disease', 'MESH:D009336', (70, 78))	('cystic change', 'Disease', 'MESH:D052177', (53, 66))	('hypointense', 'Var', (150, 161))
44510	27998280	While the incidence of serious anaphylaxis risk is approximately 10 times higher using ferumoxytol compared to most GBCAs, the absolute incidence of severe side effects remains small, approximately 1:10,000.	('ferumoxytol', 'Var', (87, 98))	('higher', 'PosReg', (74, 80))	('GBCAs', 'Chemical', '-', (116, 121))	('ferumoxytol', 'Chemical', 'MESH:D052203', (87, 98))	('anaphylaxis', 'Phenotype', 'HP:0100845', (31, 42))
44522	26248280	In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('OKN-007', 'Var', (43, 50))	('rat', 'Species', '10116', (187, 190))	('tumor', 'Disease', (86, 91))	('decrease', 'NegReg', (77, 85))	('increase', 'PosReg', (145, 153))	('perfusion rates', 'CPA', (177, 192))	('survival', 'CPA', (121, 129))	('increase', 'PosReg', (112, 120))	('OKN-007', 'Chemical', '-', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('diffusion', 'CPA', (154, 163))
44538	26248280	Immunohistochemistry (IHC) assessment of commonly studied tumor markers for cell proliferation or differentiation, hypoxia, angiogenesis, and apoptosis indicated that OKN-007 was able to significantly decrease cell proliferation (glucose transporter 1 (Glut-1) and the cell proliferation marker, MIB-1) but not cell differentiation (carbonate anhydrase IX), decrease angiogenesis (microvessel density (MVD; measured as levels of the endothelial marker, CD-31), but not the vascular endothelial growth factor (VEGF)), decrease hypoxia (hypoxia inducible factor 1 alpha (HIF-1alpha)), and increase apoptosis (cleaved caspase 3) compared with untreated controls.	('hypoxia', 'Disease', 'MESH:D000860', (535, 542))	('HIF-1alpha', 'Gene', '15251', (569, 579))	('apoptosis', 'CPA', (596, 605))	('glucose transporter 1', 'Gene', (230, 251))	('rat', 'Species', '10116', (88, 91))	('angiogenesis', 'CPA', (367, 379))	('cell proliferation', 'CPA', (210, 228))	('MIB-1', 'Gene', (296, 301))	('hypoxia', 'Disease', 'MESH:D000860', (526, 533))	('glucose transporter 1', 'Gene', '20525', (230, 251))	('HIF-1alpha', 'Gene', (569, 579))	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('MIB-1', 'Gene', '225164', (296, 301))	('Glut-1', 'Gene', '20525', (253, 259))	('OKN-007', 'Chemical', '-', (167, 174))	('tumor', 'Disease', (58, 63))	('rat', 'Species', '10116', (222, 225))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('decrease', 'NegReg', (201, 209))	('vascular endothelial growth factor', 'Gene', (473, 507))	('VEGF', 'Gene', (509, 513))	('Glut-1', 'Gene', (253, 259))	('VEGF', 'Gene', '22339', (509, 513))	('hypoxia inducible factor 1 alpha', 'Gene', (535, 567))	('decrease', 'NegReg', (358, 366))	('vascular endothelial growth factor', 'Gene', '22339', (473, 507))	('OKN-007', 'Var', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('hypoxia', 'Disease', (535, 542))	('decrease', 'NegReg', (517, 525))	('hypoxia inducible factor 1 alpha', 'Gene', '15251', (535, 567))	('hypoxia', 'Disease', (526, 533))	('increase', 'PosReg', (587, 595))	('rat', 'Species', '10116', (281, 284))	('hypoxia', 'Disease', (115, 122))
44539	26248280	OKN-007-induced decreases in Glut-1 and HIF-1alpha levels seemed to be similar in both F98 and U87 glioma models, whereas increased apoptosis seemed to be more elevated in the F98 gliomas compared to the U87 tumors.	('gliomas', 'Disease', (180, 187))	('Glut-1', 'Gene', '20525', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Disease', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('OKN-007-induced', 'Gene', (0, 15))	('OKN-007', 'Chemical', '-', (0, 7))	('U87', 'Gene', (95, 98))	('gliomas', 'Disease', 'MESH:D005910', (180, 187))	('U87', 'Gene', '641648', (204, 207))	('Glut-1', 'Gene', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('F98', 'Var', (176, 179))	('apoptosis', 'CPA', (132, 141))	('elevated', 'PosReg', (160, 168))	('gliomas', 'Phenotype', 'HP:0009733', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('HIF-1alpha', 'Gene', '15251', (40, 50))	('glioma', 'Disease', (180, 186))	('U87', 'Gene', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('tumors', 'Disease', (208, 214))	('HIF-1alpha', 'Gene', (40, 50))	('U87', 'Gene', '641648', (95, 98))	('decreases', 'NegReg', (16, 25))
44542	26248280	(2013), where they found that OKN-007 mediates its antitumor effect in HCC cells (Huh7) via the suppression of TGFbeta1/SMAD2 and Hedgehog/GLI1 signaling by inhibiting sulfatase 2 (SULF2) enzymatic activity.	('SMAD2', 'Gene', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('suppression', 'NegReg', (96, 107))	('TGFbeta1', 'Gene', '21803', (111, 119))	('Huh7', 'CellLine', 'CVCL:0336', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('inhibiting', 'NegReg', (157, 167))	('sulfatase 2', 'Gene', '72043', (168, 179))	('GLI1', 'Gene', (139, 143))	('tumor', 'Disease', (55, 60))	('GLI1', 'Gene', '14632', (139, 143))	('OKN-007', 'Chemical', '-', (30, 37))	('SMAD2', 'Gene', '17126', (120, 125))	('TGFbeta1', 'Gene', (111, 119))	('OKN-007', 'Var', (30, 37))	('sulfatase 2', 'Gene', (168, 179))
44557	26248280	The passaged pediatric glioblastoma culture IC-3752GBM was implanted intracerebrally in athymic nude mice (n = 24) (OMRF IACUC protocols # 13-51 and # 13-53).	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('IC-3752GBM', 'Var', (44, 54))	('pediatric glioblastoma', 'Disease', (13, 35))	('nude mice', 'Species', '10090', (96, 105))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (13, 35))
44604	26248280	For statistical analysis, Student t-tests (independent-samples, two-tailed t-test) were used to assess the differences between means of the normal, untreated, and OKN-007 treated pediatric IC-3752GBM glioma mice.	('glioma', 'Disease', (200, 206))	('OKN-007', 'Chemical', '-', (163, 170))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('mice', 'Species', '10090', (207, 211))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('IC-3752GBM', 'Var', (189, 199))
44606	26248280	Macroscopic, histological, immunohistochemical and MRI characteristics of the novel orthotopic xenograft pediatric glioblastoma (pGBM) model IC-3752GBM and the effects of OKN-007 to inhibit IC-3752GBM tumor culture growth were described in this report.	('IC-3752GBM', 'Var', (141, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('pediatric glioblastoma', 'Disease', (105, 127))	('pGBM', 'Chemical', '-', (129, 133))	('IC-3752GBM tumor', 'Disease', 'MESH:C537984', (190, 206))	('IC-3752GBM tumor', 'Disease', (190, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (105, 127))	('OKN-007', 'Chemical', '-', (171, 178))
44611	26248280	Overall, OKN-007 was found to significantly increase animal survival (p<0.0223) (median survival of 25.5 days) compared to untreated tumor-bearing mice (median survival of 19.5 days).	('mice', 'Species', '10090', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('increase', 'PosReg', (44, 52))	('OKN-007', 'Chemical', '-', (9, 16))	('animal survival', 'CPA', (53, 68))	('OKN-007', 'Var', (9, 16))	('tumor', 'Disease', (133, 138))
44625	26248280	Fig 4C shows that the untreated IC-3752GBM pGBM mice demonstrated significantly lower NAAt/Chot (p = 0.0001) and higher Chot/Cren (p = 0.0325), Chot/NAAt (p = 0.0075), Lip0.9t/Cren (p = 0.0363) and Lip1.3t/Cren (p = 0.0009) ratios when compared to the normal athymic mouse brain.	('Lip0', 'Chemical', '-', (168, 172))	('Cre', 'Chemical', 'MESH:D003401', (125, 128))	('Chot', 'Chemical', '-', (91, 95))	('mouse', 'Species', '10090', (267, 272))	('Lip0.9t/Cren', 'MPA', (168, 180))	('Lip1', 'Gene', (198, 202))	('Chot', 'Chemical', '-', (120, 124))	('rat', 'Species', '10116', (60, 63))	('Chot', 'Chemical', '-', (144, 148))	('lower', 'NegReg', (80, 85))	('Cre', 'Chemical', 'MESH:D003401', (176, 179))	('IC-3752GBM', 'Var', (32, 42))	('NAA', 'Chemical', 'MESH:C000179', (86, 89))	('pGBM', 'Chemical', '-', (43, 47))	('NAA', 'Chemical', 'MESH:C000179', (149, 152))	('mice', 'Species', '10090', (48, 52))	('higher', 'PosReg', (113, 119))	('Lip1', 'Gene', '233977', (198, 202))	('Cre', 'Chemical', 'MESH:D003401', (206, 209))	('rat', 'Species', '10116', (224, 227))	('pGBM', 'Gene', (43, 47))
44631	26248280	In our study, with the use of DWI, the untreated group showed significantly higher (p = 0.0060) (1.161 +- 0.04538, n = 11) normalized ADC values in the tumor regions when compared to the normal mice brains (1.003 +- 0.009358, n = 6) (Fig 5A-5G).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('1.161 +- 0.04538', 'Var', (97, 113))	('tumor', 'Disease', (152, 157))	('normalized ADC values', 'MPA', (123, 144))	('higher', 'PosReg', (76, 82))	('mice', 'Species', '10090', (194, 198))
44659	26248280	This is the first description of the macroscopy, histology, immunohistochemistry and MRI characterizations of the novel orthotopic xenograft pediatric glioblastoma (pGBM) model IC-3752GBM, and assessing the ability of OKN-007 to inhibit IC-3752GBM tumor cell growth.	('IC-3752GBM tumor', 'Disease', (237, 253))	('IC-3752GBM', 'Var', (177, 187))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (141, 163))	('inhibit', 'NegReg', (229, 236))	('pGBM', 'Chemical', '-', (165, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('IC-3752GBM tumor', 'Disease', 'MESH:C537984', (237, 253))	('OKN-007', 'Chemical', '-', (218, 225))	('pediatric glioblastoma', 'Disease', (141, 163))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
44663	26248280	OKN-007 was found to significantly decrease tumor volumes (p < 0.05), as measured by MRI, and increase survival (p < 0.001) in F98 glioma-bearing rats.	('glioma', 'Disease', (131, 137))	('OKN-007', 'Chemical', '-', (0, 7))	('OKN-007', 'Var', (0, 7))	('increase', 'PosReg', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('rats', 'Species', '10116', (146, 150))	('decrease', 'NegReg', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('survival', 'CPA', (103, 111))	('tumor', 'Disease', (44, 49))
44665	26248280	From gross examination of the IC-3752GBM pGBM (Fig 1A-1B), the tumors were characterized as a yellowish gray, poorly demarcated mass, with multifocal areas of necrosis.	('necrosis', 'Disease', (159, 167))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('pGBM', 'Chemical', '-', (41, 45))	('necrosis', 'Disease', 'MESH:D009336', (159, 167))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('IC-3752GBM pGBM', 'Var', (30, 45))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
44668	26248280	loss of heterozygosity) associated with the original patient tumor.	('loss of heterozygosity', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('patient', 'Species', '9606', (53, 60))
44669	26248280	The survival time of IC-3752GBM pGBM mice was significantly increased in all treated mice (p<0.05) and the responsive group (p<0.001) after OKN-007 therapy, as we also have previously reported in adult glioma models.	('mice', 'Species', '10090', (85, 89))	('pGBM', 'Chemical', '-', (32, 36))	('adult glioma', 'Disease', 'MESH:D005910', (196, 208))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('survival time', 'CPA', (4, 17))	('adult glioma', 'Disease', (196, 208))	('IC-3752GBM', 'Var', (21, 31))	('OKN-007', 'Chemical', '-', (140, 147))	('increased', 'PosReg', (60, 69))	('mice', 'Species', '10090', (37, 41))
44679	26248280	For the responsive mice, our results were similar to prior adult glioma studies of our group, which showed that OKN-007 had a dramatic effect on regressing tumor formation in rat F98 and C6, and human U87 xenograft glioma models.	('human', 'Species', '9606', (195, 200))	('OKN-007', 'Var', (112, 119))	('U87', 'Gene', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('U87', 'Gene', '641648', (201, 204))	('adult glioma', 'Disease', 'MESH:D005910', (59, 71))	('xenograft glioma', 'Disease', (205, 221))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('xenograft glioma', 'Disease', 'MESH:D005910', (205, 221))	('rat', 'Species', '10116', (175, 178))	('OKN-007', 'Chemical', '-', (112, 119))	('tumor', 'Disease', (156, 161))	('adult glioma', 'Disease', (59, 71))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('mice', 'Species', '10090', (19, 23))
44682	26248280	Possibly there is a resistance that develops in some of the cells which overtake the growth of the responsive cells in the OKN-007-NR group, whereas in the OKN-007-R group the responsive cells predominate.	('OKN-007-NR', 'Var', (123, 133))	('growth', 'MPA', (85, 91))	('OKN-007', 'Chemical', '-', (156, 163))	('OKN-007-R', 'Chemical', '-', (156, 165))	('overtake', 'PosReg', (72, 80))	('OKN-007', 'Chemical', '-', (123, 130))
44702	26248280	In our study, we measured the peak areas of Cho, Cre, NAA, Lip0.9, and Lip1.3 in the normal brain of athymic nude mice and untreated and OKN-007 treated IC-3752GBM pGBM bearing mice.	('IC-3752GBM', 'Var', (153, 163))	('Lip1', 'Gene', (71, 75))	('Cho', 'Chemical', 'MESH:D002794', (44, 47))	('Lip0', 'Chemical', '-', (59, 63))	('pGBM', 'Chemical', '-', (164, 168))	('nude mice', 'Species', '10090', (109, 118))	('Cre', 'Chemical', 'MESH:D003401', (49, 52))	('mice', 'Species', '10090', (114, 118))	('Lip1', 'Gene', '233977', (71, 75))	('mice', 'Species', '10090', (177, 181))	('OKN-007', 'Chemical', '-', (137, 144))	('NAA', 'Chemical', 'MESH:C000179', (54, 57))
44704	26248280	The untreated IC-3752GBM pGBM mice demonstrated significantly lower NAAt/Chot (p < 0.001) and higher Chot/Cren (p < 0.05), Chot/NAAt (p < 0.01), Lip0.9t/Cren (p < 0.05) and Lip1.3t/Cren (p < 0.001) ratios when compared to the normal athymic mouse brain (Fig 4C), which corroborates with metabolite profiles observed in human GBM.	('NAAt/Chot', 'MPA', (68, 77))	('Chot', 'Chemical', '-', (123, 127))	('Lip1', 'Gene', '233977', (173, 177))	('Cre', 'Chemical', 'MESH:D003401', (181, 184))	('higher', 'PosReg', (94, 100))	('IC-3752GBM', 'Var', (14, 24))	('NAA', 'Chemical', 'MESH:C000179', (68, 71))	('Lip0.9t/Cren', 'MPA', (145, 157))	('human', 'Species', '9606', (319, 324))	('mice', 'Species', '10090', (30, 34))	('rat', 'Species', '10116', (276, 279))	('rat', 'Species', '10116', (42, 45))	('rat', 'Species', '10116', (198, 201))	('Chot', 'Chemical', '-', (73, 77))	('NAA', 'Chemical', 'MESH:C000179', (128, 131))	('Cre', 'Chemical', 'MESH:D003401', (106, 109))	('Cre', 'Chemical', 'MESH:D003401', (153, 156))	('Lip1', 'Gene', (173, 177))	('mouse', 'Species', '10090', (241, 246))	('lower', 'NegReg', (62, 67))	('pGBM', 'Chemical', '-', (25, 29))	('Chot/NAAt', 'MPA', (123, 132))	('Lip0', 'Chemical', '-', (145, 149))	('Chot', 'Chemical', '-', (101, 105))
44732	26248280	Antiangiogenic therapy might affect tumor vessels in 3 different ways: no effect at all; excessive destruction of blood vessels and a reduction in perfusion leading to increased hypoxia, necrosis, and/or invasion; or after pruning of some abnormal vessels the overall structure of the remaining tumor vessels may resemble normal vessels, which potentially results in an increase in absolute blood perfusion.	('absolute blood perfusion', 'MPA', (382, 406))	('invasion', 'CPA', (204, 212))	('affect', 'Reg', (29, 35))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('perfusion', 'MPA', (147, 156))	('abnormal vessels', 'Phenotype', 'HP:0002597', (239, 255))	('tumor', 'Disease', (36, 41))	('pruning', 'Var', (223, 230))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('necrosis', 'Disease', 'MESH:D009336', (187, 195))	('increase', 'PosReg', (370, 378))	('tumor', 'Disease', (295, 300))	('necrosis', 'Disease', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('increased', 'PosReg', (168, 177))	('hypoxia', 'Disease', (178, 185))	('reduction', 'NegReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))
44733	26248280	In this study, we measured the changes in normalized relative cerebral blood perfusion (rCBF) in normal athymic mouse brains, and in untreated and OKN-007 treated IC-3752GBM pGBM mice, using the ASL perfusion MRI technique.	('IC-3752GBM', 'Var', (163, 173))	('mice', 'Species', '10090', (179, 183))	('rCBF', 'Gene', (88, 92))	('pGBM', 'Chemical', '-', (174, 178))	('rCBF', 'Gene', '362686', (88, 92))	('mouse', 'Species', '10090', (112, 117))	('OKN-007', 'Chemical', '-', (147, 154))	('relative cerebral blood perfusion', 'MPA', (53, 86))
44736	26248280	Interestingly, the drug did not seem to affect the normal perfusion of the brain, as no differences were found between values in the contralateral regions of OKN-007-R and OKN-007-NR and untreated animals (Fig 6G), being consistent with the findings from previous research studies in OKN-007-treated C6 gliomas.	('OKN-007-R', 'Var', (158, 167))	('OKN-007', 'Chemical', '-', (172, 179))	('OKN-007-R', 'Chemical', '-', (158, 167))	('gliomas', 'Phenotype', 'HP:0009733', (303, 310))	('OKN-007-treated C6 gliomas', 'Disease', (284, 310))	('OKN-007-treated C6 gliomas', 'Disease', 'MESH:C567307', (284, 310))	('glioma', 'Phenotype', 'HP:0009733', (303, 309))	('OKN-007', 'Chemical', '-', (284, 291))	('OKN-007', 'Chemical', '-', (158, 165))
44738	26248280	The positive effect of OKN-007 on perfusion and diffusion properties in IC-3752GBM pGBM bearing mice indicates a promising influence of the drug on tumor microvasculature, which was also shown previously in a rat adult glioma model by our group.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('mice', 'Species', '10090', (96, 100))	('adult glioma', 'Disease', 'MESH:D005910', (213, 225))	('OKN-007', 'Gene', (23, 30))	('tumor', 'Disease', (148, 153))	('diffusion properties', 'MPA', (48, 68))	('positive', 'PosReg', (4, 12))	('perfusion', 'MPA', (34, 43))	('rat', 'Species', '10116', (209, 212))	('influence', 'Reg', (123, 132))	('adult glioma', 'Disease', (213, 225))	('pGBM', 'Chemical', '-', (83, 87))	('OKN-007', 'Chemical', '-', (23, 30))	('IC-3752GBM', 'Var', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
44739	26248280	In our study, we were also able to demonstrate that OKN-007 acts as an antiangiogenic agent in the IC-3752GBM pGBM model.	('IC-3752GBM', 'Var', (99, 109))	('OKN-007', 'Chemical', '-', (52, 59))	('OKN-007', 'Var', (52, 59))	('pGBM', 'Chemical', '-', (110, 114))	('antiangiogenic agent', 'MPA', (71, 91))	('rat', 'Species', '10116', (42, 45))
44743	26248280	Indeed, alterations to inflammatory pathways can modify angiogenesis, and inflammatory mediators are known to modulate blood:brain barrier permeability.	('rat', 'Species', '10116', (12, 15))	('alterations', 'Var', (8, 19))	('inflammatory pathways', 'Pathway', (23, 44))	('blood:brain barrier permeability', 'CPA', (119, 151))	('modify', 'Reg', (49, 55))	('angiogenesis', 'CPA', (56, 68))	('modulate', 'Reg', (110, 118))
44745	26248280	We also assessed the effect of OKN-007 regarding the immunoexpression of tumor signaling molecules such as PDGFRalpha, SULF2, and decorin in the IC-3752GBM pGBM model.	('OKN-007', 'Chemical', '-', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PDGFRalpha', 'Gene', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('IC-3752GBM', 'Var', (145, 155))	('pGBM', 'Chemical', '-', (156, 160))
44746	26248280	The epidermal growth factor receptor is the predominant receptor tyrosine kinase targeted by both amplification and mutation in adult glioblastomas.	('epidermal growth factor receptor', 'Gene', (4, 36))	('mutation', 'Var', (116, 124))	('epidermal growth factor receptor', 'Gene', '13649', (4, 36))	('glioblastomas', 'Phenotype', 'HP:0012174', (134, 147))	('receptor tyrosine kinase', 'Gene', (56, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (134, 147))	('amplification', 'Var', (98, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('glioblastomas', 'Disease', (134, 147))	('receptor tyrosine kinase', 'Gene', '22174', (56, 80))
44747	26248280	Another study revealed that the high expression of phosphorylated PDGFRalpha has a significant association with malignant histology in pediatric gliomas.	('pediatric gliomas', 'Disease', (135, 152))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('association', 'Reg', (95, 106))	('PDGFRalpha', 'Gene', (66, 76))	('malignant', 'Disease', (112, 121))	('phosphorylated', 'Var', (51, 65))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('pediatric gliomas', 'Disease', 'MESH:D005910', (135, 152))
44753	26248280	Furthermore, the ablation of SULF2 decreases tumor growth, prolongs host survival and decreases the activity of PDGFRalpha, as well as related downstream signaling pathways in human and mouse malignant gliomas.	('malignant gliomas', 'Disease', 'MESH:D005910', (192, 209))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (202, 208))	('gliomas', 'Phenotype', 'HP:0009733', (202, 209))	('decreases', 'NegReg', (86, 95))	('host survival', 'CPA', (68, 81))	('ablation', 'Var', (17, 25))	('malignant gliomas', 'Disease', (192, 209))	('human', 'Species', '9606', (176, 181))	('decreases tumor', 'Disease', 'MESH:D009369', (35, 50))	('SULF2', 'Gene', (29, 34))	('PDGFRalpha', 'Protein', (112, 122))	('mouse', 'Species', '10090', (186, 191))	('prolongs', 'PosReg', (59, 67))	('decreases tumor', 'Disease', (35, 50))	('activity', 'MPA', (100, 108))
44758	26248280	Furthermore, OKN-007 was able to significantly decrease the immunoexpression of PDGFRalpha (p < 0.05) and significantly increase the expression of decorin (p < 0.05) in responsive IC-3752GBM pGBM tumor bearing mice, compared to untreated animals, which may be also associated to the inhibition of tumor angiogenesis and cell proliferation which was also observed in the OKN-007-R treated animals from this study.	('OKN-007-R', 'Chemical', '-', (370, 379))	('OKN-007', 'Var', (13, 20))	('tumor', 'Disease', (196, 201))	('decrease', 'NegReg', (47, 55))	('immunoexpression', 'MPA', (60, 76))	('cell proliferation', 'CPA', (320, 338))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (297, 302))	('mice', 'Species', '10090', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('rat', 'Species', '10116', (332, 335))	('decorin', 'Protein', (147, 154))	('OKN-007', 'Chemical', '-', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('PDGFRalpha', 'Protein', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('OKN-007', 'Chemical', '-', (370, 377))	('expression', 'MPA', (133, 143))	('increase', 'PosReg', (120, 128))	('IC-3752GBM', 'Var', (180, 190))	('pGBM', 'Chemical', '-', (191, 195))
44760	26248280	The data taken as a whole indicates that OKN-007 may possibly be an effective anti-cancer agent for some patients with pHGGs by inhibiting cell proliferation and angiogenesis, potentially via the PDGFRalpha pathway, and could be considered as an additional therapy for pediatric brain tumor patients.	('OKN-007', 'Chemical', '-', (41, 48))	('brain tumor', 'Phenotype', 'HP:0030692', (279, 290))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('OKN-007', 'Var', (41, 48))	('patients', 'Species', '9606', (291, 299))	('brain tumor', 'Disease', (279, 290))	('cell proliferation', 'CPA', (139, 157))	('rat', 'Species', '10116', (151, 154))	('inhibiting', 'NegReg', (128, 138))	('brain tumor', 'Disease', 'MESH:D001932', (279, 290))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('angiogenesis', 'CPA', (162, 174))	('cancer', 'Disease', (83, 89))
44767	25347738	In this study, we demonstrate that in EGFRvIII-expressing GBM cells, the urokinase receptor (uPAR) functions as a major activator of SFKs, controlling phosphorylation of downstream targets such as p130Cas and Tyr-845 in the EGFR in vitro and in vivo.	('EGFR', 'Gene', '1956', (38, 42))	('p130Cas', 'Gene', (197, 204))	('SFK', 'Gene', (133, 136))	('EGFR', 'Gene', (224, 228))	('EGFR', 'Gene', (38, 42))	('uPAR', 'Gene', '5329', (93, 97))	('phosphorylation', 'MPA', (151, 166))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('p130Cas', 'Gene', '9564', (197, 204))	('SFK', 'Gene', '2534;6714;83805', (133, 136))	('Tyr-845', 'Var', (209, 216))	('uPAR', 'Gene', (93, 97))	('Tyr', 'Chemical', 'MESH:D014443', (209, 212))	('EGFR', 'Gene', '1956', (224, 228))
44768	25347738	When EGFRvIII expression in GBM cells was neutralized, either genetically or by treating the cells with Gefitinib, paradoxically, the cells demonstrated increased cell migration.	('neutralized', 'Var', (42, 53))	('increased', 'PosReg', (153, 162))	('cell migration', 'CPA', (163, 177))	('EGFR', 'Gene', '1956', (5, 9))	('GBM', 'Phenotype', 'HP:0012174', (28, 31))	('EGFR', 'Gene', (5, 9))	('Gefitinib', 'Chemical', 'MESH:D000077156', (104, 113))
44771	25347738	The increase in GBM cell migration, induced by genetic or pharmacologic targeting of the EGFR, was blocked by Dasatinib, highlighting the central role of SFKs in uPAR-promoted cell migration.	('Dasatinib', 'Chemical', 'MESH:D000069439', (110, 119))	('SFK', 'Gene', (154, 157))	('EGFR', 'Gene', (89, 93))	('uPAR', 'Gene', '5329', (162, 166))	('GBM cell migration', 'CPA', (16, 34))	('SFK', 'Gene', '2534;6714;83805', (154, 157))	('targeting', 'Var', (72, 81))	('uPAR', 'Gene', (162, 166))	('increase', 'PosReg', (4, 12))	('EGFR', 'Gene', '1956', (89, 93))	('GBM', 'Phenotype', 'HP:0012174', (16, 19))
44776	25347738	By phosphorylating Tyr-845 in the activated EGF receptor (EGFR), SFKs promote activation of the transcription factor, STAT5b, which supports cancer cell proliferation and survival.	('EGFR', 'Gene', '1956', (58, 62))	('EGF receptor', 'Gene', '1956', (44, 56))	('EGF receptor', 'Gene', (44, 56))	('SFK', 'Gene', '2534;6714;83805', (65, 68))	('STAT5b', 'Gene', '6777', (118, 124))	('EGFR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Tyr-845', 'Var', (19, 26))	('SFK', 'Gene', (65, 68))	('Tyr', 'Chemical', 'MESH:D014443', (19, 22))	('STAT5b', 'Gene', (118, 124))	('activation', 'PosReg', (78, 88))	('phosphorylating Tyr-845', 'Var', (3, 26))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('supports', 'PosReg', (132, 140))	('cancer', 'Disease', (141, 147))
44777	25347738	Phospho-Tyr-845 also binds cytochrome C oxidase subunit II, which may be involved in cancer cell survival when the EGFR translocates to mitochondria.	('Phospho-Tyr-845', 'Var', (0, 15))	('binds', 'Interaction', (21, 26))	('Tyr', 'Chemical', 'MESH:D014443', (8, 11))	('cytochrome C oxidase subunit II', 'Gene', '4513', (27, 58))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('EGFR', 'Gene', '1956', (115, 119))	('cancer', 'Disease', (85, 91))	('cytochrome C oxidase subunit II', 'Gene', (27, 58))	('EGFR', 'Gene', (115, 119))	('involved', 'Reg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
44778	25347738	A second gene product that plays a central role in GBM pathogenesis is the EGF receptor (EGFR), which is frequently amplified or over-expressed and in many cases, may be truncated to form a constitutively active mutant called EGFR variant III (EGFRvIII).	('EGFR', 'Gene', '1956', (244, 248))	('EGFR', 'Gene', (89, 93))	('variant', 'Var', (231, 238))	('EGFR', 'Gene', (244, 248))	('EGF receptor', 'Gene', '1956', (75, 87))	('EGF receptor', 'Gene', (75, 87))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('EGFR', 'Gene', '1956', (226, 230))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (226, 230))
44781	25347738	We previously demonstrated that in GBM cells, phosphorylation of Tyr-845 in EGFRvIII is dependent on the urokinase receptor (uPAR), a GPI-anchored membrane protein that interacts with integrins, FPR-like receptor-1 (FPRL1), and various RTKs to form a multiprotein complex with potent cell-signaling activity.	('interacts', 'Interaction', (169, 178))	('Tyr', 'Chemical', 'MESH:D014443', (65, 68))	('uPAR', 'Gene', '5329', (125, 129))	('FPRL1', 'Gene', '2358', (216, 221))	('EGFR', 'Gene', '1956', (76, 80))	('FPR-like receptor-1', 'Gene', '2358', (195, 214))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('FPR-like receptor-1', 'Gene', (195, 214))	('EGFR', 'Gene', (76, 80))	('uPAR', 'Gene', (125, 129))	('phosphorylation', 'MPA', (46, 61))	('FPRL1', 'Gene', (216, 221))	('Tyr-845', 'Var', (65, 72))	('cell-signaling activity', 'MPA', (284, 307))
44782	25347738	The role of uPAR in phosphorylation of Tyr-845 in EGFRvIII may reflect a physical interaction between uPAR and EGFRvIII that increases availability of Tyr-845, as has been reported previously for uPAR and wt-EGFR.	('uPAR', 'Gene', (102, 106))	('EGFR', 'Gene', '1956', (111, 115))	('increases', 'PosReg', (125, 134))	('uPAR', 'Gene', (196, 200))	('EGFR', 'Gene', '1956', (208, 212))	('Tyr-845', 'Var', (39, 46))	('uPAR', 'Gene', '5329', (12, 16))	('uPAR', 'Gene', '5329', (102, 106))	('EGFR', 'Gene', (111, 115))	('phosphorylation', 'MPA', (20, 35))	('EGFR', 'Gene', '1956', (50, 54))	('Tyr', 'Chemical', 'MESH:D014443', (39, 42))	('EGFR', 'Gene', (208, 212))	('uPAR', 'Gene', '5329', (196, 200))	('EGFR', 'Gene', (50, 54))	('availability', 'MPA', (135, 147))	('Tyr', 'Chemical', 'MESH:D014443', (151, 154))	('uPAR', 'Gene', (12, 16))
44786	25347738	In this study, first we examined the role of uPAR in activation of SFKs in GBM cells by measuring phosphorylation of Tyr-416, which reports the fully activated form of SFKs, and two SFK substrates, Tyr-845 in the EGFR and p130Cas.	('phosphorylation', 'MPA', (98, 113))	('Tyr', 'Chemical', 'MESH:D014443', (117, 120))	('EGFR', 'Gene', (213, 217))	('SFK', 'Gene', '2534;6714;83805', (67, 70))	('uPAR', 'Gene', (45, 49))	('SFK', 'Gene', (168, 171))	('SFK', 'Gene', (182, 185))	('SFK', 'Gene', '2534;6714;83805', (168, 171))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))	('Tyr-845', 'Var', (198, 205))	('p130Cas', 'Gene', (222, 229))	('Tyr', 'Chemical', 'MESH:D014443', (198, 201))	('p130Cas', 'Gene', '9564', (222, 229))	('SFK', 'Gene', '2534;6714;83805', (182, 185))	('uPAR', 'Gene', '5329', (45, 49))	('SFK', 'Gene', (67, 70))	('EGFR', 'Gene', '1956', (213, 217))
44787	25347738	Our results demonstrate that in EGFRvIII-expressing GBM cells and in cells in which EGFRvIII expression was neutralized, uPAR functions as a general activator of SFKs, affecting substrates in addition to EGFR Tyr-845.	('neutralized', 'Var', (108, 119))	('substrates', 'MPA', (178, 188))	('SFK', 'Gene', '2534;6714;83805', (162, 165))	('uPAR', 'Gene', '5329', (121, 125))	('EGFR', 'Gene', '1956', (32, 36))	('activator', 'MPA', (149, 158))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (204, 208))	('affecting', 'Reg', (168, 177))	('EGFR', 'Gene', (32, 36))	('SFK', 'Gene', (162, 165))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('uPAR', 'Gene', (121, 125))	('EGFR', 'Gene', (204, 208))	('Tyr', 'Chemical', 'MESH:D014443', (209, 212))
44790	25347738	We now report that blocking EGFRvIII gene expression paradoxically promotes cell migration.	('EGFR', 'Gene', '1956', (28, 32))	('promotes', 'PosReg', (67, 75))	('cell migration', 'CPA', (76, 90))	('EGFR', 'Gene', (28, 32))	('blocking', 'Var', (19, 27))
44795	25347738	Importantly, the uPA-dependent increase in GBM cell migration that accompanied EGFRvIII blockade was reversed by the SFK-targeting cancer therapeutic, Dasatinib.	('cancer', 'Disease', (131, 137))	('blockade', 'Var', (88, 96))	('Dasatinib', 'Chemical', 'MESH:D000069439', (151, 160))	('GBM', 'Phenotype', 'HP:0012174', (43, 46))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('GBM cell migration', 'CPA', (43, 61))	('SFK', 'Gene', '2534;6714;83805', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('uPA', 'Gene', (17, 20))	('SFK', 'Gene', (117, 120))	('uPA', 'Gene', '5328', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('increase', 'PosReg', (31, 39))
44800	25347738	We previously reported that uPAR gene-silencing decreases phosphorylation of Tyr-845 in EGFRvIII in U373MG cells.	('uPAR', 'Gene', '5329', (28, 32))	('decreases', 'NegReg', (48, 57))	('uPAR', 'Gene', (28, 32))	('Tyr', 'Chemical', 'MESH:D014443', (77, 80))	('EGFR', 'Gene', '1956', (88, 92))	('gene-silencing', 'Var', (33, 47))	('phosphorylation of Tyr-845', 'MPA', (58, 84))	('U373MG', 'CellLine', 'CVCL:2219', (100, 106))	('EGFR', 'Gene', (88, 92))
44801	25347738	Tyr-845 is a well described SFK substrate.	('SFK', 'Gene', '2534;6714;83805', (28, 31))	('Tyr', 'Chemical', 'MESH:D014443', (0, 3))	('Tyr-845', 'Var', (0, 7))	('SFK', 'Gene', (28, 31))
44802	25347738	1B confirms our original result, showing that Tyr-845 phosphorylation in EGFRvIII is substantially decreased by uPAR gene-silencing.	('Tyr-845 phosphorylation', 'MPA', (46, 69))	('decreased', 'NegReg', (99, 108))	('uPAR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (73, 77))	('gene-silencing', 'Var', (117, 131))	('EGFR', 'Gene', (73, 77))	('Tyr', 'Chemical', 'MESH:D014443', (46, 49))	('uPAR', 'Gene', '5329', (112, 116))
44803	25347738	To test whether the decrease in phospho-Tyr-845 reflects decreased SFK activity, or a distinct mechanism, such as altered availability of the substrate, first we examined phosphorylation of SFK Tyr-416, which was decreased by uPAR gene-silencing.	('SFK', 'Gene', (67, 70))	('phospho-Tyr-845', 'MPA', (32, 47))	('SFK', 'Gene', '2534;6714;83805', (67, 70))	('uPAR', 'Gene', (226, 230))	('Tyr', 'Chemical', 'MESH:D014443', (40, 43))	('SFK', 'Gene', '2534;6714;83805', (190, 193))	('Tyr', 'Chemical', 'MESH:D014443', (194, 197))	('activity', 'MPA', (71, 79))	('decreased', 'NegReg', (57, 66))	('Tyr-416', 'Var', (194, 201))	('uPAR', 'Gene', '5329', (226, 230))	('gene-silencing', 'Var', (231, 245))	('SFK', 'Gene', (190, 193))
44805	25347738	We therefore examined phosphorylation of a second SFK substrate, p130Cas, and demonstrated that uPAR gene-silencing decreases phospho-p130Cas as well.	('SFK', 'Gene', (50, 53))	('p130Cas', 'Gene', '9564', (65, 72))	('uPAR', 'Gene', (96, 100))	('p130Cas', 'Gene', (134, 141))	('SFK', 'Gene', '2534;6714;83805', (50, 53))	('gene-silencing', 'Var', (101, 115))	('p130Cas', 'Gene', '9564', (134, 141))	('decreases', 'NegReg', (116, 125))	('p130Cas', 'Gene', (65, 72))	('uPAR', 'Gene', '5329', (96, 100))
44807	25347738	Although in EGFRvIII-expressing U373MG cells, uPAR gene-silencing most substantially affected Tyr-845 phosphorylation, the effects on phosphorylation of Tyr-416 in SFKs and p130Cas suggest that uPAR functions as an general SFK activator in these cells, even though EGFRvIII expresses constitutive activity and also activates SFKs.	('SFK', 'Gene', (164, 167))	('p130Cas', 'Gene', '9564', (173, 180))	('SFK', 'Gene', '2534;6714;83805', (325, 328))	('uPAR', 'Gene', '5329', (194, 198))	('uPAR', 'Gene', (46, 50))	('EGFR', 'Gene', (12, 16))	('SFK', 'Gene', '2534;6714;83805', (223, 226))	('EGFR', 'Gene', (265, 269))	('Tyr-845 phosphorylation', 'MPA', (94, 117))	('SFK', 'Gene', '2534;6714;83805', (164, 167))	('uPAR', 'Gene', '5329', (46, 50))	('gene-silencing', 'Var', (51, 65))	('affected', 'Reg', (85, 93))	('EGFR', 'Gene', '1956', (12, 16))	('Tyr', 'Chemical', 'MESH:D014443', (153, 156))	('p130Cas', 'Gene', (173, 180))	('uPAR', 'Gene', (194, 198))	('SFK', 'Gene', (325, 328))	('U373MG', 'CellLine', 'CVCL:2219', (32, 38))	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('EGFR', 'Gene', '1956', (265, 269))	('SFK', 'Gene', (223, 226))
44811	25347738	uPAR gene-silencing reduced phosphorylation of SFK Tyr-416 in EGFRvIII-expressing U87MG cells and phosphorylation of the SFK substrates: EGFR Tyr-845 and p130Cas, without having a major effect on the total level of SFKs (Fig.	('reduced', 'NegReg', (20, 27))	('phosphorylation', 'MPA', (98, 113))	('SFK', 'Gene', '2534;6714;83805', (121, 124))	('SFK', 'Gene', (47, 50))	('U87MG', 'CellLine', 'CVCL:0022', (82, 87))	('p130Cas', 'Gene', (154, 161))	('uPAR', 'Gene', (0, 4))	('SFK', 'Gene', '2534;6714;83805', (215, 218))	('EGFR', 'Gene', (137, 141))	('Tyr-416', 'Var', (51, 58))	('Tyr', 'Chemical', 'MESH:D014443', (51, 54))	('EGFR', 'Gene', '1956', (62, 66))	('SFK', 'Gene', '2534;6714;83805', (47, 50))	('p130Cas', 'Gene', '9564', (154, 161))	('uPAR', 'Gene', '5329', (0, 4))	('gene-silencing', 'Var', (5, 19))	('Tyr-845', 'Var', (142, 149))	('EGFR', 'Gene', '1956', (137, 141))	('SFK', 'Gene', (121, 124))	('SFK', 'Gene', (215, 218))	('Tyr', 'Chemical', 'MESH:D014443', (142, 145))	('EGFR', 'Gene', (62, 66))	('phosphorylation', 'MPA', (28, 43))
44812	25347738	In the U87MG model system, the effects of uPAR gene-silencing on phosphorylation of SFK Tyr-416, EGFRvIII Tyr-845, and p130Cas were similar in magnitude.	('uPAR', 'Gene', '5329', (42, 46))	('SFK', 'Gene', (84, 87))	('EGFR', 'Gene', '1956', (97, 101))	('uPAR', 'Gene', (42, 46))	('p130Cas', 'Gene', (119, 126))	('EGFR', 'Gene', (97, 101))	('phosphorylation', 'MPA', (65, 80))	('Tyr', 'Chemical', 'MESH:D014443', (88, 91))	('Tyr-845', 'Var', (106, 113))	('SFK', 'Gene', '2534;6714;83805', (84, 87))	('Tyr-416', 'Var', (88, 95))	('U87MG', 'CellLine', 'CVCL:0022', (7, 12))	('Tyr', 'Chemical', 'MESH:D014443', (106, 109))	('gene-silencing', 'Var', (47, 61))	('p130Cas', 'Gene', '9564', (119, 126))
44814	25347738	The previously reported activity of uPAR in controlling phosphorylation of Tyr-845 in EGFRvIII probably reflects, at least in part, the general activity of uPAR in SFK activation in EGFRvIII-expressing cells, although a direct interaction between uPAR and EGFRvIII cannot be ruled out by the studies presented here.	('SFK', 'Gene', (164, 167))	('Tyr', 'Chemical', 'MESH:D014443', (75, 78))	('uPAR', 'Gene', '5329', (247, 251))	('activity', 'MPA', (24, 32))	('EGFR', 'Gene', '1956', (182, 186))	('controlling phosphorylation of', 'MPA', (44, 74))	('EGFR', 'Gene', '1956', (86, 90))	('activation', 'PosReg', (168, 178))	('SFK', 'Gene', '2534;6714;83805', (164, 167))	('uPAR', 'Gene', (36, 40))	('uPAR', 'Gene', (156, 160))	('EGFR', 'Gene', (256, 260))	('uPAR', 'Gene', (247, 251))	('EGFR', 'Gene', (182, 186))	('uPAR', 'Gene', '5329', (36, 40))	('Tyr-845', 'Var', (75, 82))	('uPAR', 'Gene', '5329', (156, 160))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', '1956', (256, 260))
44819	25347738	1E shows that EGF increased phosphorylation of Tyr-416 in SFKs in wt-EGFR over-expressing cells; however, uPAR gene-silencing decreased phospho-Tyr-416 both before and after EGF treatment.	('decreased', 'NegReg', (126, 135))	('EGFR', 'Gene', '1956', (69, 73))	('SFK', 'Gene', '2534;6714;83805', (58, 61))	('SFK', 'Gene', (58, 61))	('phospho-Tyr-416', 'MPA', (136, 151))	('gene-silencing', 'Var', (111, 125))	('uPAR', 'Gene', (106, 110))	('EGFR', 'Gene', (69, 73))	('phosphorylation', 'MPA', (28, 43))	('Tyr', 'Chemical', 'MESH:D014443', (47, 50))	('uPAR', 'Gene', '5329', (106, 110))	('Tyr', 'Chemical', 'MESH:D014443', (144, 147))
44828	25347738	uPAR gene-silencing almost entirely blocked affinity precipitation of EGFRvIII with GST-SH2 in U373MG cells (Fig.	('affinity precipitation', 'MPA', (44, 66))	('blocked', 'NegReg', (36, 43))	('EGFR', 'Gene', '1956', (70, 74))	('U373MG', 'CellLine', 'CVCL:2219', (95, 101))	('uPAR', 'Gene', (0, 4))	('EGFR', 'Gene', (70, 74))	('uPAR', 'Gene', '5329', (0, 4))	('gene-silencing', 'Var', (5, 19))
44835	25347738	uPAR and phospho-Tyr-845 co-localized in the plasma membranes of many cells.	('phospho-Tyr-845', 'Var', (9, 24))	('uPAR', 'Gene', (0, 4))	('uPAR', 'Gene', '5329', (0, 4))	('Tyr', 'Chemical', 'MESH:D014443', (17, 20))
44843	25347738	To study the role of uPAR in SFK activation when EGFRvIII expression is neutralized, we silenced uPAR in control and Dox-treated cells.	('EGFR', 'Gene', '1956', (49, 53))	('uPAR', 'Gene', '5329', (97, 101))	('EGFR', 'Gene', (49, 53))	('Dox', 'Chemical', 'MESH:D004318', (117, 120))	('uPAR', 'Gene', (21, 25))	('uPAR', 'Gene', '5329', (21, 25))	('SFK', 'Gene', '2534;6714;83805', (29, 32))	('uPAR', 'Gene', (97, 101))	('silenced', 'Var', (88, 96))	('SFK', 'Gene', (29, 32))
44844	25347738	1A shows that uPAR gene silencing was 95% effective.	('uPAR', 'Gene', (14, 18))	('uPAR', 'Gene', '5329', (14, 18))	('gene silencing', 'Var', (19, 33))
44846	25347738	4B shows that SFK phospho-Tyr-416 was decreased by uPAR gene-silencing in EGFRvIII-deficient Dox-treated cells, indicating that uPAR plays a significant role in maintaining SFK activation when EGFRvIII is neutralized in GBM cells.	('Tyr', 'Chemical', 'MESH:D014443', (26, 29))	('uPAR', 'Gene', '5329', (51, 55))	('decreased', 'NegReg', (38, 47))	('SFK', 'Gene', '2534;6714;83805', (14, 17))	('uPAR', 'Gene', '5329', (128, 132))	('gene-silencing', 'Var', (56, 70))	('uPAR', 'Gene', (51, 55))	('Dox', 'Chemical', 'MESH:D004318', (93, 96))	('SFK', 'Gene', '2534;6714;83805', (173, 176))	('EGFR', 'Gene', '1956', (193, 197))	('GBM', 'Phenotype', 'HP:0012174', (220, 223))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (193, 197))	('SFK', 'Gene', (173, 176))	('uPAR', 'Gene', (128, 132))	('SFK', 'Gene', (14, 17))	('EGFR', 'Gene', (74, 78))
44855	25347738	To explore the role of uPAR in SFK activation in ESC cells, we silenced uPAR in the ESC1, ESC2, and ESC5 cells.	('SFK', 'Gene', '2534;6714;83805', (31, 34))	('uPAR', 'Gene', (23, 27))	('uPAR', 'Gene', '5329', (72, 76))	('silenced', 'Var', (63, 71))	('ESC2', 'Gene', (90, 94))	('SFK', 'Gene', (31, 34))	('uPAR', 'Gene', (72, 76))	('uPAR', 'Gene', '5329', (23, 27))	('ESC2', 'Gene', '84901', (90, 94))
44858	25347738	In each of the ESC cell lines, uPAR gene-silencing decreased phospho-Tyr-416 (Fig.	('Tyr', 'Chemical', 'MESH:D014443', (69, 72))	('uPAR', 'Gene', '5329', (31, 35))	('phospho-Tyr-416', 'MPA', (61, 76))	('decreased', 'NegReg', (51, 60))	('uPAR', 'Gene', (31, 35))	('gene-silencing', 'Var', (36, 50))
44859	25347738	4D), indicating a role for uPAR in controlling SFK activation in tumor cells that acquire resistance to EGFR deficiency in vivo.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('deficiency', 'Var', (109, 119))	('SFK', 'Gene', (47, 50))	('EGFR', 'Gene', (104, 108))	('uPAR', 'Gene', (27, 31))	('SFK', 'Gene', '2534;6714;83805', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('EGFR', 'Gene', '1956', (104, 108))	('uPAR', 'Gene', '5329', (27, 31))
44863	25347738	Neutralization of EGFRvIII expression was associated with a 2.3 +- 0.4-fold increase in cell migration (p<0.05) (Fig.	('increase', 'PosReg', (76, 84))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('cell migration', 'CPA', (88, 102))	('Neutralization', 'Var', (0, 14))
44864	25347738	uPAR gene-silencing blocked the increase in cell migration observed in Dox-treated cells.	('uPAR', 'Gene', (0, 4))	('Dox', 'Chemical', 'MESH:D004318', (71, 74))	('uPAR', 'Gene', '5329', (0, 4))	('gene-silencing', 'Var', (5, 19))	('cell migration', 'CPA', (44, 58))
44866	25347738	Next, we examined ESC cells, in which EGFRvIII deficiency was induced in vivo.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('deficiency', 'Var', (47, 57))
44869	25347738	Thus, we tested whether uPA gene-silencing affects migration of EGFRvIII-expressing and -deficient U373MG cells and ESC cells.	('gene-silencing', 'Var', (28, 42))	('U373MG', 'CellLine', 'CVCL:2219', (99, 105))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('uPA', 'Gene', (24, 27))	('tested', 'Reg', (9, 15))	('uPA', 'Gene', '5328', (24, 27))
44870	25347738	5C, uPA gene-silencing completely blocked the increase in cell migration observed when EGFRvIII expression was neutralized by treating U373MG cells with Dox in vitro.	('U373MG', 'CellLine', 'CVCL:2219', (135, 141))	('cell migration', 'CPA', (58, 72))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))	('uPA', 'Gene', (4, 7))	('gene-silencing', 'Var', (8, 22))	('Dox', 'Chemical', 'MESH:D004318', (153, 156))	('uPA', 'Gene', '5328', (4, 7))	('blocked', 'NegReg', (34, 41))
44871	25347738	uPA gene-silencing also substantially inhibited migration of the ESC cells, effectively neutralizing any advantage in cell migration compared with the parental cells.	('migration', 'CPA', (48, 57))	('gene-silencing', 'Var', (4, 18))	('inhibited', 'NegReg', (38, 47))	('cell migration', 'CPA', (118, 132))	('uPA', 'Gene', '5328', (0, 3))	('uPA', 'Gene', (0, 3))
44872	25347738	2 confirms that uPA gene-silencing was >95% effective in the three ESC cell lines.	('uPA', 'Gene', (16, 19))	('gene-silencing', 'Var', (20, 34))	('uPA', 'Gene', '5328', (16, 19))
44878	25347738	uPA gene-silencing had a modest effect on migration of the control cells; however, in the Gefitinib-treated cells, a more robust effect was observed.	('migration', 'CPA', (42, 51))	('gene-silencing', 'Var', (4, 18))	('uPA', 'Gene', '5328', (0, 3))	('uPA', 'Gene', (0, 3))	('Gefitinib', 'Chemical', 'MESH:D000077156', (90, 99))
44879	25347738	uPA gene-silencing inhibited migration of Gefitinib-treated cells by 66 +- 3% (p<0.01).	('inhibited', 'NegReg', (19, 28))	('gene-silencing', 'Var', (4, 18))	('migration', 'CPA', (29, 38))	('Gefitinib', 'Chemical', 'MESH:D000077156', (42, 51))	('uPA', 'Gene', '5328', (0, 3))	('uPA', 'Gene', (0, 3))
44883	25347738	Dasatinib was extremely effective at inhibiting U373MG cell migration, especially when EGFRvIII expression was neutralized and cell migration stimulated by uPA (Fig.	('cell migration', 'CPA', (127, 141))	('U373MG cell migration', 'CPA', (48, 69))	('uPA', 'Gene', (156, 159))	('EGFR', 'Gene', '1956', (87, 91))	('uPA', 'Gene', '5328', (156, 159))	('neutralized', 'Var', (111, 122))	('EGFR', 'Gene', (87, 91))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('U373MG', 'CellLine', 'CVCL:2219', (48, 54))	('inhibiting', 'NegReg', (37, 47))
44891	25347738	Thus, in all of our model systems, targeting SFKs blocked the increase in cell migration associated with EGFRvIII neutralization and activation of the uPAR signaling system.	('cell migration', 'CPA', (74, 88))	('SFK', 'Gene', '2534;6714;83805', (45, 48))	('neutralization', 'Var', (114, 128))	('blocked', 'NegReg', (50, 57))	('uPAR', 'Gene', (151, 155))	('EGFR', 'Gene', '1956', (105, 109))	('SFK', 'Gene', (45, 48))	('activation', 'PosReg', (133, 143))	('EGFR', 'Gene', (105, 109))	('uPAR', 'Gene', '5329', (151, 155))	('increase', 'PosReg', (62, 70))
44897	25347738	One known cause of resistance to EGFR TKIs is mutation in PTEN, which sustains activation of signaling pathways that are downstream of the EGFR.	('PTEN', 'Gene', '5728', (58, 62))	('cause', 'Reg', (10, 15))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', '1956', (139, 143))	('signaling pathways', 'Pathway', (93, 111))	('activation', 'PosReg', (79, 89))	('EGFR', 'Gene', (33, 37))	('EGFR', 'Gene', (139, 143))	('mutation', 'Var', (46, 54))	('PTEN', 'Gene', (58, 62))
44906	25347738	In a human GBM propagated as a xenograft, the extent of phosphorylation of Tyr-845 in EGFRvIII correlated with uPAR immunopositivity at the single cell level.	('uPAR', 'Gene', '5329', (111, 115))	('EGFR', 'Gene', '1956', (86, 90))	('GBM', 'Phenotype', 'HP:0012174', (11, 14))	('Tyr-845', 'Var', (75, 82))	('EGFR', 'Gene', (86, 90))	('Tyr', 'Chemical', 'MESH:D014443', (75, 78))	('uPAR', 'Gene', (111, 115))	('phosphorylation', 'MPA', (56, 71))	('human', 'Species', '9606', (5, 10))
44912	25347738	In our model systems, when EGFRvIII was neutralized, uPAR remained an important activator of SFKs; however, the decrease in SFK activation induced by uPAR gene-silencing was incomplete, suggesting that, in these cells, SFKs may be activated by proximal receptors other than EGFRvIII and in addition to uPAR.	('SFK', 'Gene', '2534;6714;83805', (219, 222))	('EGFR', 'Gene', '1956', (27, 31))	('uPAR', 'Gene', (53, 57))	('EGFR', 'Gene', (27, 31))	('SFK', 'Gene', '2534;6714;83805', (93, 96))	('SFK', 'Gene', '2534;6714;83805', (124, 127))	('uPAR', 'Gene', (150, 154))	('uPAR', 'Gene', '5329', (302, 306))	('SFK', 'Gene', (219, 222))	('gene-silencing', 'Var', (155, 169))	('SFK', 'Gene', (124, 127))	('EGFR', 'Gene', '1956', (274, 278))	('uPAR', 'Gene', '5329', (53, 57))	('uPAR', 'Gene', '5329', (150, 154))	('SFK', 'Gene', (93, 96))	('uPAR', 'Gene', (302, 306))	('EGFR', 'Gene', (274, 278))
44916	25347738	Because uPA was expressed at increased levels in GBM cells when EGFRvIII was genetically neutralized or when the cells were treated with Gefitinib, we explored the effects of these treatments on GBM cell migration.	('uPA', 'Gene', '5328', (8, 11))	('genetically neutralized', 'Var', (77, 100))	('Gefitinib', 'Chemical', 'MESH:D000077156', (137, 146))	('increased', 'PosReg', (29, 38))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('GBM', 'Phenotype', 'HP:0012174', (195, 198))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('uPA', 'Gene', (8, 11))
44918	25347738	Silencing of uPA or uPAR blocked the increase in cell migration associated with EGFRvIII inactivation.	('inactivation', 'Var', (89, 101))	('cell migration', 'CPA', (49, 63))	('uPAR', 'Gene', (20, 24))	('uPA', 'Gene', (13, 16))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('uPA', 'Gene', '5328', (13, 16))	('increase', 'PosReg', (37, 45))	('uPA', 'Gene', '5328', (20, 23))	('uPA', 'Gene', (20, 23))	('Silencing', 'Var', (0, 9))	('uPAR', 'Gene', '5329', (20, 24))
44922	25347738	uPAR-signaling provides resistance to the negative consequences of EGFRvIII neutralization and allows the cells to survive.	('neutralization', 'Var', (76, 90))	('uPAR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('uPAR', 'Gene', '5329', (0, 4))
44933	25347738	Escaper tumor cell lines (ESC1, ESC2, ESC5), which were derived from U373MG cell xenografts that re-established growth following loss of EGFRvIII in vivo, also are previously described.	('EGFR', 'Gene', (137, 141))	('growth', 'MPA', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('loss', 'Var', (129, 133))	('tumor', 'Disease', (8, 13))	('ESC2', 'Gene', (32, 36))	('U373MG', 'CellLine', 'CVCL:2219', (69, 75))	('ESC2', 'Gene', '84901', (32, 36))	('EGFR', 'Gene', '1956', (137, 141))
44936	25347738	Antibody that detects phospho-Tyr-416 in c-Src and cross-reacts with the equivalent epitope in other SFKs was from Cell Signaling Technology.	('SFK', 'Gene', '2534;6714;83805', (101, 104))	('phospho-Tyr-416', 'Var', (22, 37))	('Tyr', 'Chemical', 'MESH:D014443', (30, 33))	('c-Src', 'Gene', (41, 46))	('SFK', 'Gene', (101, 104))	('c-Src', 'Gene', '6714', (41, 46))
44938	25347738	Antibody that detects phospho-Tyr-845 in the EGFR was from Invitrogen.	('EGFR', 'Gene', (45, 49))	('Tyr', 'Chemical', 'MESH:D014443', (30, 33))	('EGFR', 'Gene', '1956', (45, 49))	('phospho-Tyr-845', 'Var', (22, 37))
44964	25347738	Sections were immunostained with primary antibodies targeting phospho-Tyr-845 (1:150; Abcam) and human uPAR (1:75; Dako) for 1 h at 37 C using the Ventana Discovery Ultra Platform.	('uPAR', 'Gene', '5329', (103, 107))	('Tyr', 'Chemical', 'MESH:D014443', (70, 73))	('human', 'Species', '9606', (97, 102))	('uPAR', 'Gene', (103, 107))	('phospho-Tyr-845', 'Var', (62, 77))
44987	24939046	The cytotoxicity of MTIC is primarily due to methylation of DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication.	('guanine', 'Chemical', 'MESH:D006147', (94, 101))	('DNA replication', 'MPA', (130, 145))	('cytotoxicity', 'Disease', (4, 16))	('inhibition', 'NegReg', (116, 126))	('MTIC', 'Chemical', '-', (20, 24))	('methylation', 'Var', (45, 56))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
45049	24939046	We found that TMZ significantly prolonged the length of survival of glioma-bearing mice (Figure 7B).	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('prolonged', 'PosReg', (32, 41))	('TMZ', 'Var', (14, 17))	('TMZ', 'Chemical', 'MESH:D000077204', (14, 17))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('length of survival', 'CPA', (46, 64))	('mice', 'Species', '10090', (83, 87))	('glioma', 'Disease', (68, 74))
45088	24939046	In vivo, CNF1 was more effective than TMZ in prolonging survival of tumor-bearing mice.	('tumor', 'Disease', (68, 73))	('mice', 'Species', '10090', (82, 86))	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('prolonging', 'PosReg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CNF1', 'Var', (9, 13))
45149	23658659	Hypermethylation of PCGTs has been previously shown to be associated with aging.	('PCGTs', 'Chemical', '-', (20, 25))	('Hypermethylation', 'Var', (0, 16))	('PCGTs', 'Gene', (20, 25))	('associated', 'Reg', (58, 68))
45158	23658659	We compared the list of DAGs on SNP 6 and the list of DMGs, and found three genes that are both heterozygously deleted and hypermethylated in the old group (HHEX, ITGA8, RASGEF1A).	('DMGs', 'Chemical', '-', (54, 58))	('ITGA8', 'Gene', (163, 168))	('HHEX', 'Gene', '3087', (157, 161))	('HHEX', 'Gene', (157, 161))	('hypermethylated', 'Var', (123, 138))	('ITGA8', 'Gene', '8516', (163, 168))	('RASGEF1A', 'Gene', (170, 178))	('DAGs', 'Chemical', '-', (24, 28))	('RASGEF1A', 'Gene', '221002', (170, 178))
45163	23658659	There are two genes that stand out: TP53 is mutated in 19 old samples and in only one young sample (Fisher's exact test p-value<0.068).	('TP53', 'Gene', (36, 40))	('stand out', 'Phenotype', 'HP:0003698', (25, 34))	('TP53', 'Gene', '7157', (36, 40))	('mutated', 'Var', (44, 51))
45164	23658659	GRM3 is mutated in 3 out of 12 young samples and none of the old samples (Fisher's exact test p-value<0.01645).	('mutated', 'Var', (8, 15))	('GRM3', 'Gene', '2913', (0, 4))	('GRM3', 'Gene', (0, 4))
45198	23658659	Thus, our results are consistent with the cancer stem cell hypothesis of gliomagenesis being most prevalent in the older GBMs, in part through hypermethylation of PCGTs.	('glioma', 'Disease', (73, 79))	('PCGTs', 'Gene', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('PCGTs', 'Chemical', '-', (163, 168))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('hypermethylation', 'Var', (143, 159))
45228	33925455	Modulators of tumor blood flow reduce flow resistance through vasodilation and increase the blood pressure with vasoconstrictors, thereby also increasing the transvascular hydrostatic gradient.	('increase', 'PosReg', (79, 87))	('tumor', 'Disease', (14, 19))	('increasing', 'PosReg', (143, 153))	('blood pressure with vasoconstrictors', 'MPA', (92, 128))	('transvascular hydrostatic gradient', 'MPA', (158, 192))	('reduce', 'NegReg', (31, 37))	('vasodilation', 'MPA', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('increase the blood pressure', 'Phenotype', 'HP:0032263', (79, 106))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('flow resistance', 'MPA', (38, 53))	('Modulators', 'Var', (0, 10))
45280	33925455	Glioblastoma Xenograft: Forty-five minutes after irradiation, we performed a vascular permeability assay in a selected group of mice; MRT + Cisplatin (n = 4), MRT alone (n = 7), Cisplatin alone (n = 4), and control (n = 4).	('Glioblastoma', 'Disease', (0, 12))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('mice', 'Species', '10090', (128, 132))	('Cisplatin', 'Chemical', 'MESH:D002945', (178, 187))	('MRT', 'Var', (134, 137))	('Cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))
45310	33925455	These results confirm that MRT can also induce vascular permeability in this mammalian tumor model, and thus, vascular permeability is not restricted to the CAM (avian).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('vascular permeability', 'MPA', (47, 68))	('mammalian', 'Species', '9606', (77, 86))	('MRT', 'Var', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('induce', 'Reg', (40, 46))
45317	33925455	In contrast, tumors treated with the combination of MRT + Cisplatin remained unchanged until approximately 22 days after treatment, when their growth rate began to abate slowly.	('MRT', 'Var', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('rat', 'Species', '10116', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('Cisplatin', 'Chemical', 'MESH:D002945', (58, 67))
45319	33925455	Accordingly, images of tumor progression (Figure 5b) show the best treatment results on animals subjected to MRT + Cisplatin in comparison with the other experimental groups; with a 2.75-fold decrease in comparison with MRT alone, and a 5.25-fold decrease compared to Cisplatin alone.	('decrease', 'NegReg', (192, 200))	('decrease', 'NegReg', (247, 255))	('MRT', 'Var', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('Cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('Cisplatin', 'Chemical', 'MESH:D002945', (268, 277))
45329	33925455	It induces a transient, vascular permeability window in CAM, beginning 15 min after MRT (75 Gy) and ending at 4 h. The extravasation of FITC-dextran (MW 2 x 106 Dalton, size of 27 nm) was visible as green "clouds" diffusing between high-dose microbeam regions, which indicates a penetration depth of a few hundreds of micrometers.	('extravasation', 'MPA', (119, 132))	('rat', 'Species', '10116', (284, 287))	('FITC-dextran', 'Chemical', 'MESH:C015219', (136, 148))	('MW 2 x 106', 'Var', (150, 160))
45349	33925455	First, it was confirmed that MRT could also induce a vascular permeability window in the glioblastoma xenograft model, as shown by the extravasated FITC-dextran 45 min after 150 Gy of MRT (Figure 3).	('vascular permeability window', 'MPA', (53, 81))	('glioblastoma', 'Disease', (89, 101))	('FITC-dextran', 'Chemical', 'MESH:C015219', (148, 160))	('MRT', 'Var', (29, 32))	('extravasated FITC-dextran', 'MPA', (135, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))
45350	33925455	Secondly, we showed the treatment efficacy of combining 150 Gy MRT + Cisplatin in two separate trials, where tumor measurements were performed with a digital caliper or more accurately with MRI, in each respective trial.	('Cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('rat', 'Species', '10116', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MRT', 'Var', (63, 66))	('tumor', 'Disease', (109, 114))	('rat', 'Species', '10116', (90, 93))
45351	33925455	The combined treatment of 150 Gy MRT + Cisplatin achieved the best tumor control among all treatment groups (Figure 4 and Figure 5).	('Cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MRT', 'Var', (33, 36))	('tumor', 'Disease', (67, 72))
45374	32348734	Specifically, there is strong evidence of discordance between methylation status and protein expression level, with variable reports of correlation with patient outcome.	('methylation', 'Var', (62, 73))	('protein expression level', 'MPA', (85, 109))	('patient', 'Species', '9606', (153, 160))
45386	32348734	For example, in a set of 53 glioblastoma and 10 anaplastic astrocytoma, a strong correlation between mRNA expression level and promoter methylation status was found (p<0.0001); however, 6 patients with a methylated promoter expressed high mRNA levels and 6 patients with an unmethylated promoter expressed low mRNA levels.	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (48, 70))	('glioblastoma', 'Disease', (28, 40))	('mRNA expression level', 'MPA', (101, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (257, 265))	('methylated', 'Var', (204, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('high mRNA levels', 'MPA', (234, 250))	('anaplastic astrocytoma', 'Disease', (48, 70))
45400	32348734	Importantly, the 9.5% of patients who fell within the "gray zone" of intermediate methylation between the optimal and technical cutoffs had a significant survival benefit compared to those patients who were "truly" unmethylated.	('methylation', 'Var', (82, 93))	('benefit', 'PosReg', (163, 170))	('survival', 'CPA', (154, 162))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (189, 197))
45408	32348734	Methylation also occurs in the MGMT gene body, and methylation of exonic regions may result in increased MGMT expression in some patients, which could partially explain why MGMT transcript levels may differ from what is expected by the promoter methylation status.	('MGMT', 'Gene', '4255', (31, 35))	('MGMT', 'Gene', (31, 35))	('patients', 'Species', '9606', (129, 137))	('MGMT', 'Gene', '4255', (105, 109))	('MGMT', 'Gene', (105, 109))	('MGMT', 'Gene', '4255', (173, 177))	('methylation', 'Var', (51, 62))	('MGMT', 'Gene', (173, 177))	('increased', 'PosReg', (95, 104))
45410	32348734	In patients with an unmethylated promoter, gene body hypomethylation resulted in decreased MGMT expression to a similar degree of those with a methylated promoter.	('decreased', 'NegReg', (81, 90))	('body hypomethylation', 'Var', (48, 68))	('MGMT', 'Gene', (91, 95))	('patients', 'Species', '9606', (3, 11))	('hypomethylation', 'Var', (53, 68))	('MGMT', 'Gene', '4255', (91, 95))
45414	32348734	For example, hypomethylation of the gene body in D-566MG and SF-295 cells may possibly explain the decreased MGMT expression in these cells with an unmethylated promoter.	('hypomethylation', 'Var', (13, 28))	('decreased', 'NegReg', (99, 108))	('SF-295', 'CellLine', 'CVCL:1690', (61, 67))	('MGMT', 'Gene', (109, 113))	('MGMT', 'Gene', '4255', (109, 113))	('D-566MG', 'CellLine', 'CVCL:1166', (49, 56))
45415	32348734	It would be interesting to know whether the high MGMT expression in LN-18 and YH-13 cells occurs primarily as a result of an unmethylated promoter or hypermethylation of the gene body (Figure 1A-C).	('MGMT', 'Gene', '4255', (49, 53))	('MGMT', 'Gene', (49, 53))	('hypermethylation', 'Var', (150, 166))	('YH-13', 'CellLine', 'CVCL:1795', (78, 83))
45429	32348734	Low MGMT protein or gene expression has been found to be significantly associated with improved patient survival or treatment response independently of MGMT promoter methylation, and further, has also been found to be an independent prognostic marker in glioblastoma patients by multivariate analysis.	('MGMT', 'Gene', '4255', (4, 8))	('patient', 'Species', '9606', (267, 274))	('patient survival', 'CPA', (96, 112))	('patients', 'Species', '9606', (267, 275))	('improved', 'PosReg', (87, 95))	('MGMT', 'Gene', (152, 156))	('treatment response', 'CPA', (116, 134))	('patient', 'Species', '9606', (96, 103))	('MGMT', 'Gene', '4255', (152, 156))	('gene expression', 'MPA', (20, 35))	('glioblastoma', 'Disease', (254, 266))	('glioblastoma', 'Disease', 'MESH:D005909', (254, 266))	('glioblastoma', 'Phenotype', 'HP:0012174', (254, 266))	('MGMT', 'Gene', (4, 8))	('Low', 'Var', (0, 3))
45430	32348734	Stratifying patients into four subgroups based on combined analysis of methylation and expression (methylated + low expression, methylated + high expression, unmethylated + low expression, unmethylated + high expression) appears to give the most accurate prediction of patient outcome.	('unmethylated + low expression', 'Var', (158, 187))	('patients', 'Species', '9606', (12, 20))	('methylated + high expression', 'Var', (128, 156))	('patient', 'Species', '9606', (269, 276))	('unmethylated + high expression', 'Var', (189, 219))	('patient', 'Species', '9606', (12, 19))
45433	32348734	Combined analysis in a set of 121 glioblastoma patients revealed a better outcome in methylated, IHC-negative patients compared to unmethylated, IHC-positive patients.	('methylated', 'Var', (85, 95))	('patients', 'Species', '9606', (47, 55))	('glioblastoma', 'Disease', (34, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('patients', 'Species', '9606', (158, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('patients', 'Species', '9606', (110, 118))
45437	32348734	Stratification of patients into subgroups incorporating both methylation and expression parameters may very likely enhance the prognostic and/or predictive value of MGMT methylation status (see Outstanding Questions).	('enhance', 'PosReg', (115, 122))	('patients', 'Species', '9606', (18, 26))	('methylation', 'Var', (170, 181))	('MGMT', 'Gene', (165, 169))	('MGMT', 'Gene', '4255', (165, 169))
45439	32348734	30 - 60% of all glioblastoma patients have a methylated MGMT promoter; yet, those expressing MGMT due to an unmethylated promoter or alternate mechanism will likely respond poorly to standard alkylating therapy.	('patients', 'Species', '9606', (29, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('MGMT', 'Gene', '4255', (93, 97))	('MGMT', 'Gene', (56, 60))	('MGMT', 'Gene', (93, 97))	('MGMT', 'Gene', '4255', (56, 60))	('methylated', 'Var', (45, 55))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
45450	32348734	Though the O6-methylguanine (O6-MeG) adduct is the least frequent lesion, it is the primary mechanism of temozolomide cytotoxicity.	('O6-MeG', 'Chemical', 'MESH:C008449', (29, 35))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (11, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('O6-methylguanine', 'Var', (11, 27))	('temozolomide', 'Chemical', 'MESH:D000077204', (105, 117))	('cytotoxicity', 'Disease', (118, 130))
45457	32348734	Hypermethylation at CpG sites within this region typically results in epigenetic silencing of MGMT transcripts.	('epigenetic silencing', 'MPA', (70, 90))	('MGMT', 'Gene', '4255', (94, 98))	('Hypermethylation', 'Var', (0, 16))	('MGMT', 'Gene', (94, 98))	('results in', 'Reg', (59, 69))
45459	32348734	An unmethylated promoter often results in high MGMT protein expression, which allows the repair of O6-MeG and promotes resistance to TMZ (Figure IB).	('O6-MeG', 'Chemical', 'MESH:C008449', (99, 105))	('MGMT', 'Gene', (47, 51))	('resistance to TMZ', 'MPA', (119, 136))	('promotes', 'PosReg', (110, 118))	('TMZ', 'Chemical', 'MESH:D000077204', (133, 136))	('repair', 'MPA', (89, 95))	('MGMT', 'Gene', '4255', (47, 51))	('results in', 'Reg', (31, 41))	('O6-MeG', 'Var', (99, 105))
45461	32348734	Although the addition of TMZ to radiotherapy brought significant survival benefit in patients with MGMT methylated glioblastoma, a modest benefit was also noted in patients with an unmethylated promoter.	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('methylated', 'Var', (104, 114))	('patients', 'Species', '9606', (85, 93))	('MGMT', 'Gene', (99, 103))	('glioblastoma', 'Disease', (115, 127))	('patients', 'Species', '9606', (164, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))	('MGMT', 'Gene', '4255', (99, 103))	('survival', 'MPA', (65, 73))	('TMZ', 'Chemical', 'MESH:D000077204', (25, 28))	('benefit', 'PosReg', (74, 81))
45490	31586689	Next, we described the landmark papers as well as recent progress in single-cell sequencing technologies in resolving brain complexity (see the "Applications of single-cell sequencing in brain studies" section) in terms of: (1) the diversity and heterogeneity of cell types in the brain, (2) the dynamic changes in brain cell types, expression profiles, and the accumulation of somatic mutations during development and aging, (3) the associations between brain cell types and neuronal diseases, and (4) the contributions of glioma stem cells and macrophages to the intratumoral heterogeneity of brain cancer.	('seq', 'Gene', (173, 176))	('seq', 'Gene', '3772396', (173, 176))	('glioma', 'Phenotype', 'HP:0009733', (524, 530))	('cancer', 'Phenotype', 'HP:0002664', (601, 607))	('brain cancer', 'Phenotype', 'HP:0030692', (595, 607))	('mutations', 'Var', (386, 395))	('seq', 'Gene', (81, 84))	('seq', 'Gene', '3772396', (81, 84))	('neuronal diseases', 'Disease', (476, 493))	('brain cancer', 'Disease', (595, 607))	('associations', 'Interaction', (434, 446))	('tumor', 'Disease', 'MESH:D009369', (570, 575))	('glioma', 'Disease', (524, 530))	('brain cancer', 'Disease', 'MESH:D001932', (595, 607))	('neuronal diseases', 'Disease', 'MESH:D009410', (476, 493))	('tumor', 'Phenotype', 'HP:0002664', (570, 575))	('tumor', 'Disease', (570, 575))	('glioma', 'Disease', 'MESH:D005910', (524, 530))
45506	31586689	Applied to frozen samples in human tissue banks, single-nucleus RNA sequencing methods have shown to be more promising than the whole-cell RNA-seq.	('seq', 'Gene', (143, 146))	('single-nucleus', 'Var', (49, 63))	('seq', 'Gene', '3772396', (143, 146))	('seq', 'Gene', (68, 71))	('seq', 'Gene', '3772396', (68, 71))	('human', 'Species', '9606', (29, 34))
45568	31586689	One of these methods, scGESTALT, utilizes Cas9 to generates random mutations in the lineage barcode at the 3'UTR of DsRed transgene, which is later transcribed with the DsRed mRNA and sequenced with other transcripts in zebrafish brain, allowing the simultaneous detection of cell lineage and transcriptome information.	('zebrafish', 'Species', '7955', (220, 229))	('seq', 'Gene', (184, 187))	('seq', 'Gene', '3772396', (184, 187))	('mutations', 'Var', (67, 76))	('DsRed transgene', 'Gene', (116, 131))
45578	31586689	These findings also shed light on the pattern and frequency of somatic mutations, and further imply that pathogenic somatic mutations can also lead to various neurodevelopmental and neurodegenerative diseases.	('neurodegenerative diseases', 'Disease', (182, 208))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (182, 208))	('mutations', 'Var', (124, 133))	('neurodevelopmental', 'Disease', (159, 177))	('lead to', 'Reg', (143, 150))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (182, 208))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (182, 207))
45582	31586689	sampled all immune cells in the brain of wild-type and AD mouse model (5 x FAD mice, which expresses five human familial AD gene mutations) using scRNA-seq.	('AD', 'Disease', 'MESH:D000544', (55, 57))	('AD', 'Disease', (55, 57))	('mouse', 'Species', '10090', (58, 63))	('seq', 'Gene', (152, 155))	('seq', 'Gene', '3772396', (152, 155))	('human', 'Species', '9606', (106, 111))	('AD', 'Phenotype', 'HP:0002511', (76, 78))	('mutations', 'Var', (129, 138))	('mice', 'Species', '10090', (79, 83))	('AD', 'Disease', 'MESH:D000544', (121, 123))	('AD', 'Disease', (121, 123))	('AD', 'Phenotype', 'HP:0002511', (121, 123))	('AD', 'Disease', 'MESH:D000544', (76, 78))	('AD', 'Phenotype', 'HP:0002511', (55, 57))	('AD', 'Disease', (76, 78))
45594	31586689	Common genomic alterations in gliomas include mutations in IDH1, TP53, ATRX, and TERT promoter, amplification and rearrangements of EGFR, MET, and PDGFRA, as well as deletions of chromosome 1p/19q and CDKN2A .	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('CDKN2A', 'Gene', '12578', (201, 207))	('IDH1', 'Gene', '15926', (59, 63))	('PDGFRA', 'Gene', '18595', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('CDKN2A', 'Gene', (201, 207))	('mutations', 'Var', (46, 55))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('PDGFRA', 'Gene', (147, 153))	('TP53', 'Gene', (65, 69))	('TERT', 'Gene', '21752', (81, 85))	('IDH1', 'Gene', (59, 63))	('deletions', 'Var', (166, 175))	('ATRX', 'Gene', '22589', (71, 75))	('amplification', 'Var', (96, 109))	('TP53', 'Gene', '22059', (65, 69))	('TERT', 'Gene', (81, 85))	('EGFR', 'Gene', (132, 136))	('MET', 'Gene', (138, 141))	('gliomas', 'Disease', (30, 37))	('EGFR', 'Gene', '13649', (132, 136))	('rearrangements', 'Var', (114, 128))	('ATRX', 'Gene', (71, 75))
45597	31586689	found that (i) within the same tumor, different cells express distinct EGFR or PDGFRA isoforms; (ii) multiple EGFR oncogenic variants are coexpressed in the same cell; and (iii) some cells express receptor and ligand other than EGFR or PDGFRA.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PDGFRA', 'Gene', '18595', (79, 85))	('EGFR', 'Gene', (110, 114))	('EGFR', 'Gene', '13649', (110, 114))	('tumor', 'Disease', (31, 36))	('PDGFRA', 'Gene', (79, 85))	('variants', 'Var', (125, 133))	('PDGFRA', 'Gene', '18595', (236, 242))	('PDGFRA', 'Gene', (236, 242))	('EGFR', 'Gene', (228, 232))	('EGFR', 'Gene', '13649', (228, 232))	('EGFR', 'Gene', (71, 75))	('EGFR', 'Gene', '13649', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
45598	31586689	These results suggest that heterogeneity of different tumor clones contributes to the failure of EGFR and PDGFRA inhibitors for glioma treatment.	('glioma', 'Disease', (128, 134))	('inhibitors', 'Var', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('EGFR', 'Gene', (97, 101))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('EGFR', 'Gene', '13649', (97, 101))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PDGFRA', 'Gene', '18595', (106, 112))	('tumor', 'Disease', (54, 59))	('failure', 'NegReg', (86, 93))	('PDGFRA', 'Gene', (106, 112))
45610	31586689	Compared to the less aggressive low-grade glioma, the proportion of undifferentiated, cycling stem/progenitor cells was much higher in DIPG with histone H3 lysine-to-methionine mutations.	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('lysine', 'Chemical', 'MESH:C114808', (156, 162))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('lysine-to-methionine mutations', 'Var', (156, 186))	('higher', 'PosReg', (125, 131))	('histone H3', 'Protein', (145, 155))	('glioma', 'Disease', (42, 48))	('methionine', 'Chemical', 'MESH:D008715', (166, 176))
45656	30585246	The intercellular cooperation among GBM cells has also been highlighted by the effects of leukemia inhibitory factor (LIF) and IL-6 on the maintenance of the balance between tumor cells expressing oncogenic mutation of the epidermal growth factor receptor variant III (EGFRvIII) and those with the wild type EGFR gene.	('tumor', 'Disease', (174, 179))	('epidermal growth factor receptor', 'Gene', (223, 255))	('leukemia inhibitory factor', 'Gene', (90, 116))	('EGFR', 'Gene', '1956', (269, 273))	('EGFR', 'Gene', (269, 273))	('IL-6', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('LIF', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('epidermal growth factor receptor', 'Gene', '1956', (223, 255))	('LIF', 'Gene', '3976', (118, 121))	('leukemia inhibitory factor', 'Gene', '3976', (90, 116))	('EGFR', 'Gene', '1956', (308, 312))	('IL-6', 'Gene', '3569', (127, 131))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))	('mutation', 'Var', (207, 215))	('EGFR', 'Gene', (308, 312))	('GBM', 'Phenotype', 'HP:0012174', (36, 39))
45658	30585246	In this case specialized physical cell-to-cell interfaces serve as gateways to transfer multiple molecular components between cells, including through junctions, tunneling nanotubes (TNTs), or tumor microtubes (TMs).	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tunneling', 'Var', (162, 171))	('tumor microtubes', 'Disease', (193, 209))	('tumor microtubes', 'Disease', 'MESH:D009369', (193, 209))
45678	30585246	Uniquely, cancer cell-derived EVs contain mutant, oncogenic or otherwise disease-specific and pathological proteins and nucleic acids.	('mutant', 'Var', (42, 48))	('proteins', 'Protein', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
45680	30585246	Glioma EVs may also contain wild-type EGFR, PTEN, and mutant IDH1, while EVs of medulloblastoma cells carry DNA comprising MYC amplicon (as reviewed in).	('EGFR', 'Gene', '1956', (38, 42))	('Glioma EVs', 'Disease', (0, 10))	('medulloblastoma', 'Disease', (80, 95))	('EGFR', 'Gene', (38, 42))	('MYC', 'Gene', '4609', (123, 126))	('IDH1', 'Gene', '3417', (61, 65))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('IDH1', 'Gene', (61, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (80, 95))	('PTEN', 'Gene', (44, 48))	('Glioma EVs', 'Disease', 'MESH:D005910', (0, 10))	('PTEN', 'Gene', '5728', (44, 48))	('medulloblastoma', 'Phenotype', 'HP:0002885', (80, 95))	('mutant', 'Var', (54, 60))	('MYC', 'Gene', (123, 126))
45695	30585246	It is of interest to note that YB1 is among the most upregulated genes in pediatric high-grade glioma, along with another vesicle transport-associated protein SNX3, which may suggest that EV-mediated trafficking of regulatory RNAs could play a role in the pathogenesis of this disease, otherwise already linked to profound deregulation of epigenetic circuitry.	('SNX3', 'Gene', (159, 163))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('SNX3', 'Gene', '8724', (159, 163))	('YB1', 'Gene', (31, 34))	('YB1', 'Gene', '4904', (31, 34))	('glioma', 'Disease', (95, 101))	('EV-mediated', 'Var', (188, 199))	('upregulated', 'PosReg', (53, 64))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
45706	30585246	For example, EV-mediated removal of miR-23b from cancer cells was shown to relieve the molecular breaks on tumor invasion to trigger elevated aggressiveness.	('elevated aggressiveness', 'Disease', (133, 156))	('miR-23b', 'Gene', (36, 43))	('removal', 'Var', (25, 32))	('aggressiveness', 'Phenotype', 'HP:0000718', (142, 156))	('molecular breaks', 'MPA', (87, 103))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('miR-23b', 'Gene', '407011', (36, 43))	('relieve', 'NegReg', (75, 82))	('elevated aggressiveness', 'Disease', 'MESH:D001523', (133, 156))	('cancer', 'Disease', (49, 55))
45724	30585246	It is noteworthy that a considerable progress has been achieved in molecular classification of GBM, which is now known to comprise several disease entities, such as proneural, neural, classical and mesenchymal tumors (also recently re-classified as IDH1 mutant tumors and three subgroups of IDH1 wild-type GBMs:RTK I, RTK II and Mesenchymal).	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('IDH1', 'Gene', '3417', (249, 253))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('mutant', 'Var', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('GBM', 'Disease', (95, 98))	('GBM', 'Phenotype', 'HP:0012174', (306, 309))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('IDH1', 'Gene', (291, 295))	('neural', 'Disease', (176, 182))	('mesenchymal tumors', 'Disease', 'MESH:C535700', (198, 216))	('GBM', 'Phenotype', 'HP:0012174', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('IDH1', 'Gene', (249, 253))	('tumors', 'Disease', (210, 216))	('IDH1', 'Gene', '3417', (291, 295))	('mesenchymal tumors', 'Disease', (198, 216))
45725	30585246	Similarly, the extensive analysis of driver genes involved in GBM progression resulted in identification of several recurrent mutations either common or subtype-specific, including mutant TERT promoter, IDH1 gene, EGFR (including EGFRvIII deletion mutant), PDGFRA, PTEN, TP53, CDKN2A/B, ATRX and several others.	('EGFR', 'Gene', '1956', (230, 234))	('TERT', 'Gene', (188, 192))	('TERT', 'Gene', '7015', (188, 192))	('EGFR', 'Gene', '1956', (214, 218))	('mutations', 'Var', (126, 135))	('CDKN2A/B', 'Gene', (277, 285))	('EGFR', 'Gene', (230, 234))	('PDGFRA', 'Gene', '5156', (257, 263))	('TP53', 'Gene', (271, 275))	('PDGFRA', 'Gene', (257, 263))	('PTEN', 'Gene', (265, 269))	('EGFR', 'Gene', (214, 218))	('IDH1', 'Gene', (203, 207))	('ATRX', 'Gene', (287, 291))	('mutant', 'Var', (181, 187))	('ATRX', 'Gene', '546', (287, 291))	('PTEN', 'Gene', '5728', (265, 269))	('GBM', 'Phenotype', 'HP:0012174', (62, 65))	('CDKN2A/B', 'Gene', '1029;1030', (277, 285))	('TP53', 'Gene', '7157', (271, 275))	('IDH1', 'Gene', '3417', (203, 207))
45726	30585246	While several of these mutations possess a potent transforming potential in experimental systems and some are druggable (e.g., EGFR) this knowledge has yet to translate into more effective therapy.	('transforming potential', 'CPA', (50, 72))	('mutations', 'Var', (23, 32))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
45740	30585246	In another study, the loss of miR-128 was shown to be an early event in GBM pathogenesis with several consequences to the GSC molecular landscape.	('miR-1', 'Gene', '79187', (30, 35))	('GBM', 'Disease', (72, 75))	('consequences', 'Reg', (102, 114))	('miR-1', 'Gene', (30, 35))	('GBM', 'Phenotype', 'HP:0012174', (72, 75))	('loss', 'Var', (22, 26))
45764	30585246	This change disorganizes sprouting processes of the endothelium and facilitates cancer cell metastasis to the brain and other organs.	('facilitates', 'PosReg', (68, 79))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('disorganizes', 'NegReg', (12, 24))	('sprouting processes of the endothelium', 'CPA', (25, 63))	('change', 'Var', (5, 11))
45772	30585246	For example, co-expression of a specific ncRNA and stem cell markers in circulating EVs may inform about the state of this RNA in the cancer stem cell population in that tumor, samples of which may not be surgically inaccessible.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('inform about', 'Reg', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('co-expression', 'Var', (13, 26))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', (170, 175))	('expression', 'Species', '29278', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
45798	30585246	The majority of studies involving EV-based RNA therapy focused on gene-silencing approaches including those predicated on small interfering RNAs (siRNAs), shRNA (short hairpin RNA) and miRNA.	('miR', 'Gene', '29116', (185, 188))	('miR', 'Gene', (185, 188))	('small', 'Var', (122, 127))
45812	30585246	These processes are of potential significance in the biology and diagnosis of brain malignancies where driver mutations, changes in the epigenome and in the microenvironment fuel the disease process, while profoundly affecting ncRNA networks.	('ncRNA networks', 'MPA', (227, 241))	('changes', 'Reg', (121, 128))	('fuel', 'PosReg', (174, 178))	('mutations', 'Var', (110, 119))	('affecting', 'Reg', (217, 226))	('brain malignancies', 'Phenotype', 'HP:0030692', (78, 96))	('brain malignancies', 'Disease', (78, 96))	('brain malignancies', 'Disease', 'MESH:D001932', (78, 96))	('epigenome', 'MPA', (136, 145))
45826	30290821	These results suggest that the positive charge on liposomes L1 and L2, which is known to promote binding to cell membrane, facilitates carboplatin accumulation in cancer cells explaining their higher efficacy in vitro.	('promote', 'PosReg', (89, 96))	('positive charge', 'Var', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('binding', 'Interaction', (97, 104))	('carboplatin accumulation', 'MPA', (135, 159))	('carboplatin', 'Chemical', 'MESH:D016190', (135, 146))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('facilitates', 'PosReg', (123, 134))
45827	30290821	Conversely, negatively charged and pegylated liposome (L4) seems to diffuse over a larger distance in the tumor, and consequently significantly increased the median survival time of the animals.	('negatively charged', 'Var', (12, 30))	('increased', 'PosReg', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('L4', 'Gene', '300079', (55, 57))	('median survival time', 'CPA', (158, 178))	('tumor', 'Disease', (106, 111))
45835	30290821	Amongst the platinum compounds tested (carboplatin, cisplatin and oxaliplatin), carboplatin exhibited the lowest toxicity while providing the best survival benefits.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('survival benefits', 'CPA', (147, 164))	('toxicity', 'Disease', (113, 121))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (66, 77))	('carboplatin', 'Chemical', 'MESH:D016190', (39, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('platinum', 'Chemical', 'MESH:D010984', (12, 20))	('carboplatin', 'Var', (80, 91))	('carboplatin', 'Chemical', 'MESH:D016190', (80, 91))
45839	30290821	Although CED increases the accumulation of carboplatin in tumor, its concentration decreases rapidly.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('concentration', 'MPA', (69, 82))	('rat', 'Species', '10116', (76, 79))	('carboplatin', 'Chemical', 'MESH:D016190', (43, 54))	('accumulation', 'MPA', (27, 39))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('carboplatin', 'Protein', (43, 54))	('CED', 'Var', (9, 12))
45872	30290821	Drug delivery to cancer cells can be affected by the presence of negative or positive charge and also of PEG on the liposome surface.	('affected', 'Reg', (37, 45))	('PEG', 'Chemical', '-', (105, 108))	('negative', 'Var', (65, 73))	('Drug delivery to cancer', 'Disease', 'MESH:D009369', (0, 23))	('Drug delivery to cancer', 'Disease', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('PEG', 'Var', (105, 108))
45876	30290821	The addition of PEG on the cationic liposome (L2) decreased by 10 times the concentration of carboplatin in the F98 cells relative to the non-pegylated L1, but it still resulted in a 23 times higher accumulation than free carboplatin.	('rat', 'Species', '10116', (83, 86))	('carboplatin', 'Chemical', 'MESH:D016190', (222, 233))	('F98', 'CellLine', 'CVCL:3510', (112, 115))	('accumulation', 'MPA', (199, 211))	('concentration', 'MPA', (76, 89))	('higher', 'PosReg', (192, 198))	('decreased', 'NegReg', (50, 59))	('carboplatin', 'Chemical', 'MESH:D016190', (93, 104))	('PEG', 'Var', (16, 19))	('PEG', 'Chemical', '-', (16, 19))
45886	30290821	The highest anti-tumor efficiency was observed with the anionic pegylated liposomal carboplatin L4, with a MeST of 49.5 days, which is significantly better than that achieved with free carboplatin (p = 0.0335), and the cationic liposome L1 (p = 0.0008).	('carboplatin', 'Chemical', 'MESH:D016190', (84, 95))	('tumor', 'Disease', (17, 22))	('carboplatin', 'Chemical', 'MESH:D016190', (185, 196))	('L4', 'Gene', '300079', (96, 98))	('better', 'PosReg', (149, 155))	('MeST', 'Chemical', '-', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('anionic pegylated', 'Var', (56, 73))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
45918	30290821	The negatively charged Lipoplatin  and its empty version without cisplatin were highly neurotoxic when given by CED in rat brain resulting in death immediately following or within a few days after administration.	('neurotoxic', 'Disease', (87, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('Lipoplatin', 'Protein', (23, 33))	('rat', 'Species', '10116', (205, 208))	('rat', 'Species', '10116', (119, 122))	('negatively charged', 'Var', (4, 22))	('neurotoxic', 'Disease', 'MESH:D020258', (87, 97))	('death', 'Disease', 'MESH:D003643', (142, 147))	('death', 'Disease', (142, 147))
45919	30290821	Intracranial injection of liposomes without drug, composed of lecithin-cholesterol-dicetyl phosphate (net negative charge) or lecithin-cholesterol-stearylamine (net positive charge) induced epileptic seizures and some deaths due to respiratory failure immediately after injection, and a subsequent widespread tissue necrosis.	('seizures', 'Disease', (200, 208))	('lecithin-cholesterol-dicetyl phosphate', 'Chemical', '-', (62, 100))	('necrosis', 'Disease', (316, 324))	('tissue necrosis', 'Phenotype', 'HP:0010885', (309, 324))	('deaths', 'Disease', (218, 224))	('respiratory failure', 'Phenotype', 'HP:0002878', (232, 251))	('widespread tissue', 'CPA', (298, 315))	('respiratory failure', 'Disease', (232, 251))	('induced', 'Reg', (182, 189))	('lecithin-cholesterol-stearylamine', 'Var', (126, 159))	('lecithin-cholesterol-stearylamine', 'Chemical', '-', (126, 159))	('deaths', 'Disease', 'MESH:D003643', (218, 224))	('respiratory failure', 'Disease', 'MESH:D012131', (232, 251))	('seizures', 'Disease', 'MESH:D012640', (200, 208))	('epileptic', 'Disease', (190, 199))	('epileptic', 'Disease', 'MESH:D004827', (190, 199))	('necrosis', 'Disease', 'MESH:D009336', (316, 324))	('seizures', 'Phenotype', 'HP:0001250', (200, 208))
45921	30290821	The 2 negatively charged liposomes L3 and the pegylated L4 were better tolerated as their MTD was about 2-times higher than that of free carboplatin.	('pegylated', 'Var', (46, 55))	('carboplatin', 'Chemical', 'MESH:D016190', (137, 148))	('higher', 'PosReg', (112, 118))	('rat', 'Species', '10116', (75, 78))	('L4', 'Gene', '300079', (56, 58))	('MTD', 'MPA', (90, 93))
45927	30290821	Another benefit of adding PEG is to increase the stability of drug encapsulation in liposomes, which can potentially reduce its toxicity to non-target cells.	('PEG', 'Chemical', '-', (26, 29))	('increase', 'PosReg', (36, 44))	('stability', 'MPA', (49, 58))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('toxicity', 'Disease', (128, 136))	('reduce', 'NegReg', (117, 123))	('PEG', 'Var', (26, 29))
45939	30290821	Pegylation of the anionic liposome reduced the net negative charge of the liposome L4, and this modification seems to have reduced the interaction between the liposome and the cancer cells, since no improvement of carboplatin accumulation in the F98 cells occured.	('carboplatin', 'Chemical', 'MESH:D016190', (214, 225))	('reduced', 'NegReg', (35, 42))	('Pegylation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('modification', 'Var', (96, 108))	('interaction', 'Interaction', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('L4', 'Gene', '300079', (83, 85))	('F98', 'CellLine', 'CVCL:3510', (246, 249))	('reduced', 'NegReg', (123, 130))
45940	30290821	It was previously suggested that PEG can reduce the uptake of liposome by cells, because the binding of these polymers to cell membranes decreases the cell surface hydrophobicity, which reduces the fluid phase of endocytic process, and consequently compromises the internalization of liposome.	('PEG', 'Var', (33, 36))	('uptake of liposome', 'MPA', (52, 70))	('PEG', 'Chemical', '-', (33, 36))	('polymers', 'Chemical', 'MESH:D011108', (110, 118))	('compromises', 'NegReg', (249, 260))	('binding', 'Interaction', (93, 100))	('reduce', 'NegReg', (41, 47))	('cell surface hydrophobicity', 'MPA', (151, 178))	('reduces', 'NegReg', (186, 193))	('decreases', 'NegReg', (137, 146))	('fluid phase of endocytic process', 'MPA', (198, 230))	('internalization of liposome', 'MPA', (265, 292))
45945	30290821	Presumably, steric shielding caused by PEG reduces the rate of liposome binding to cells in the brain during CED.	('PEG', 'Var', (39, 42))	('PEG', 'Chemical', '-', (39, 42))	('binding', 'Interaction', (72, 79))	('rate', 'MPA', (55, 59))	('rat', 'Species', '10116', (55, 58))	('liposome', 'Protein', (63, 71))	('reduces', 'NegReg', (43, 50))
46004	28187762	We show that PD0325901 significantly increases aggregate cohesion, stiffness, and viscosity but only when tumor cells have access to high concentrations of fibronectin.	('stiffness', 'CPA', (67, 76))	('viscosity', 'MPA', (82, 91))	('PD0325901', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('fibronectin', 'Gene', (156, 167))	('increases', 'PosReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PD0325901', 'Chemical', 'MESH:C506614', (13, 22))	('aggregate cohesion', 'CPA', (47, 65))	('tumor', 'Disease', (106, 111))	('fibronectin', 'Gene', '2335', (156, 167))
46006	28187762	Inhibition of the MAPK/ERK pathway by PD0325901 may be an effective therapy for reducing dispersal and growth of GBM cells.	('growth', 'CPA', (103, 109))	('Inhibition', 'NegReg', (0, 10))	('MAPK', 'Gene', (18, 22))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'Gene', (23, 26))	('PD0325901', 'Var', (38, 47))	('dispersal', 'CPA', (89, 98))	('MAPK', 'Gene', '5595;5594;5595', (18, 22))	('PD0325901', 'Chemical', 'MESH:C506614', (38, 47))	('reducing', 'NegReg', (80, 88))
46012	28187762	For example, gamma-linolenic acid (GLA) up-regulates E-cadherin expression and inhibits invasion of lung, colon, breast, melanoma, and liver cancer.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('inhibits', 'NegReg', (79, 87))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('colon', 'Disease', (106, 111))	('gamma-linolenic acid', 'Chemical', 'MESH:D017965', (13, 33))	('expression', 'MPA', (64, 74))	('invasion', 'CPA', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('lung', 'Disease', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('liver cancer', 'Disease', 'MESH:D006528', (135, 147))	('up-regulates', 'PosReg', (40, 52))	('breast', 'Disease', (113, 119))	('GLA', 'Chemical', 'MESH:D017965', (35, 38))	('liver cancer', 'Phenotype', 'HP:0002896', (135, 147))	('liver cancer', 'Disease', (135, 147))	('gamma-linolenic acid', 'Var', (13, 33))
46026	28187762	Clinical trials using various MEK inhibitors, such as trametinib, cobimetinib and CI 1040 (PD184352) have been shown to shrink some melanomas, specifically those with BRAF mutations.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('mutations', 'Var', (172, 181))	('trametinib', 'Chemical', 'MESH:C560077', (54, 64))	('CI 1040', 'Chemical', 'MESH:C120227', (82, 89))	('PD184352', 'Chemical', 'MESH:C120227', (91, 99))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('MEK', 'Gene', '5609', (30, 33))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('shrink', 'NegReg', (120, 126))	('MEK', 'Gene', (30, 33))	('melanomas', 'Disease', (132, 141))	('cobimetinib', 'Chemical', 'MESH:C574276', (66, 77))
46027	28187762	The MEK inhibitor PD0325901 has also demonstrated efficacy in melanoma cell lines independent of BRAF status.	('melanoma', 'Disease', (62, 70))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('PD0325901', 'Chemical', 'MESH:C506614', (18, 27))	('PD0325901', 'Var', (18, 27))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
46028	28187762	Experimental models have demonstrated in vitro and in vivo efficacy of PD0325901 in controlling tumor growth in animal models of GBM, although studies have identified possible issues with limited access through the blood-brain barrier.	('PD0325901', 'Var', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PD0325901', 'Chemical', 'MESH:C506614', (71, 80))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
46029	28187762	To our knowledge, there is only one ongoing phase-2 trial testing the effects of PD0325901 on tumor growth in patients with neurofibromatosis type -1 (NF1) or plexiform neurofibromas NCT02096471), and none testing efficacy in GBM.	('neurofibromatosis type -1', 'Gene', (124, 149))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (124, 141))	('neurofibromas', 'Disease', (169, 182))	('neurofibromas', 'Phenotype', 'HP:0001067', (169, 182))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (159, 182))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('neurofibromatosis type -1', 'Gene', '4763', (124, 149))	('neurofibromas', 'Disease', 'MESH:D009455', (169, 182))	('PD0325901', 'Chemical', 'MESH:C506614', (81, 90))	('tumor', 'Disease', (94, 99))	('NF1', 'Gene', (151, 154))	('PD0325901', 'Gene', (81, 90))	('NF1', 'Gene', '4763', (151, 154))	('NCT02096471', 'Var', (183, 194))	('patients', 'Species', '9606', (110, 118))
46030	28187762	Inasmuch as MEK inhibitors target pathways that can also influence actin organization and remodeling of the ECM, we asked whether PD0325901 could also serve to impact mechanisms that regulate dispersal of primary human GBM cells.	('impact', 'Reg', (160, 166))	('actin', 'MPA', (67, 72))	('human', 'Species', '9606', (213, 218))	('influence', 'Reg', (57, 66))	('PD0325901', 'Var', (130, 139))	('PD0325901', 'Chemical', 'MESH:C506614', (130, 139))	('dispersal', 'CPA', (192, 201))	('MEK', 'Gene', (12, 15))	('MEK', 'Gene', '5609', (12, 15))
46033	28187762	We also quantified the effects of PD0325901 on spheroid mechanical properties including cohesion, stiffness and viscosity.	('PD0325901', 'Var', (34, 43))	('viscosity', 'MPA', (112, 121))	('cohesion', 'CPA', (88, 96))	('PD0325901', 'Chemical', 'MESH:C506614', (34, 43))	('effects', 'Reg', (23, 30))	('stiffness', 'MPA', (98, 107))
46035	28187762	Finally, we determined whether PD0325901 could also influence the growth rate of both 2D and 3D cultures of GBM.	('PD0325901', 'Var', (31, 40))	('PD0325901', 'Chemical', 'MESH:C506614', (31, 40))	('influence', 'Reg', (52, 61))	('growth rate', 'CPA', (66, 77))
46046	28187762	To confirm that PD0325901 inhibited ERK1/2 phosphorylation, cells were treated with either dimethyl sulfoxide (DMSO, vehicle control) or 1 muM PD0325901 overnight under standard tissue culture conditions.	('PD0325901', 'Var', (16, 25))	('phosphorylation', 'MPA', (43, 58))	('inhibited', 'NegReg', (26, 35))	('PD0325901', 'Chemical', 'MESH:C506614', (16, 25))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (91, 109))	('ERK1/2', 'Gene', (36, 42))	('muM', 'Gene', '56925', (139, 142))	('PD0325901', 'Chemical', 'MESH:C506614', (143, 152))	('ERK1/2', 'Gene', '5595;5594', (36, 42))	('DMSO', 'Chemical', 'MESH:D004121', (111, 115))	('muM', 'Gene', (139, 142))
46048	28187762	Gels were blotted to PVDF and probed with anti-phospho P44/42 MAPK or P44/42 MAPK antibodies (Cell Signaling Technologies, Danvers, MA) and appropriate HRP-conjugated secondary antibodies.	('MAPK', 'Gene', (77, 81))	('PVDF', 'Chemical', 'MESH:C024865', (21, 25))	('MAPK', 'Gene', '5595;5594;5595', (77, 81))	('MAPK', 'Gene', '5595;5594;5595', (62, 66))	('MAPK', 'Gene', (62, 66))	('anti-phospho P44/42', 'Var', (42, 61))
46060	28187762	50-100 mum diameter aggregates of DMSO or PD0325901-treated GBM-1-4 were deposited into 12-well tissue culture plates containing 2mls of pre-warmed TCM.	('mum', 'Gene', '56925', (7, 10))	('DMSO', 'Chemical', 'MESH:D004121', (34, 38))	('mum', 'Gene', (7, 10))	('PD0325901', 'Chemical', 'MESH:C506614', (42, 51))	('PD0325901-treated', 'Var', (42, 59))
46068	28187762	Studies have previously demonstrated a growth-inhibitory role for PD0325901 in GBM.	('PD0325901', 'Chemical', 'MESH:C506614', (66, 75))	('GBM', 'Disease', (79, 82))	('PD0325901', 'Var', (66, 75))	('growth-inhibitory role', 'MPA', (39, 61))
46069	28187762	Figure 1a shows that PD0325901 treatment down-regulates p-ERK, the downstream effector of MEK, in all 4 primary GBM cell lines.	('PD0325901', 'Var', (21, 30))	('down-regulates', 'NegReg', (41, 55))	('ERK', 'Gene', '5594', (58, 61))	('MEK', 'Gene', (90, 93))	('MEK', 'Gene', '5609', (90, 93))	('PD0325901', 'Chemical', 'MESH:C506614', (21, 30))	('ERK', 'Gene', (58, 61))
46070	28187762	Unlike Dex, PD0325901 did not induce FNMA (Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (12, 21))	('FNMA', 'Disease', (37, 41))	('Dex', 'Chemical', 'MESH:D003907', (7, 10))	('PD0325901', 'Var', (12, 21))
46073	28187762	PD0325901 treatment also gave rise to the organization of actin into stress fibers when cells were grown as conventional 2D culture (Fig.	('gave rise to', 'Reg', (25, 37))	('PD0325901', 'Var', (0, 9))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))	('organization', 'MPA', (42, 54))
46074	28187762	Moreover, PD0325901 treatment resulted in the localization of p-FAK at sites of cell-ECM attachment (Fig.	('FAK', 'Gene', (64, 67))	('resulted in', 'Reg', (30, 41))	('FAK', 'Gene', '5747', (64, 67))	('PD0325901', 'Var', (10, 19))	('localization', 'MPA', (46, 58))	('PD0325901', 'Chemical', 'MESH:C506614', (10, 19))
46075	28187762	These results indicate that PD0325901 treatment activates mechanisms involved in regulating cell motility and mechanical properties of single cells or cellular aggregates.	('mechanical properties of', 'CPA', (110, 134))	('PD0325901', 'Var', (28, 37))	('PD0325901', 'Chemical', 'MESH:C506614', (28, 37))	('activates', 'PosReg', (48, 57))	('cell motility', 'CPA', (92, 105))
46076	28187762	We first generated measurements of aggregate cohesion for GBM-1-4 treated in either DMSO or PD0325901, and confirmed that the cohesion measured was reflective of a true tissue surface tension (Table 1).	('PD0325901', 'Var', (92, 101))	('DMSO', 'Chemical', 'MESH:D004121', (84, 88))	('PD0325901', 'Chemical', 'MESH:C506614', (92, 101))	('cohesion', 'MPA', (126, 134))	('aggregate cohesion', 'MPA', (35, 53))
46079	28187762	Figure 2a shows that PD0325901 treatment did not have an effect on aggregate surface tension.	('PD0325901', 'Chemical', 'MESH:C506614', (21, 30))	('PD0325901', 'Var', (21, 30))	('aggregate surface tension', 'MPA', (67, 92))
46081	28187762	2b), suggesting that the effects of PD0325901 may be through enhancement of alpha5beta1 integrin-fibronectin interaction.	('PD0325901', 'Var', (36, 45))	('fibronectin', 'Gene', (97, 108))	('PD0325901', 'Chemical', 'MESH:C506614', (36, 45))	('enhancement', 'PosReg', (61, 72))	('fibronectin', 'Gene', '2335', (97, 108))
46083	28187762	Interestingly, for aggregates generated in 30 mug/ml sFn (30 sFn), PD0325901 treatment slightly increased stiffness (Fig.	('increased', 'PosReg', (96, 105))	('PD0325901', 'Var', (67, 76))	('PD0325901', 'Chemical', 'MESH:C506614', (67, 76))	('sFn', 'Chemical', '-', (61, 64))	('sFn', 'Chemical', '-', (53, 56))	('stiffness', 'MPA', (106, 115))
46085	28187762	This suggests that fibronectin is an absolute requirement for PD0325901 to alter mechanical properties.	('fibronectin', 'Gene', '2335', (19, 30))	('alter', 'Reg', (75, 80))	('fibronectin', 'Gene', (19, 30))	('PD0325901', 'Var', (62, 71))	('PD0325901', 'Chemical', 'MESH:C506614', (62, 71))	('mechanical', 'MPA', (81, 91))
46086	28187762	The effects of PD0325901 on cell shape, actin reorganization and aggregate viscoelasticity translate to significant changes in tumor cell behavior.	('PD0325901', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cell shape', 'CPA', (28, 38))	('effects', 'Reg', (4, 11))	('tumor', 'Disease', (127, 132))	('PD0325901', 'Chemical', 'MESH:C506614', (15, 24))	('changes', 'Reg', (116, 123))	('actin reorganization', 'CPA', (40, 60))	('aggregate', 'MPA', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
46087	28187762	Notably, PD0325901 treatment rendered GBM cells more resistant to shear-induced detachment (Fig.	('shear-induced detachment', 'CPA', (66, 90))	('PD0325901', 'Chemical', 'MESH:C506614', (9, 18))	('resistant', 'CPA', (53, 62))	('more', 'PosReg', (48, 52))	('PD0325901', 'Var', (9, 18))
46088	28187762	For all lines, cleared area was reduced approximately 3-fold in response to PD0325901 treatment, indicating a significant decrease in cell motility.	('cleared area', 'CPA', (15, 27))	('PD0325901', 'Chemical', 'MESH:C506614', (76, 85))	('cell motility', 'CPA', (134, 147))	('decrease', 'NegReg', (122, 130))	('reduced', 'NegReg', (32, 39))	('PD0325901', 'Var', (76, 85))
46089	28187762	When experiments were performed in TCM containing 5 mug/ml mouse monoclonal anti-human fibronectin antibody, the motility of PD0325901-treated cells was restored to levels comparable to those of DMSO controls (Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (125, 134))	('mouse', 'Species', '10090', (59, 64))	('PD0325901-treated', 'Var', (125, 142))	('fibronectin', 'Gene', (87, 98))	('DMSO', 'Chemical', 'MESH:D004121', (195, 199))	('motility', 'CPA', (113, 121))	('fibronectin', 'Gene', '2335', (87, 98))	('human', 'Species', '9606', (81, 86))
46091	28187762	These results indicate that the principal mechanism of PD0325901-mediated decrease in motility is alpha5beta1 integrin-fibronectin dependent.	('decrease', 'NegReg', (74, 82))	('PD0325901', 'Chemical', 'MESH:C506614', (55, 64))	('fibronectin', 'Gene', '2335', (119, 130))	('motility', 'CPA', (86, 94))	('PD0325901-mediated', 'Var', (55, 73))	('fibronectin', 'Gene', (119, 130))
46092	28187762	Figure 3c shows that spheroids of GBM cells differ in baseline dispersal velocities and that PD0325901 treatment reduces DV relative to DMSO controls.	('DMSO', 'Chemical', 'MESH:D004121', (136, 140))	('baseline dispersal velocities', 'MPA', (54, 83))	('reduces', 'NegReg', (113, 120))	('PD0325901', 'Var', (93, 102))	('PD0325901', 'Chemical', 'MESH:C506614', (93, 102))
46097	28187762	PD0325901 treatment also resulted in a significant reduction in z-axis dispersal for three of the four lines (Fig.	('PD0325901', 'Var', (0, 9))	('z-axis dispersal', 'CPA', (64, 80))	('reduction', 'NegReg', (51, 60))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))
46098	28187762	The z-axis dispersal distance of PD0325901-treated GBM-1 and GBM-2 cells was approximately 2-fold less than that of the vehicle controls.	('PD0325901-treated', 'Var', (33, 50))	('z-axis dispersal distance', 'CPA', (4, 29))	('less', 'NegReg', (98, 102))	('PD0325901', 'Chemical', 'MESH:C506614', (33, 42))
46099	28187762	Previous studies demonstrated that the growth rate of various immortalized GBM cell lines was markedly reduced by PD0325901.	('reduced', 'NegReg', (103, 110))	('growth rate of', 'CPA', (39, 53))	('PD0325901', 'Var', (114, 123))	('PD0325901', 'Chemical', 'MESH:C506614', (114, 123))
46100	28187762	Figure 5 (a, b) shows that PD0325901 significantly decreases the growth rate of conventional 2D cultures of GBM-1-4 as compared to DMSO controls.	('DMSO', 'Chemical', 'MESH:D004121', (131, 135))	('decreases', 'NegReg', (51, 60))	('growth rate', 'CPA', (65, 76))	('PD0325901', 'Var', (27, 36))	('PD0325901', 'Chemical', 'MESH:C506614', (27, 36))
46102	28187762	In fact, PD0325901 treated aggregates appeared to decrease in size over time.	('PD0325901', 'Chemical', 'MESH:C506614', (9, 18))	('PD0325901 treated', 'Var', (9, 26))	('size', 'MPA', (62, 66))	('decrease', 'NegReg', (50, 58))
46104	28187762	This appears to be the case inasmuch as PD0325901 treatment resulted in more compact aggregates (Additional file 1: Figure S3, Panel c).	('PD0325901', 'Chemical', 'MESH:C506614', (40, 49))	('PD0325901 treatment', 'Var', (40, 59))	('more', 'PosReg', (72, 76))
46109	28187762	In this study, we explore whether inhibition of the MAPK/ERK pathway, a critical regulator of processes underlying invasion and metastasis, could have similar effects on GBM dispersal.	('inhibition', 'Var', (34, 44))	('effects', 'Reg', (159, 166))	('MAPK', 'Gene', (52, 56))	('ERK', 'Gene', '5594', (57, 60))	('MAPK', 'Gene', '5595;5594;5595', (52, 56))	('GBM dispersal', 'CPA', (170, 183))	('ERK', 'Gene', (57, 60))
46110	28187762	We tested the effects of the MEK inhibitor, PD0325901, on 4 primary GBM cell lines that were previously used to assess the effects of Dex on dispersal.	('MEK', 'Gene', '5609', (29, 32))	('PD0325901', 'Var', (44, 53))	('tested', 'Reg', (3, 9))	('PD0325901', 'Chemical', 'MESH:C506614', (44, 53))	('MEK', 'Gene', (29, 32))	('Dex', 'Chemical', 'MESH:D003907', (134, 137))
46112	28187762	We therefore assessed whether our lines are responsive to PD0325901 by determining whether treatment results in a decrease in the levels of phospho-ERK.	('ERK', 'Gene', (148, 151))	('PD0325901', 'Chemical', 'MESH:C506614', (58, 67))	('PD0325901', 'Var', (58, 67))	('decrease', 'NegReg', (114, 122))	('ERK', 'Gene', '5594', (148, 151))
46113	28187762	In contrast to Dex, treatment with PD0325901 did not result in a significant increase in FNMA.	('PD0325901', 'Chemical', 'MESH:C506614', (35, 44))	('PD0325901', 'Var', (35, 44))	('FNMA', 'Disease', (89, 93))	('Dex', 'Chemical', 'MESH:D003907', (15, 18))
46115	28187762	Stiffening of the ECM is considered to be a hallmark of fibrotic lesions and has been demonstrated to modulate cell invasion and migration.	('Stiffening', 'Var', (0, 10))	('hallmark of fibrotic lesions', 'Disease', (44, 72))	('migration', 'CPA', (129, 138))	('cell invasion', 'CPA', (111, 124))	('modulate', 'Reg', (102, 110))	('hallmark of fibrotic lesions', 'Disease', 'MESH:D051437', (44, 72))
46116	28187762	Unexpectedly, PD0325901 treatment only resulted in a modest increase in aggregate stiffness but not of viscosity.	('PD0325901', 'Var', (14, 23))	('PD0325901', 'Chemical', 'MESH:C506614', (14, 23))	('increase', 'PosReg', (60, 68))	('aggregate stiffness', 'MPA', (72, 91))
46119	28187762	Accordingly, tumors able to respond to PD0325901 and in the presence of high concentrations of fibronectin, could, in principle, become stiffer and more viscous.	('viscous', 'MPA', (153, 160))	('PD0325901', 'Var', (39, 48))	('tumors', 'Disease', (13, 19))	('fibronectin', 'Gene', '2335', (95, 106))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('PD0325901', 'Chemical', 'MESH:C506614', (39, 48))	('fibronectin', 'Gene', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('stiffer', 'CPA', (136, 143))
46124	28187762	In GBM spheroids, the increase in viscosity in response to PD0325901 treatment was likely due to higher binding energy between the activated alpha5beta1 integrin and fibronectin.	('higher', 'PosReg', (97, 103))	('PD0325901', 'Var', (59, 68))	('binding', 'Interaction', (104, 111))	('fibronectin', 'Gene', (166, 177))	('increase', 'PosReg', (22, 30))	('PD0325901', 'Chemical', 'MESH:C506614', (59, 68))	('viscosity', 'MPA', (34, 43))	('alpha5beta1 integrin', 'Protein', (141, 161))	('fibronectin', 'Gene', '2335', (166, 177))
46128	28187762	Since PD0325901 treatment did not restore FNMA, it is likely that decreased motility rather than increased cohesion is the physical mechanism that restrains the detachment of tumor cells from the mass.	('restrains', 'NegReg', (147, 156))	('tumor', 'Disease', (175, 180))	('decreased', 'NegReg', (66, 75))	('PD0325901', 'Var', (6, 15))	('detachment', 'CPA', (161, 171))	('motility', 'CPA', (76, 84))	('PD0325901', 'Chemical', 'MESH:C506614', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
46129	28187762	For three of the four primary GBM lines, PD0325901 also significantly reduced the ability of single GBM cells to disperse through an astrocyte-seeded scaffold.	('reduced', 'NegReg', (70, 77))	('PD0325901', 'Var', (41, 50))	('PD0325901', 'Chemical', 'MESH:C506614', (41, 50))
46130	28187762	It is not possible to differentiate between the effects of PD0325901 on decreased motility and ability to disperse through the scaffold, however, it is possible that on a single cell level, the re-organization of actin into stress fibers may have effectively rendered cells less compliant and inhibited their capacity to sufficiently deform and squeeze through pores established by the physical environment established by the scaffold.	('less', 'NegReg', (274, 278))	('PD0325901', 'Var', (59, 68))	('inhibited', 'NegReg', (293, 302))	('PD0325901', 'Chemical', 'MESH:C506614', (59, 68))
46132	28187762	Other studies have demonstrated in vivo efficacy of PD0325901 in reducing tumor growth in preclinical orthotopic models of glioblastoma.	('glioblastoma', 'Disease', (123, 135))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('reducing', 'NegReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('tumor', 'Disease', (74, 79))	('PD0325901', 'Var', (52, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('PD0325901', 'Chemical', 'MESH:C506614', (52, 61))
46133	28187762	Our study provides compelling evidence that PD0325901 can also reduce dispersal.	('PD0325901', 'Var', (44, 53))	('PD0325901', 'Chemical', 'MESH:C506614', (44, 53))	('dispersal', 'CPA', (70, 79))	('reduce', 'NegReg', (63, 69))
46145	28187762	Containing the primary or recurrent tumor by interstitial administration of MEK inhibitors could significantly improve delivery of chemotherapeutic agents and increase the likelihood of total surgical resection.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('MEK', 'Gene', (76, 79))	('delivery of chemotherapeutic agents', 'MPA', (119, 154))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MEK', 'Gene', '5609', (76, 79))	('improve', 'PosReg', (111, 118))	('tumor', 'Disease', (36, 41))	('increase', 'PosReg', (159, 167))	('inhibitors', 'Var', (80, 90))
46167	26869992	Additionally, there is a functional peroxisome proliferator response element (PPRE) in the HMGCS2 promoter (-105 to -92).	('HMGCS2', 'Gene', (91, 97))	('HMGCS2', 'Gene', '15360', (91, 97))	('-105 to -92', 'Var', (108, 119))
46233	26869992	Our previous in vitro and in vivo studies conducted on various malignant cell lines of neurocetodermal origin demonstrated that fenofibrate inhibited proliferation, migration, invasion, metastatic tumor formation, and affected energy homeostasis, which led to metabolic catastrophe.	('affected', 'Reg', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('fenofibrate', 'Var', (128, 139))	('inhibited', 'NegReg', (140, 149))	('fenofibrate', 'Chemical', 'MESH:D011345', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('led to', 'Reg', (253, 259))	('energy homeostasis', 'MPA', (227, 245))	('migration', 'CPA', (165, 174))	('tumor', 'Disease', (197, 202))	('invasion', 'CPA', (176, 184))	('metabolic catastrophe', 'CPA', (260, 281))	('proliferation', 'CPA', (150, 163))
46267	26869992	Transcription of HMGCS1 is not normally regulated by PPARa; thus, the observed positive effect of both fenofibrate and MK886 on HMGCS1 protein level was quite unexpected, particularly the additive stimulation of HMGCS1 expression in the cells treated with both fenofibrate and MK886 in wt B16 F10 (Figure 3E).	('HMGCS1', 'Gene', (212, 218))	('HMGCS1', 'Gene', (17, 23))	('HMGCS1', 'Gene', '208715', (212, 218))	('HMGCS1', 'Gene', '208715', (17, 23))	('expression', 'MPA', (219, 229))	('fenofibrate', 'Chemical', 'MESH:D011345', (261, 272))	('protein level', 'MPA', (135, 148))	('HMGCS1', 'Gene', (128, 134))	('fenofibrate', 'Chemical', 'MESH:D011345', (103, 114))	('HMGCS1', 'Gene', '208715', (128, 134))	('MK886', 'Var', (277, 282))	('stimulation', 'PosReg', (197, 208))	('MK886', 'Chemical', 'MESH:C060893', (277, 282))	('MK886', 'Chemical', 'MESH:C060893', (119, 124))
46276	26869992	ACL phosphorylation at Ser 455 (by PKA and Akt) enhances its enzymatic activity.	('ACL phosphorylation', 'MPA', (0, 19))	('Akt', 'Gene', '11651', (43, 46))	('Ser 455', 'Var', (23, 30))	('Akt', 'Gene', (43, 46))	('Ser', 'Chemical', 'MESH:D012694', (23, 26))	('enhances', 'PosReg', (48, 56))	('enzymatic activity', 'MPA', (61, 79))
46289	26869992	In cells with PPARa depletion or overexpression, the effect of fenofibrate was hardly visible.	('overexpression', 'PosReg', (33, 47))	('PPARa', 'Protein', (14, 19))	('fenofibrate', 'Chemical', 'MESH:D011345', (63, 74))	('depletion', 'Var', (20, 29))
46297	26869992	Neither the knock down of PPARa protein level nor its overexpression affected the ability of cells to produce and release bHB.	('produce', 'MPA', (102, 109))	('bHB', 'Chemical', 'MESH:D020155', (122, 125))	('PPARa', 'Gene', (26, 31))	('knock down', 'Var', (12, 22))	('release bHB', 'MPA', (114, 125))
46300	26869992	Interestingly, both fenofibrate and the PPARa inhibitor MK886 also upregulated the levels of cytoplasmic HMGCS1, an enzyme involved in cholesterol synthesis.	('inhibitor MK886', 'Var', (46, 61))	('cholesterol', 'Chemical', 'MESH:D002784', (135, 146))	('MK886', 'Var', (56, 61))	('fenofibrate', 'Chemical', 'MESH:D011345', (20, 31))	('PPARa', 'Gene', (40, 45))	('MK886', 'Chemical', 'MESH:C060893', (56, 61))	('HMGCS1', 'Gene', (105, 111))	('upregulated', 'PosReg', (67, 78))	('HMGCS1', 'Gene', '208715', (105, 111))
46329	26869992	Recently, a reciprocally opposite regulation between p53 and ME1 and ME2 has been reported, showing that p53 knock out increases malic enzymes expression and that this gives the tumor cells a growth advantage, facilitating glutaminolytic flux and lipogenesis.	('p53', 'Gene', '22060', (53, 56))	('ME1', 'Gene', '17436', (61, 64))	('malic enzymes', 'Enzyme', (129, 142))	('lipogenesis', 'MPA', (247, 258))	('knock out', 'Var', (109, 118))	('p53', 'Gene', (105, 108))	('ME2', 'Gene', (69, 72))	('increases malic enzymes expression', 'Phenotype', 'HP:0003232', (119, 153))	('facilitating', 'PosReg', (210, 222))	('p53', 'Gene', '22060', (105, 108))	('tumor', 'Disease', (178, 183))	('ME2', 'Gene', '107029', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('growth advantage', 'CPA', (192, 208))	('expression', 'MPA', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('increases', 'PosReg', (119, 128))	('glutaminolytic flux', 'MPA', (223, 242))	('ME1', 'Gene', (61, 64))	('p53', 'Gene', (53, 56))
46345	23242178	In fact, recent evidence indicates that p53 may stall tumor growth via other, less-characterized cellular functions.	('p53', 'Var', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('stall', 'NegReg', (48, 53))	('tumor', 'Disease', (54, 59))
46347	23242178	The recent development of small molecules targeting the p53 repressors MDM2 and MDM4, as well as molecules seemingly restoring the wild-type conformation of mutant p53, has generated much momentum in the field of p53-based therapies.	('mutant', 'Var', (157, 163))	('MDM2', 'Gene', '4193', (71, 75))	('conformation', 'MPA', (141, 153))	('MDM2', 'Gene', (71, 75))	('MDM4', 'Gene', '4194', (80, 84))	('MDM4', 'Gene', (80, 84))	('p53', 'Gene', (164, 167))
46356	23242178	p21 works as a cyclin-dependent kinase (CDK) inhibitor, associating with and inhibiting various cyclin-CDK complexes.	('CDK', 'Gene', (103, 106))	('inhibiting', 'NegReg', (77, 87))	('cyclin', 'Gene', '5111', (15, 21))	('CDK', 'Gene', (40, 43))	('CDK', 'Gene', '983;1017;1019;1020;1021;1024', (103, 106))	('cyclin', 'Gene', (15, 21))	('cyclin', 'Gene', '5111', (96, 102))	('CDK', 'Gene', '983;1017;1019;1020;1021;1024', (40, 43))	('p21', 'Var', (0, 3))	('cyclin', 'Gene', (96, 102))
46377	23242178	In NSCLC and HCC cell lines, TRAIL resistance correlates positively with miR-221/222 expression, and overexpression of PTEN and TIMP3 or knock-down of miR-221/222 confers increased TRAIL sensitivity.	('miR-221', 'Gene', (73, 80))	('miR-221', 'Gene', '407006', (73, 80))	('increased', 'PosReg', (171, 180))	('miR-221', 'Gene', (151, 158))	('overexpression', 'PosReg', (101, 115))	('miR-221', 'Gene', '407006', (151, 158))	('HCC', 'Phenotype', 'HP:0001402', (13, 16))	('TRAIL', 'Gene', '8743', (181, 186))	('TIMP3', 'Gene', (128, 133))	('TIMP3', 'Gene', '7078', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('PTEN', 'Gene', (119, 123))	('TRAIL', 'Gene', '8743', (29, 34))	('expression', 'MPA', (85, 95))	('NSCLC', 'Disease', (3, 8))	('knock-down', 'Var', (137, 147))	('TRAIL', 'Gene', (181, 186))	('PTEN', 'Gene', '5728', (119, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('TRAIL', 'Gene', (29, 34))
46383	23242178	The FAS mRNA is targeted by let-7/miR-98 and miR-20a (Figure 1).	('FAS', 'Chemical', 'MESH:C038178', (4, 7))	('miR-20a', 'Var', (45, 52))	('miR-98', 'Gene', (34, 40))	('miR-98', 'Gene', '407054', (34, 40))
46385	23242178	Indeed, ectopic expression of miR-98 leads to FAS downregulation and a decrease in FasL-induced apoptosis.	('downregulation', 'NegReg', (50, 64))	('ectopic expression', 'Var', (8, 26))	('miR-98', 'Gene', '407054', (30, 36))	('FasL', 'Gene', (83, 87))	('decrease', 'NegReg', (71, 79))	('FasL', 'Gene', '356', (83, 87))	('FAS', 'Chemical', 'MESH:C038178', (46, 49))	('miR-98', 'Gene', (30, 36))	('FAS', 'CPA', (46, 49))
46389	23242178	Importantly, inhibition of miR-20a activity significantly reduces the metastatic potential of osteosarcoma cells, purportedly by restoring sensitivity of FasL in the lung microenvironment.	('reduces', 'NegReg', (58, 65))	('activity', 'MPA', (35, 43))	('FasL', 'Gene', '356', (154, 158))	('FasL', 'Gene', (154, 158))	('inhibition', 'Var', (13, 23))	('miR-20a', 'Gene', (27, 34))	('restoring', 'PosReg', (129, 138))	('osteosarcoma', 'Disease', (94, 106))	('osteosarcoma', 'Phenotype', 'HP:0002669', (94, 106))	('sensitivity', 'MPA', (139, 150))	('osteosarcoma', 'Disease', 'MESH:D012516', (94, 106))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('metastatic potential of', 'CPA', (70, 93))
46395	23242178	Expression of all these miRNAs is upregulated by p53 either via direct transactivation or, in the case of miR-143-145, at the level of processing.	('miR-143', 'Gene', '406935', (106, 113))	('Expression', 'MPA', (0, 10))	('upregulated', 'PosReg', (34, 45))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (106, 109))	('miR-143', 'Gene', (106, 113))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('p53', 'Var', (49, 52))
46409	23242178	Ectopic expression of Musashi-1 correlates with oncogenesis, whereas siRNA-mediated ablation of Musashi-1 coincides with tumor regression and cancer cell growth arrest in mouse xenografts of human colorectal cancer origin.	('Musashi-1', 'Gene', (22, 31))	('colorectal cancer', 'Disease', (197, 214))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('oncogenesis', 'Disease', (48, 59))	('ablation', 'Var', (84, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('cancer cell growth arrest', 'Disease', (142, 167))	('tumor', 'Disease', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Musashi-1', 'Gene', (96, 105))	('cancer cell growth arrest', 'Disease', 'MESH:D006323', (142, 167))	('human', 'Species', '9606', (191, 196))	('mouse', 'Species', '10090', (171, 176))	('growth arrest', 'Phenotype', 'HP:0001510', (154, 167))	('Ectopic expression', 'MPA', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
46424	23242178	In addition to the impact of miRNAs and RBPs on the expression of p53 target mRNAs discussed so far, p53 itself activates transcription of both miRNAs and RBPs that in turn create another post-transcriptional regulatory layer within the network.	('p53', 'Var', (101, 104))	('transcription', 'MPA', (122, 135))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('activates', 'PosReg', (112, 121))	('RBP', 'Gene', (155, 158))	('miR', 'Gene', '220972', (144, 147))	('RBP', 'Gene', '57794', (155, 158))	('create', 'Reg', (173, 179))	('miR', 'Gene', (144, 147))	('RBP', 'Gene', (40, 43))	('RBP', 'Gene', '57794', (40, 43))
46438	23242178	Indeed, ectopic expression of miR-34a in cancer cell lines leads to decreased protein levels of these targets and increased cell-cycle arrest in the G1 phase.	('decreased', 'NegReg', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ectopic expression', 'Var', (8, 26))	('protein levels of these targets', 'MPA', (78, 109))	('increased', 'PosReg', (114, 123))	('cell-cycle arrest in the G1 phase', 'CPA', (124, 157))	('miR-34a', 'Gene', (30, 37))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
46441	23242178	Interestingly, while MET is a direct target of miR-34a, EGFR is downregulated by the post-transcriptional regulation of one of its activating transcription factors, Yin Yang-1.	('post-transcriptional regulation', 'MPA', (85, 116))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('MET', 'MPA', (21, 24))	('Yin Yang-1', 'Gene', '7528', (165, 175))	('Yin Yang-1', 'Gene', (165, 175))	('miR-34a', 'Var', (47, 54))	('downregulated', 'NegReg', (64, 77))
46442	23242178	Abrogation of this regulatory mechanism, which induces a hyper-activated growth factor cascade is a poor clinical marker in glioblastoma multiforme patients, where concomitant loss of miR-34a and amplification of EGFR correlates with significantly decreased survival time.	('patients', 'Species', '9606', (148, 156))	('induces', 'Reg', (47, 54))	('loss', 'NegReg', (176, 180))	('EGFR', 'Gene', (213, 217))	('miR-34a', 'Protein', (184, 191))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (124, 147))	('survival time', 'CPA', (258, 271))	('decreased', 'NegReg', (248, 257))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('amplification', 'Var', (196, 209))	('glioblastoma multiforme', 'Disease', (124, 147))	('hyper-activated growth factor cascade', 'MPA', (57, 94))	('EGFR', 'Gene', '1956', (213, 217))
46443	23242178	Acting downstream of RTK signaling, miR-34a also targets several members of the RAS/RAF/MAPK pathway as well as PIK3R2, a regulatory subunit of PI3K and perhaps the second most commonly deregulated oncogene, next to RAS.	('PIK3R2', 'Gene', '5296', (112, 118))	('PIK3R2', 'Gene', (112, 118))	('miR-34a', 'Var', (36, 43))	('RAF', 'Gene', '22882', (84, 87))	('RAF', 'Gene', (84, 87))	('targets', 'Reg', (49, 56))
46446	23242178	miR-34a has clearly been shown to target the 3'-UTR of BCL2 mRNA, which may have important implications in the cellular response to MDM2 inhibitors.	('miR-34a', 'Var', (0, 7))	('BCL2', 'Gene', '596', (55, 59))	("3'-UTR", 'MPA', (45, 51))	('implications', 'Reg', (91, 103))	('target', 'Reg', (34, 40))	('BCL2', 'Gene', (55, 59))	('MDM2', 'Gene', '4193', (132, 136))	('MDM2', 'Gene', (132, 136))
46447	23242178	Indeed, in cancer cell lines where MDM2 inhibitors induce cell-cycle arrest, the response can be switched to apoptosis via BCL2 shRNAs or BH3 mimetics.	('BCL2', 'Gene', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('inhibitors', 'Var', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cell-cycle arrest', 'CPA', (58, 75))	('cancer', 'Disease', (11, 17))	('BCL2', 'Gene', '596', (123, 127))	('MDM2', 'Gene', '4193', (35, 39))	('MDM2', 'Gene', (35, 39))
46451	23242178	miR-205 is commonly repressed in human breast cancer, and reintroduction of miR-205 into highly aggressive triple-negative breast cancer cell lines leads to decreased cell proliferation and cell-cycle arrest.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('miR-205', 'Gene', '406988', (76, 83))	('cell-cycle arrest', 'CPA', (190, 207))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('breast cancer', 'Disease', (123, 136))	('miR-205', 'Gene', (76, 83))	('miR-205', 'Gene', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('human', 'Species', '9606', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('miR-205', 'Gene', '406988', (0, 7))	('reintroduction', 'Var', (58, 72))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('decreased', 'NegReg', (157, 166))	('breast cancer', 'Disease', (39, 52))	('cell proliferation', 'CPA', (167, 185))
46453	23242178	The Zaffaroni group showed that reintroduction of miR-205 into prostate cancer cells is sufficient to suggest a reversal of EMT, as highlighted by changes in cell morphology, increased cell-to-cell adhesion, and decreased invasiveness.	('decreased', 'NegReg', (212, 221))	('miR-205', 'Gene', (50, 57))	('reintroduction', 'Var', (32, 46))	('cell morphology', 'CPA', (158, 173))	('miR-205', 'Gene', '406988', (50, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('changes', 'Reg', (147, 154))	('Zaffaroni', 'Chemical', '-', (4, 13))	('invasiveness', 'CPA', (222, 234))	('prostate cancer', 'Disease', (63, 78))	('cell-to-cell adhesion', 'CPA', (185, 206))	('increased', 'PosReg', (175, 184))
46466	23242178	p53 also induces QKI, an RBP belonging to the signaling transduction and activation of RNA family.	('RBP', 'Gene', (25, 28))	('QKI', 'Disease', (17, 20))	('RBP', 'Gene', '57794', (25, 28))	('p53', 'Var', (0, 3))	('induces', 'Reg', (9, 16))
46468	23242178	Thus, by upregulating both the miRNA and an RBP that stabilizes it, p53 strongly reinforces miR-20a action.	('RBP', 'Gene', '57794', (44, 47))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('reinforces', 'PosReg', (81, 91))	('p53', 'Var', (68, 71))	('miR', 'Gene', (31, 34))	('miR', 'Gene', '220972', (31, 34))	('upregulating', 'PosReg', (9, 21))	('RBP', 'Gene', (44, 47))
46471	23242178	For example, deletion of p21 and 14-3-3sigma impairs p53-dependent cell-cycle arrest, and ablation of PUMA and BAX renders cells refractory to p53-induced apoptosis.	('14-3-3sigma', 'Gene', (33, 44))	('p21', 'Gene', (25, 28))	('14-3-3sigma', 'Gene', '2810', (33, 44))	('deletion', 'Var', (13, 21))	('PUMA', 'Gene', (102, 106))	('impairs', 'NegReg', (45, 52))	('BAX', 'Gene', '581', (111, 114))	('BAX', 'Gene', (111, 114))	('p53-dependent cell-cycle arrest', 'CPA', (53, 84))	('ablation', 'Var', (90, 98))
46473	23242178	p21 inhibits cell-cycle progression, binding pre-formed CDK/cyclin complexes and preventing ATP binding by the kinase subunit.	('inhibits', 'NegReg', (4, 12))	('CDK', 'Gene', (56, 59))	('binding', 'Interaction', (37, 44))	('ATP binding', 'MPA', (92, 103))	('cyclin', 'Gene', '5111', (60, 66))	('ATP', 'Chemical', 'MESH:D000255', (92, 95))	('CDK', 'Gene', '983;1017;1019;1020;1021;1024', (56, 59))	('cell-cycle progression', 'CPA', (13, 35))	('cyclin', 'Gene', (60, 66))	('preventing', 'NegReg', (81, 91))	('p21', 'Var', (0, 3))
46483	23242178	Interestingly, CD44 is also a target of miR-34a.	('CD44', 'Gene', '960', (15, 19))	('miR-34a', 'Var', (40, 47))	('CD44', 'Gene', (15, 19))
46491	23242178	Interestingly, p53 can repress BCL2 both directly via promoter binding, and indirectly via miR-34a (Figure 5).	('p53', 'Var', (15, 18))	('BCL2', 'Gene', '596', (31, 35))	('BCL2', 'Gene', (31, 35))	('miR-34a', 'Var', (91, 98))	('repress', 'NegReg', (23, 30))
46524	33328867	Overexpression of this channel has been reported in biopsies of glioblastoma patients and intriguingly the channel structure also seems to be altered, since reported that GBM cells expressed a splicing variant of the channel on the hSlo (the gene linked to the encoding part of the alpha subunit) with a consequent increase in the sensitivity to intracellular calcium concentration.	('glioblastoma', 'Disease', (64, 76))	('hSlo', 'Gene', '3778', (232, 236))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('sensitivity to intracellular calcium concentration', 'MPA', (331, 381))	('GBM', 'Phenotype', 'HP:0012174', (171, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('hSlo', 'Gene', (232, 236))	('patients', 'Species', '9606', (77, 85))	('increase', 'PosReg', (315, 323))	('splicing variant', 'Var', (193, 209))	('calcium', 'Chemical', 'MESH:D002118', (360, 367))
46534	33328867	Additionally, in the two-dimensional migration assay, there is a general consensus that blockade of BK channels does not significantly reduce migration of GBM cells.	('BK', 'Chemical', 'MESH:D001603', (100, 102))	('blockade', 'Var', (88, 96))	('migration of GBM cells', 'CPA', (142, 164))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))
46540	33328867	Their peculiar current/voltage relation (Figure 1A) is due to weak, voltage-dependent rectification and to voltage-dependent pore block, from the internal side of the channel, by magnesium and other organic cations such as polyamine.	('pore', 'MPA', (125, 129))	('rectification', 'MPA', (86, 99))	('polyamine', 'Chemical', 'MESH:D011073', (223, 232))	('magnesium', 'Chemical', 'MESH:D008274', (179, 188))	('polyamine', 'Var', (223, 232))
46557	33328867	This scenario agrees with recent experimental evidence whereby blocking Kir4.1 and BK channels reduces GBM cell migration.	('Kir4.1', 'Gene', (72, 78))	('blocking', 'Var', (63, 71))	('Kir4.1', 'Gene', '3766', (72, 78))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))	('BK', 'Chemical', 'MESH:D001603', (83, 85))	('GBM cell migration', 'CPA', (103, 121))	('reduces', 'NegReg', (95, 102))
46573	32051553	We previously showed that SIX3 can be transcriptionally silenced by DNA hypermethylation, functions as a tumor suppressor gene, and inhibits human glioblastoma transcriptionally.	('silenced', 'NegReg', (56, 64))	('DNA hypermethylation', 'Var', (68, 88))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('inhibits', 'NegReg', (132, 140))	('transcriptionally', 'MPA', (160, 177))	('SIX3', 'Gene', (26, 30))	('human', 'Species', '9606', (141, 146))	('SIX3', 'Gene', '6496', (26, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
46576	32051553	ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and methylation of SIX3 promoter.	('H3K27me3', 'Protein', (153, 161))	('SIX3', 'Gene', '6496', (44, 48))	('ZNF263', 'Gene', '10127', (0, 6))	('ZNF263', 'Gene', (0, 6))	('transcriptional', 'MPA', (111, 126))	('SIX3', 'Gene', (44, 48))	('SIX3', 'Gene', '6496', (181, 185))	('SIX3', 'Gene', (181, 185))	('SIX3', 'Gene', '6496', (140, 144))	('SIX3', 'Gene', (140, 144))	('silencing', 'NegReg', (127, 136))	('methylation', 'Var', (166, 177))
46578	32051553	Together, our findings demonstrate that epigenetic silencing of SIX3 is controlled by a sophisticated and highly ordered oncogenic signaling pathway and therefore provide new insights into initiation and progression of glioblastoma.	('SIX3', 'Gene', '6496', (64, 68))	('SIX3', 'Gene', (64, 68))	('glioblastoma', 'Disease', (219, 231))	('controlled', 'Reg', (72, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('epigenetic silencing', 'Var', (40, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))
46579	32051553	During tumorigenesis, cells undergo a genome-wide epigenetic reprogramming process, which contributes to massive overall DNA hypomethylation and specific hypermethylation at certain CpG promoters.	('tumor', 'Disease', (7, 12))	('hypomethylation', 'Var', (125, 140))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('DNA', 'MPA', (121, 124))	('hypermethylation', 'Var', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
46580	32051553	Abundant tumor suppressor genes (TSG) are reportedly silenced by DNA methylation and histone modifications in human cancer.	('DNA methylation', 'Var', (65, 80))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('histone modifications', 'Var', (85, 106))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('silenced', 'NegReg', (53, 61))	('tumor', 'Disease', (9, 14))	('human', 'Species', '9606', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
46583	32051553	Epigenetic alterations play critical roles in glioblastoma initiation and progression and give rise to various cells phenotypes.	('Epigenetic alterations', 'Var', (0, 22))	('give rise', 'Reg', (90, 99))	('roles', 'Reg', (37, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('glioblastoma initiation', 'Disease', (46, 69))	('glioblastoma initiation', 'Disease', 'MESH:D005909', (46, 69))
46584	32051553	In high-grade pediatric gliomas, high frequency of H3.3K27M mutation led to the loss of suppressive H3K27me3 modifications.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('loss', 'NegReg', (80, 84))	('H3K27me3', 'Protein', (100, 108))	('H3.3K27M mutation', 'Var', (51, 68))	('gliomas', 'Disease', (24, 31))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
46585	32051553	DNA methylation alterations have been widely reported in gliomas.	('reported', 'Reg', (45, 53))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('gliomas', 'Disease', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('methylation alterations', 'Var', (4, 27))
46587	32051553	Mutations of isocitrate dehydrogenase 1 (IDH1) have been shown to be sufficient to establish G-CIMP by remodeling the methylome.	('remodeling', 'Reg', (103, 113))	('G-CIMP', 'Chemical', '-', (93, 99))	('methylome', 'MPA', (118, 127))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('isocitrate', 'Chemical', 'MESH:C034219', (13, 23))
46588	32051553	While H3.3K27M, IDH1 mutations are detected in a small fraction of glioblastoma patients, the mechanism by which oncogenic mutations remodel the epigenome are still poorly understood.	('H3.3K27M', 'Var', (6, 14))	('glioblastoma', 'Disease', (67, 79))	('patients', 'Species', '9606', (80, 88))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('IDH1', 'Gene', (16, 20))	('IDH1', 'Gene', '3417', (16, 20))	('mutations', 'Var', (21, 30))
46589	32051553	It is well established that amplification and mutations of epidermal growth factor receptor (EGFR) are the most frequent genetic event in glioblastoma, which promotes tumor growth and survival through uncontrolled activation of signaling networks and metabolic reprogramming.	('mutations', 'Var', (46, 55))	('activation', 'PosReg', (214, 224))	('signaling networks', 'Pathway', (228, 246))	('EGFR', 'Gene', '1956', (93, 97))	('promotes', 'PosReg', (158, 166))	('EGFR', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('glioblastoma', 'Disease', (138, 150))	('metabolic reprogramming', 'CPA', (251, 274))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('survival', 'CPA', (184, 192))	('amplification', 'Var', (28, 41))
46591	32051553	EGFR hyperactivation has been found to transcriptionally suppress the expression of DNA demethylase-TET oncogene family member 1 (TET1), which contributes to the hypermethylation in the promoter region of a panel of TSGs in lung cancers and glioblastomas.	('hypermethylation', 'MPA', (162, 178))	('glioblastomas', 'Disease', (241, 254))	('EGFR', 'Gene', (0, 4))	('lung cancers', 'Disease', (224, 236))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('expression', 'Species', '29278', (70, 80))	('suppress', 'NegReg', (57, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (241, 253))	('glioblastomas', 'Phenotype', 'HP:0012174', (241, 254))	('expression', 'MPA', (70, 80))	('hyperactivation', 'Var', (5, 20))	('TET1', 'Gene', (130, 134))	('lung cancers', 'Disease', 'MESH:D008175', (224, 236))	('lung cancers', 'Phenotype', 'HP:0100526', (224, 236))	('glioblastomas', 'Disease', 'MESH:D005909', (241, 254))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('EGFR', 'Gene', '1956', (0, 4))
46596	32051553	SIX3 mutations correlate with multiple CNS developmental disorders, such as holoprosencephaly, aprosencephaly, and atelencephaly.	('developmental disorders', 'Disease', 'MESH:D002658', (43, 66))	('atelencephaly', 'Disease', (115, 128))	('holoprosencephaly', 'Disease', (76, 93))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (76, 93))	('aprosencephaly', 'Disease', (95, 109))	('mutations', 'Var', (5, 14))	('SIX3', 'Gene', '6496', (0, 4))	('aprosencephaly', 'Phenotype', 'HP:0007268', (95, 109))	('developmental disorders', 'Disease', (43, 66))	('holoprosencephaly', 'Disease', 'MESH:D016142', (76, 93))	('atelencephaly', 'Disease', 'MESH:C536767', (115, 128))	('SIX3', 'Gene', (0, 4))	('aprosencephaly', 'Disease', 'MESH:D000757', (95, 109))
46600	32051553	In this study, we revealed that epigenetic silencing of SIX3 is controlled by a highly ordered signaling pathway consisting of EGFR, ZNF263, and a subset of chromatin modifiers.	('ZNF263', 'Gene', (133, 139))	('SIX3', 'Gene', '6496', (56, 60))	('SIX3', 'Gene', (56, 60))	('controlled', 'Reg', (64, 74))	('epigenetic silencing', 'Var', (32, 52))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('ZNF263', 'Gene', '10127', (133, 139))
46605	32051553	S1B), we detected SIX3 DNA methylation in the phenotypically normal astrocyte cell line HEB and three glioblastoma cell lines (U251, U87, and U118), and the level of methylation correlated inversely with the expression of SIX3 (Fig.	('glioblastoma', 'Disease', (102, 114))	('HEB', 'Gene', '6938', (88, 91))	('SIX3', 'Gene', '6496', (222, 226))	('expression', 'Species', '29278', (208, 218))	('methylation', 'Var', (27, 38))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('HEB', 'Gene', (88, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('SIX3', 'Gene', (222, 226))	('U251', 'CellLine', 'CVCL:0021', (127, 131))	('U87', 'CellLine', 'CVCL:0022', (133, 136))	('SIX3', 'Gene', '6496', (18, 22))	('SIX3', 'Gene', (18, 22))
46612	32051553	Intriguingly, it has been reported that the classic subtypes of glioblastoma are characterized by high frequencies of EGFR amplification and mutations.	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('mutations', 'Var', (141, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('amplification', 'Var', (123, 136))
46628	32051553	ChIP analysis showed that knockdown ZNF263 decreased the enrichment of H3K27me3 in the entire region of SIX3 promoter and specifically reduced the enrichment of H3K9me3 at region 2 and 3 (Fig.	('enrichment', 'MPA', (57, 67))	('H3K27me3', 'Protein', (71, 79))	('enrichment', 'MPA', (147, 157))	('H3K9me3', 'Protein', (161, 168))	('ZNF263', 'Gene', '10127', (36, 42))	('knockdown', 'Var', (26, 35))	('reduced', 'NegReg', (135, 142))	('SIX3', 'Gene', '6496', (104, 108))	('decreased', 'NegReg', (43, 52))	('ZNF263', 'Gene', (36, 42))	('SIX3', 'Gene', (104, 108))
46633	32051553	The effects of ZNF263 on H3K27me3 and H3K9me3 led us to ask whether ZNF263 alter chromatin accessibility of SIX3 promoter in glioblastoma.	('SIX3', 'Gene', (108, 112))	('effects', 'Reg', (4, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('ZNF263', 'Gene', (68, 74))	('SIX3', 'Gene', '6496', (108, 112))	('H3K27me3', 'Var', (25, 33))	('glioblastoma', 'Disease', (125, 137))	('ZNF263', 'Gene', '10127', (15, 21))	('ZNF263', 'Gene', (15, 21))	('ZNF263', 'Gene', '10127', (68, 74))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))	('chromatin accessibility', 'MPA', (81, 104))
46635	32051553	Conversely, a more extractable chromatin structure was observed upon knockdown ZNF263 (Fig.	('ZNF263', 'Gene', '10127', (79, 85))	('extractable chromatin structure', 'MPA', (19, 50))	('ZNF263', 'Gene', (79, 85))	('more', 'PosReg', (14, 18))	('knockdown', 'Var', (69, 78))
46644	32051553	No interactions were found between ZNF263 and HDAC1, SUZ12, SUV39H1, or SUV39H2 (Fig.	('SUZ12', 'Chemical', '-', (53, 58))	('ZNF263', 'Gene', '10127', (35, 41))	('interactions', 'Interaction', (3, 15))	('ZNF263', 'Gene', (35, 41))	('SUV39H2', 'Var', (72, 79))	('HDAC1', 'Gene', (46, 51))
46650	32051553	The results from TCGA showed that ZNF263 expression had no significant correlation with the expression of DNMT3A, DNMT3B, SUV29H1, SUV39H2, EED, EZH2 at the mRNA level, while positively correlating with the expression of DNMT1, SETDB1, and SUZ12 (Fig.	('expression', 'Species', '29278', (41, 51))	('ZNF263', 'Gene', (34, 40))	('DNMT3B', 'Gene', (114, 120))	('SUZ12', 'Chemical', '-', (240, 245))	('correlating', 'Reg', (186, 197))	('SUV29H1', 'CellLine', 'CVCL:2G69', (122, 129))	('DNMT3A', 'Gene', (106, 112))	('DNMT3A', 'Gene', '1788', (106, 112))	('expression', 'Species', '29278', (207, 217))	('SUV39H2', 'Var', (131, 138))	('SUV29H1', 'Var', (122, 129))	('expression', 'Species', '29278', (92, 102))	('ZNF263', 'Gene', '10127', (34, 40))
46658	32051553	We therefore determined which pathway(s) may mediate epigenetic repression of SIX3 by using pharmacological inhibitors, namely Trametinib (a MEK inhibitor), MK2206 (an AKT inhibitor), or Ruxolitinib (a JAK inhibitor).	('SIX3', 'Gene', '6496', (78, 82))	('epigenetic repression', 'Var', (53, 74))	('MK2206', 'Chemical', 'MESH:C548887', (157, 163))	('Ruxolitinib', 'Chemical', 'MESH:C540383', (187, 198))	('SIX3', 'Gene', (78, 82))	('MK2206', 'Var', (157, 163))	('Trametinib', 'Chemical', 'MESH:C560077', (127, 137))
46664	32051553	In keeping with elevated SIX3 expression, Trametinib dramatically reduced the enrichment of H3K27me3 and H3K9me3 in SIX3 promoter and enhanced RNA pol II recruitment (Fig.	('reduced', 'NegReg', (66, 73))	('H3K9me3', 'Var', (105, 112))	('enrichment', 'MPA', (78, 88))	('enhanced', 'PosReg', (134, 142))	('H3K27me3', 'Protein', (92, 100))	('SIX3', 'Gene', '6496', (116, 120))	('SIX3', 'Gene', (116, 120))	('SIX3', 'Gene', '6496', (25, 29))	('recruitment', 'MPA', (154, 165))	('RNA', 'MPA', (143, 146))	('Trametinib', 'Chemical', 'MESH:C560077', (42, 52))	('SIX3', 'Gene', (25, 29))	('expression', 'Species', '29278', (30, 40))
46667	32051553	Because ZNF263 plays a critical role in epigenetic silencing of SIX3 in glioblastoma, we next examined whether erlotinib or Trametinib induced SIX3 expression through the regulation of ZNF263.	('expression', 'MPA', (148, 158))	('Trametinib', 'Chemical', 'MESH:C560077', (124, 134))	('SIX3', 'Gene', '6496', (64, 68))	('erlotinib', 'Chemical', 'MESH:D000069347', (111, 120))	('ZNF263', 'Gene', '10127', (185, 191))	('ZNF263', 'Gene', '10127', (8, 14))	('ZNF263', 'Gene', (185, 191))	('SIX3', 'Gene', (64, 68))	('SIX3', 'Gene', '6496', (143, 147))	('expression', 'Species', '29278', (148, 158))	('glioblastoma', 'Disease', (72, 84))	('ZNF263', 'Gene', (8, 14))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('epigenetic silencing', 'Var', (40, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))	('SIX3', 'Gene', (143, 147))
46683	32051553	We next asked whether modulation of the EGFR/MAPK pathway could alter the ubiquitination of ZNF263 and consequently its stability.	('ubiquitination', 'MPA', (74, 88))	('alter', 'Reg', (64, 69))	('EGFR', 'Gene', '1956', (40, 44))	('ZNF263', 'Gene', '10127', (92, 98))	('EGFR', 'Gene', (40, 44))	('ZNF263', 'Gene', (92, 98))	('modulation', 'Var', (22, 32))	('stability', 'MPA', (120, 129))
46684	32051553	HEK293 cells were transfected with expression vectors containing HA-tagged Ubiquitin (HA-Ubiquitin) and FLAG-tagged ZNF263 (ZNF263-FLAG) and were subsequently treated with Trametinib or EGF.	('FLAG-tagged', 'Var', (104, 115))	('Trametinib', 'Chemical', 'MESH:C560077', (172, 182))	('EGF', 'Gene', (186, 189))	('ZNF263', 'Gene', '10127', (124, 130))	('EGF', 'Gene', '1950', (186, 189))	('HA-tagged', 'Var', (65, 74))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('ZNF263', 'Gene', (124, 130))	('ZNF263', 'Gene', '10127', (116, 122))	('ZNF263', 'Gene', (116, 122))	('expression vectors', 'Species', '29278', (35, 53))
46686	32051553	We also showed that ubiquitination of ZNF263 was mediated by at lysine residue 63 (K63) (Fig.	('ZNF263', 'Gene', '10127', (38, 44))	('ZNF263', 'Gene', (38, 44))	('ubiquitination', 'MPA', (20, 34))	('K63', 'Chemical', '-', (83, 86))	('lysine', 'Chemical', 'MESH:D008239', (64, 70))	('mediated', 'Reg', (49, 57))	('K63', 'Var', (83, 86))
46687	32051553	These results suggested that inhibiting EGF/MAPK pathway promotes ZNF263 degradation through the ubiquitin-proteasome pathway.	('EGF', 'Gene', (40, 43))	('degradation', 'MPA', (73, 84))	('ZNF263', 'Gene', '10127', (66, 72))	('ubiquitin-proteasome pathway', 'Pathway', (97, 125))	('ZNF263', 'Gene', (66, 72))	('EGF', 'Gene', '1950', (40, 43))	('inhibiting', 'Var', (29, 39))	('promotes', 'PosReg', (57, 65))
46695	32051553	Finally, we constructed a ZNF263 deletion mutant lacking the D domain (ZNF263-DeltaD) and tagging it with either FLAG or GFP (Fig.	('D domain', 'MPA', (61, 69))	('deletion mutant', 'Var', (33, 48))	('lacking', 'NegReg', (49, 56))	('ZNF263', 'Gene', '10127', (71, 77))	('ZNF263', 'Gene', '10127', (26, 32))	('ZNF263', 'Gene', (26, 32))	('ZNF263', 'Gene', (71, 77))
46696	32051553	We found that the D-domain deletion mutation did not alter ZNF263 translocation to the nuclei (Fig.	('translocation to the nuclei', 'MPA', (66, 93))	('ZNF263', 'Gene', (59, 65))	('D-domain deletion mutation', 'Var', (18, 44))	('ZNF263', 'Gene', '10127', (59, 65))
46702	32051553	EGFR-vIII, a constitutively active deletion mutant of EGFR that constitutes a large portion of EGFR mutants, is a therapeutic target because of its strong role in enhancing tumorigenesis and malignant progression of glioblastoma.	('malignant progression', 'CPA', (191, 212))	('vIII', 'Gene', (5, 9))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('mutants', 'Var', (100, 107))	('glioblastoma', 'Disease', (216, 228))	('glioblastoma', 'Disease', 'MESH:D005909', (216, 228))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('EGFR', 'Gene', '1956', (54, 58))	('vIII', 'Gene', '1351', (5, 9))	('enhancing', 'PosReg', (163, 172))	('EGFR', 'Gene', '1956', (95, 99))	('deletion mutant', 'Var', (35, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (95, 99))
46709	32051553	EGFR-vIII overexpression markedly increased anchorage-independent growth of HEB cells (Fig.	('HEB', 'Gene', '6938', (76, 79))	('vIII', 'Gene', (5, 9))	('EGFR', 'Gene', (0, 4))	('HEB', 'Gene', (76, 79))	('expression', 'Species', '29278', (14, 24))	('overexpression', 'Var', (10, 24))	('vIII', 'Gene', '1351', (5, 9))	('increased', 'PosReg', (34, 43))	('EGFR', 'Gene', '1956', (0, 4))
46713	32051553	EGFR-vIII ectopic expression substantially enhanced invasion and anchorage-independent growth of glioblastoma cells (Fig.	('enhanced', 'PosReg', (43, 51))	('vIII', 'Gene', (5, 9))	('EGFR', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('EGFR', 'Gene', '1956', (0, 4))	('expression', 'Species', '29278', (18, 28))	('anchorage-independent growth', 'CPA', (65, 93))	('vIII', 'Gene', '1351', (5, 9))	('ectopic expression', 'Var', (10, 28))	('invasion', 'CPA', (52, 60))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))
46717	32051553	The association analysis of EGFR copy number, EGFR mRNA, EGFR protein, and phosphorylated EGFR showed high consistency by pairs (Fig.	('copy number', 'Var', (33, 44))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (90, 94))	('EGFR', 'Gene', (46, 50))	('EGFR', 'Gene', (57, 61))
46718	32051553	In addition, SIX3 expression has inverse correlation with EGFR copy number and protein expression, respectively.	('EGFR', 'Gene', '1956', (58, 62))	('protein expression', 'MPA', (79, 97))	('EGFR', 'Gene', (58, 62))	('SIX3', 'Gene', '6496', (13, 17))	('expression', 'Species', '29278', (87, 97))	('expression', 'Species', '29278', (18, 28))	('SIX3', 'Gene', (13, 17))	('expression', 'MPA', (18, 28))	('copy number', 'Var', (63, 74))
46723	32051553	We found strong positive correlation between the level of p-EGFR (Y1173) and that of ZNF263 (Fig.	('ZNF263', 'Gene', (85, 91))	('Y1173', 'Var', (66, 71))	('EGFR', 'Gene', '1956', (60, 64))	('ZNF263', 'Gene', '10127', (85, 91))	('EGFR', 'Gene', (60, 64))
46724	32051553	While SIX3 levels correlated inversely with the levels of both p-EGFR (Y1173) and ZNF263 (Fig.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('SIX3', 'Gene', '6496', (6, 10))	('Y1173', 'Var', (71, 76))	('ZNF263', 'Gene', '10127', (82, 88))	('SIX3', 'Gene', (6, 10))	('ZNF263', 'Gene', (82, 88))
46725	32051553	Survival analysis showed that the patients with high levels of p-EGFR exhibited much poorer prognosis than those with low p-EGFR levels (Fig.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (65, 69))	('high levels', 'Var', (48, 59))	('EGFR', 'Gene', (124, 128))	('patients', 'Species', '9606', (34, 42))
46727	32051553	Altogether, we conclude that epigenetic silencing of SIX3 is controlled by a sophisticated and highly ordered oncogenic signaling pathway and therefore provide new insights into initiation and progression of glioblastoma (Fig.	('glioblastoma', 'Disease', (208, 220))	('controlled', 'Reg', (61, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (208, 220))	('SIX3', 'Gene', '6496', (53, 57))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))	('SIX3', 'Gene', (53, 57))	('epigenetic silencing', 'Var', (29, 49))
46730	32051553	One argues that hypermethylation of TSGs results from a stochastic process, such as mutations of DNMTs or TETs, which causes extensive abnormalities in the methylome, while the cells with TSG hypermethylation are enabled with selectable growth advantages.	('DNMTs', 'Gene', (97, 102))	('TETs', 'Gene', (106, 110))	('methylome', 'MPA', (156, 165))	('extensive abnormalities', 'Disease', (125, 148))	('results from', 'Reg', (41, 53))	('mutations', 'Var', (84, 93))	('extensive abnormalities', 'Disease', 'MESH:D054908', (125, 148))	('causes', 'Reg', (118, 124))	('TETs', 'Chemical', 'MESH:C010349', (106, 110))
46731	32051553	The G-CIMP phenotype that is derived from IDH1/2 mutations caused by the metabolite 2HG-mediated suppression of TETs strongly supports this model.	('G-CIMP', 'Chemical', '-', (4, 10))	('IDH1', 'Gene', '3417', (42, 46))	('mutations', 'Var', (49, 58))	('caused', 'Reg', (59, 65))	('2HG', 'Chemical', 'MESH:C019417', (84, 87))	('IDH1', 'Gene', (42, 46))	('TETs', 'Chemical', 'MESH:C010349', (112, 116))	('TETs', 'MPA', (112, 116))
46733	32051553	Michael R Green' group recently showed that K-ras mutation leads to hypermethylation of Fas in NIH3T3 cells transformation, and contributes to epigenetic silencing of the Fas and INK4-ARF locus both through elaborated signaling pathways.	('hypermethylation', 'MPA', (68, 84))	('Fas', 'Protein', (88, 91))	('INK4-ARF', 'Gene', (179, 187))	('K-ras', 'Gene', '16653', (44, 49))	('NIH3T3', 'CellLine', 'CVCL:0594', (95, 101))	('K-ras', 'Gene', (44, 49))	('epigenetic silencing', 'MPA', (143, 163))	('Fas', 'Gene', (171, 174))	('mutation', 'Var', (50, 58))
46735	32051553	ZNF304 and ZNF354B are both involved in K-ras-mediated hypermethylation of INK4-ARF and Fas, respectively.	('ZNF354B', 'Var', (11, 18))	('ZNF354B', 'Chemical', '-', (11, 18))	('INK4-ARF', 'Protein', (75, 83))	('K-ras', 'Gene', '16653', (40, 45))	('involved', 'Reg', (28, 36))	('ZNF304', 'Chemical', '-', (0, 6))	('K-ras', 'Gene', (40, 45))	('ZNF304', 'Var', (0, 6))
46736	32051553	Here, we firstly showed that EGFR/MAPK hyperactivation results in epigenetic silencing of SIX3 through ZNF263 in glioblastoma.	('glioblastoma', 'Disease', (113, 125))	('SIX3', 'Gene', '6496', (90, 94))	('SIX3', 'Gene', (90, 94))	('epigenetic silencing', 'MPA', (66, 86))	('ZNF263', 'Gene', '10127', (103, 109))	('ZNF263', 'Gene', (103, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('hyperactivation', 'Var', (39, 54))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))
46738	32051553	EGFR hyperactivation stabilizes ZNF263 protein through the MAPK pathway and subsequent suppression of ZNF263 ubiquitination.	('ZNF263', 'Gene', (102, 108))	('MAPK pathway', 'Pathway', (59, 71))	('ubiquitination', 'MPA', (109, 123))	('EGFR', 'Gene', (0, 4))	('suppression', 'NegReg', (87, 98))	('hyperactivation', 'Var', (5, 20))	('ZNF263', 'Gene', '10127', (32, 38))	('stabilizes', 'PosReg', (21, 31))	('ZNF263', 'Gene', (32, 38))	('EGFR', 'Gene', '1956', (0, 4))	('ZNF263', 'Gene', '10127', (102, 108))
46742	32051553	Bivalent chromatins are characterized by active histone modification H3K4me3 and suppressive H3K27me3 concurrently, leaving SIX3 poised for responding to extrinsic stimuli.	('SIX3', 'Gene', '6496', (124, 128))	('H3K4me3', 'Var', (69, 76))	('H3K27me3', 'Var', (93, 101))	('SIX3', 'Gene', (124, 128))
46750	32051553	Strikingly, G-CIMP tumors possess high frequency of IDH1 mutation, which occurs in almost 80% G-CIMP glioblastoma and more than 70% low-grade gliomas.	('mutation', 'Var', (57, 65))	('tumors', 'Disease', (19, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('gliomas', 'Disease', (142, 149))	('occurs', 'Reg', (73, 79))	('IDH1', 'Gene', '3417', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('G-CIMP', 'Chemical', '-', (94, 100))	('G-CIMP', 'Chemical', '-', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('G-CIMP', 'Disease', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('glioblastoma', 'Disease', (101, 113))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('IDH1', 'Gene', (52, 56))
46751	32051553	IDH1 mutant R132H (amino acid substitution at arginine 132 account for >95% IDH1 mutation in glioma), is further confirmed to induce the methylome which mirrors G-CIMP in human normal astrocytes.	('IDH1', 'Gene', (76, 80))	('glioma', 'Disease', (93, 99))	('induce', 'PosReg', (126, 132))	('R132H', 'Mutation', 'rs121913500', (12, 17))	('mutant R132H', 'Var', (5, 17))	('mutation', 'Var', (81, 89))	('IDH1', 'Gene', '3417', (76, 80))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('IDH1', 'Gene', (0, 4))	('arginine', 'Chemical', 'MESH:D001120', (46, 54))	('methylome', 'MPA', (137, 146))	('human', 'Species', '9606', (171, 176))	('G-CIMP', 'Chemical', '-', (161, 167))	('IDH1', 'Gene', '3417', (0, 4))
46752	32051553	The most popular IDH1 mutant R132H has been found to inactivate the enzyme's ability to catalyze the conversion of isocitrate to alpha-KG (a-ketoglutarate) and gain the activity to catalyze alpha-KG into 2HG (2-hydroxyglutarate).	('inactivate', 'NegReg', (53, 63))	('catalyze', 'MPA', (181, 189))	('alpha-KG', 'Chemical', '-', (190, 198))	('gain', 'PosReg', (160, 164))	('2HG', 'Chemical', 'MESH:C019417', (204, 207))	('activity', 'MPA', (169, 177))	('isocitrate', 'Chemical', 'MESH:C034219', (115, 125))	('R132H', 'Var', (29, 34))	('mutant R132H', 'Var', (22, 34))	('IDH1', 'Gene', (17, 21))	('alpha-KG', 'Chemical', '-', (129, 137))	('R132H', 'Mutation', 'rs121913500', (29, 34))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (209, 227))	('IDH1', 'Gene', '3417', (17, 21))	('a-ketoglutarate', 'Chemical', '-', (139, 154))	('catalyze', 'MPA', (88, 96))	('ability', 'MPA', (77, 84))
46754	32051553	IDH1 mutation in glioma leads to the loss alpha-KG and accumulation of 2HG, resulting in genome-wide histone and DNA methylation alterations.	('alpha-KG', 'Protein', (42, 50))	('alpha-KG', 'Chemical', '-', (42, 50))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('accumulation', 'PosReg', (55, 67))	('2HG', 'Protein', (71, 74))	('2HG', 'Chemical', 'MESH:C019417', (71, 74))	('histone', 'MPA', (101, 108))	('loss', 'NegReg', (37, 41))	('glioma', 'Disease', (17, 23))	('IDH1', 'Gene', (0, 4))	('DNA methylation alterations', 'MPA', (113, 140))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
46756	32051553	When we investigated the data from TCGA, we found that IDH1 mutant LGG tumors harbor lower expression and higher-level promoter methylation of SIX3, in comparison with IDH1 wild-type LGG samples (Fig.	('IDH1', 'Gene', '3417', (168, 172))	('expression', 'MPA', (91, 101))	('IDH1', 'Gene', '3417', (55, 59))	('lower', 'NegReg', (85, 90))	('higher-level', 'PosReg', (106, 118))	('SIX3', 'Gene', '6496', (143, 147))	('LGG', 'Disease', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('mutant', 'Var', (60, 66))	('IDH1', 'Gene', (168, 172))	('expression', 'Species', '29278', (91, 101))	('IDH1', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('SIX3', 'Gene', (143, 147))
46758	32051553	While there is no difference of SIX3 between IDH1 mutant or wild-type glioblastoma.	('IDH1', 'Gene', '3417', (45, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('SIX3', 'Gene', '6496', (32, 36))	('SIX3', 'Gene', (32, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('mutant', 'Var', (50, 56))	('glioblastoma', 'Disease', (70, 82))	('IDH1', 'Gene', (45, 49))
46759	32051553	We further investigated the data of human normal astrocytes introduced with IDH1 mutant R132H.	('IDH1', 'Gene', (76, 80))	('IDH1', 'Gene', '3417', (76, 80))	('R132H', 'Var', (88, 93))	('mutant R132H', 'Var', (81, 93))	('human', 'Species', '9606', (36, 41))	('R132H', 'Mutation', 'rs121913500', (88, 93))
46760	32051553	The data showed that SIX3 expression in IDH1 mutant astrocytes is 1.28-fold of SIX3 expression in control astrocytes.	('mutant', 'Var', (45, 51))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '3417', (40, 44))	('SIX3', 'Gene', '6496', (21, 25))	('expression', 'Species', '29278', (84, 94))	('SIX3', 'Gene', '6496', (79, 83))	('SIX3', 'Gene', (21, 25))	('expression', 'Species', '29278', (26, 36))	('SIX3', 'Gene', (79, 83))
46761	32051553	Three probes target different CpG sites of SIX3 had been found to be differently methylated between IDH1 mutant and wild-type astrocytes.	('differently', 'Reg', (69, 80))	('IDH1', 'Gene', '3417', (100, 104))	('SIX3', 'Gene', '6496', (43, 47))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('SIX3', 'Gene', (43, 47))	('IDH1', 'Gene', (100, 104))	('mutant', 'Var', (105, 111))
46762	32051553	One CpG site located 800 bp upstream TSS and another one located in intron were hypermethylated in IDH1 mutant astrocytes.	('mutant', 'Var', (104, 110))	('IDH1', 'Gene', '3417', (99, 103))	('IDH1', 'Gene', (99, 103))
46763	32051553	While the CpG site located 80 bp upstream TSS was hypomethylated in IDH1 mutant samples, and this site overlaps with the region R1 we detected and the core promoter region of SIX3 (Figs.	('hypomethylated', 'Var', (50, 64))	('IDH1', 'Gene', (68, 72))	('mutant', 'Var', (73, 79))	('SIX3', 'Gene', '6496', (175, 179))	('IDH1', 'Gene', '3417', (68, 72))	('SIX3', 'Gene', (175, 179))
46765	32051553	Above all, IDH1 mutation can affect SIX3 methylation and expression through its global effect on reshaping histone and DNA methylome, rather than in a specific pattern.	('expression', 'MPA', (57, 67))	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('SIX3', 'Gene', '6496', (36, 40))	('affect', 'Reg', (29, 35))	('SIX3', 'Gene', (36, 40))	('expression', 'Species', '29278', (57, 67))	('IDH1', 'Gene', (11, 15))
46766	32051553	In breast cancer, ZNF217 has been found to be essential for DNA hypermethylation of p15ink4b and does so by recruiting the CoREST complex to the promoter region.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('ZNF217', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('CoREST complex', 'MPA', (123, 137))	('p15ink4b', 'Var', (84, 92))	('recruiting', 'PosReg', (108, 118))
46767	32051553	The traditional view of DNA methylation-mediated transcriptional silencing is such that methylcytosine on the binding motifs of transcription factors directly blocks transcription factor binding to the chromatin, or indirectly prevents transcription factor binding due to their high-affinity binding for methyl-CpG binding-domain (MBD)-containing proteins.	('binding', 'Interaction', (292, 299))	('transcription factor', 'MPA', (236, 256))	('binding', 'Interaction', (257, 264))	('methylcytosine', 'Chemical', '-', (88, 102))	('methyl-CpG', 'Protein', (304, 314))	('binding', 'Interaction', (187, 194))	('methylcytosine', 'Var', (88, 102))	('blocks', 'NegReg', (159, 165))	('transcription factor', 'MPA', (166, 186))	('prevents', 'NegReg', (227, 235))
46779	32051553	Moreover, our mass-spectrum data showed several protein phosphatases binding with ZNF263, including PP1 and PP2A, which dephosphorylated and promoted degradation of c-Myc.	('PP2A', 'Var', (108, 112))	('protein phosphatases', 'Enzyme', (48, 68))	('degradation', 'MPA', (150, 161))	('dephosphorylated', 'MPA', (120, 136))	('binding', 'Interaction', (69, 76))	('c-Myc', 'MPA', (165, 170))	('promoted', 'PosReg', (141, 149))	('ZNF263', 'Gene', '10127', (82, 88))	('ZNF263', 'Gene', (82, 88))
46780	32051553	Using Phospho-(Ser/Thr) antibody, we noticed that inhibition of MAPKs decreased the phosphorylated ZNF263 level (Fig.	('ZNF263', 'Gene', (99, 105))	('inhibition', 'Var', (50, 60))	('Thr', 'Chemical', 'MESH:D013912', (19, 22))	('decreased', 'NegReg', (70, 79))	('MAPKs', 'Gene', (64, 69))	('ZNF263', 'Gene', '10127', (99, 105))	('Ser', 'Chemical', 'MESH:D012694', (15, 18))
46781	32051553	In combination of all these analyses, we can conclude that ZNF263 as a potential substrate of MAPKs, and phosphorylation of ZNF263 by MAPKs stabilizes ZNF263 protein from being degraded via UPPs.	('protein', 'Protein', (158, 165))	('ZNF263', 'Gene', '10127', (151, 157))	('ZNF263', 'Gene', (151, 157))	('ZNF263', 'Gene', '10127', (59, 65))	('ZNF263', 'Gene', '10127', (124, 130))	('ZNF263', 'Gene', (59, 65))	('phosphorylation', 'Var', (105, 120))	('stabilizes', 'PosReg', (140, 150))	('ZNF263', 'Gene', (124, 130))	('MAPKs', 'Gene', (134, 139))
46787	32051553	All astrocytoma cell lines were subjected to short tandem repeat test.	('astrocytoma', 'Disease', 'MESH:D001254', (4, 15))	('subjected', 'Reg', (32, 41))	('astrocytoma', 'Disease', (4, 15))	('astrocytoma', 'Phenotype', 'HP:0009592', (4, 15))	('short tandem repeat', 'Var', (45, 64))
46820	31646241	Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer's disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood-brain barrier.	('Hydroxycarboxylic Acid', 'Chemical', 'MESH:D000596', (109, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (293, 305))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (269, 288))	("Alzheimer's disease", 'Disease', (269, 288))	('K-604', 'Var', (212, 217))	('SOAT-1', 'Gene', '20652', (193, 199))	('SOAT-1', 'Gene', (193, 199))	('ACAT-1', 'Gene', (186, 192))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (269, 288))	('solubility', 'MPA', (333, 343))	('ACAT-1', 'Gene', '110446', (186, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (293, 305))	('Cholesterol O', 'Chemical', 'MESH:D002784', (28, 41))	('K-604', 'Chemical', 'MESH:C520671', (212, 217))	('acyl-CoA', 'Chemical', 'MESH:D000214', (144, 152))	('K-604', 'Chemical', 'MESH:C520671', (70, 75))	('Acyl-CoA', 'Chemical', 'MESH:D000214', (19, 27))	('glioblastoma', 'Disease', (293, 305))	('cholesterol O', 'Chemical', 'MESH:D002784', (153, 166))
46822	31646241	In cerebral tissue, the AUC of K-604 after intranasal administration (10 muL; 108 mug of K-604/mouse) was 772 ng min/g, whereas that after oral administration (166 mug of K-604/mouse) was 8.9 ng min/g.	('AUC', 'MPA', (24, 27))	('K-604', 'Var', (31, 36))	('rat', 'Species', '10116', (152, 155))	('rat', 'Species', '10116', (62, 65))	('K-604', 'Chemical', 'MESH:C520671', (31, 36))	('muL', 'Gene', '68729', (73, 76))	('mouse', 'Species', '10090', (177, 182))	('muL', 'Gene', (73, 76))	('K-604', 'Chemical', 'MESH:C520671', (171, 176))	('K-604', 'Chemical', 'MESH:C520671', (89, 94))	('mouse', 'Species', '10090', (95, 100))
46884	31646241	The transitions of the protonated precursor ions to the selected product ions were from m/z 503 to m/z 353 for K-604 and from m/z 507 to m/z 353 for K-604-d4 (internal standard).	('m/z 353', 'Var', (99, 106))	('K-604', 'Var', (111, 116))	('m/z 353', 'Var', (137, 144))	('m/z 503', 'Var', (88, 95))	('K-604', 'Chemical', 'MESH:C520671', (111, 116))	('K-604-d4', 'Var', (149, 157))	('K-604', 'Chemical', 'MESH:C520671', (149, 154))	('K-604-d4', 'Chemical', 'MESH:C520671', (149, 157))
46917	31646241	Regarding the actual feasibility of oral administration, the delivery efficiency of K-604 is not expected to be as high as that of carbamazepine, and systemic adverse effects may result from high doses.	('carbamazepine', 'Chemical', 'MESH:D002220', (131, 144))	('K-604', 'Var', (84, 89))	('K-604', 'Chemical', 'MESH:C520671', (84, 89))	('result', 'Reg', (179, 185))	('rat', 'Species', '10116', (49, 52))
46946	31646241	In the initial time range (after 5 to 45 min) after administration of 50 muL of K-604, the drug concentrations (870, 449, 250, and 77 ng/mL) in the plasma were approximately 6- to 10-fold higher than those (83, 44, 32, and 12 ng/g) in the cerebral tissue.	('rat', 'Species', '10116', (103, 106))	('K-604', 'Var', (80, 85))	('higher', 'PosReg', (188, 194))	('rat', 'Species', '10116', (60, 63))	('K-604', 'Chemical', 'MESH:C520671', (80, 85))	('muL', 'Gene', '68729', (73, 76))	('muL', 'Gene', (73, 76))
46950	31646241	The Cmax of K-604 (156 ng/g) in the olfactory bulb tissue exceeded that of K-604 (146 ng/mL) in the plasma.	('K-604', 'Chemical', 'MESH:C520671', (12, 17))	('Cmax', 'MPA', (4, 8))	('K-604', 'Var', (12, 17))	('K-604', 'Chemical', 'MESH:C520671', (75, 80))
46951	31646241	In the initial time range (from 5 to 45 min) after administration of 10 muL of K-604, the drug concentrations (142, 90, 33, and 10 ng/mL) in the plasma were slightly higher than those (156, 51, 15, and 6 ng/g) in the olfactory bulb tissue.	('K-604', 'Chemical', 'MESH:C520671', (79, 84))	('higher', 'PosReg', (166, 172))	('drug concentrations', 'MPA', (90, 109))	('rat', 'Species', '10116', (102, 105))	('muL', 'Gene', '68729', (72, 75))	('rat', 'Species', '10116', (59, 62))	('K-604', 'Var', (79, 84))	('muL', 'Gene', (72, 75))
46959	31646241	We established that K-604 could be efficiently delivered along the olfactory route to the brain via intranasal administration while minimizing systemic circulation in the lung and digestive tract.	('minimizing', 'NegReg', (132, 142))	('rat', 'Species', '10116', (119, 122))	('systemic circulation', 'MPA', (143, 163))	('K-604', 'Var', (20, 25))	('K-604', 'Chemical', 'MESH:C520671', (20, 25))
46962	31646241	At 5 min after intranasal administration of 108 mug of K-604 per mouse, the Cmax values of the plasma were 274, 217, and 283 ng/mL, respectively, and the Cmax values of the cerebral tissue were 39, 32, and 47 ng/g, respectively.	('K-604', 'Var', (55, 60))	('mouse', 'Species', '10090', (65, 70))	('K-604', 'Chemical', 'MESH:C520671', (55, 60))	('rat', 'Species', '10116', (34, 37))	('Cmax', 'MPA', (76, 80))
46969	31646241	Our final interest was to evaluate whether K-604 has the therapeutic potential to alter lipid profiles in the brain even with a short exposure time.	('lipid profiles', 'MPA', (88, 102))	('K-604', 'Chemical', 'MESH:C520671', (43, 48))	('alter', 'Reg', (82, 87))	('K-604', 'Var', (43, 48))
46971	31646241	Notably, K-604 dramatically decreased the CE levels from 0.70 to 0.04 mumol/g in the brains of mice even after a single daily dose administration for 7 days (Figure 9).	('mice', 'Species', '10090', (95, 99))	('decreased', 'NegReg', (28, 37))	('K-604', 'Var', (9, 14))	('rat', 'Species', '10116', (139, 142))	('K-604', 'Chemical', 'MESH:C520671', (9, 14))	('CE levels', 'MPA', (42, 51))
46983	31646241	reported that ablation of the ACAT-1 gene in an AD model mouse ameliorates amyloid pathology by increasing 24S-OHC content in the brain.	('AD', 'Disease', (48, 50))	('24S-OHC content', 'MPA', (107, 122))	('ACAT-1', 'Gene', '110446', (30, 36))	('24S-OHC', 'Chemical', 'MESH:C496310', (107, 114))	('amyloid pathology', 'MPA', (75, 92))	('ACAT-1', 'Gene', (30, 36))	('increasing', 'PosReg', (96, 106))	('AD', 'Disease', 'MESH:D000544', (48, 50))	('AD', 'Phenotype', 'HP:0002511', (48, 50))	('ameliorates', 'PosReg', (63, 74))	('mouse', 'Species', '10090', (57, 62))	('rat', 'Species', '10116', (69, 72))	('ablation', 'Var', (14, 22))
46984	31646241	The physiological range of 24S-OHC has been shown to have an inhibitory effect on Abeta production.	('24S-OHC', 'Chemical', 'MESH:C496310', (27, 34))	('inhibitory', 'NegReg', (61, 71))	('Abeta production', 'MPA', (82, 98))	('24S-OHC', 'Var', (27, 34))
46985	31646241	Because intranasal administration of K-604 demonstrated efficacious ACAT-1 inhibition even in a short exposure period, less than 2 h, K-604 should provide promising results for the treatment of GBM and AD.	('GBM', 'Phenotype', 'HP:0012174', (194, 197))	('rat', 'Species', '10116', (50, 53))	('inhibition', 'NegReg', (75, 85))	('ACAT-1', 'Gene', '110446', (68, 74))	('GBM', 'Disease', (194, 197))	('AD', 'Disease', 'MESH:D000544', (202, 204))	('K-604', 'Var', (134, 139))	('K-604', 'Chemical', 'MESH:C520671', (37, 42))	('rat', 'Species', '10116', (27, 30))	('AD', 'Phenotype', 'HP:0002511', (202, 204))	('ACAT-1', 'Gene', (68, 74))	('AD', 'Disease', (202, 204))	('K-604', 'Chemical', 'MESH:C520671', (134, 139))
46994	31646241	Hence, we verified the working hypothesis that the drug concentration of K-604 in the olfactory bulb could be markedly increased by decreasing or disrupting the thickness of olfactory epithelial cells, leading to enhanced drug permeability.	('rat', 'Species', '10116', (63, 66))	('decreasing', 'NegReg', (132, 142))	('K-604', 'Var', (73, 78))	('enhanced', 'PosReg', (213, 221))	('drug concentration', 'MPA', (51, 69))	('thickness of olfactory epithelial cells', 'CPA', (161, 200))	('K-604', 'Chemical', 'MESH:C520671', (73, 78))	('drug permeability', 'MPA', (222, 239))	('disrupting', 'NegReg', (146, 156))	('increased', 'PosReg', (119, 128))
47013	31646241	Fifth, K-604 was very effectively targeted to the mouse brain where it decreased CE levels from 0.70 to 0.04 mumol/g with only a single daily dose for 7 days.	('K-604', 'Chemical', 'MESH:C520671', (7, 12))	('CE levels', 'MPA', (81, 90))	('decreased', 'NegReg', (71, 80))	('mouse', 'Species', '10090', (50, 55))	('K-604', 'Var', (7, 12))
47015	31646241	Based on the above results, we have established a potential intranasal administration method to efficiently deliver K-604 into the brain for the treatment of GBM and AD.	('AD', 'Disease', 'MESH:D000544', (166, 168))	('AD', 'Disease', (166, 168))	('AD', 'Phenotype', 'HP:0002511', (166, 168))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('K-604', 'Var', (116, 121))	('rat', 'Species', '10116', (79, 82))	('K-604', 'Chemical', 'MESH:C520671', (116, 121))	('GBM', 'Disease', (158, 161))
47030	31620245	We could also demonstrate a significantly increased survival in vivo in rats inoculated intracerebrally with glioma cells pre-coated with anti-C1-INH antibodies.	('increased', 'PosReg', (42, 51))	('anti-C1-INH', 'Var', (138, 149))	('rat', 'Species', '10116', (72, 75))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('glioma', 'Disease', (109, 115))	('rats', 'Species', '10116', (72, 76))	('rat', 'Species', '10116', (21, 24))	('survival', 'CPA', (52, 60))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
47042	31620245	also presented that PP2A, protein phosphatase 2 catalytic subunit alpha, a tumor suppressor protein, might be a possible target in pancreatic cancer, and reported that activating this gene together with administration of the drug Penfluridol increased sensitivity of pancreatic cancer cells to this treatment.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('PP2A', 'Gene', (20, 24))	('pancreatic cancer', 'Disease', 'MESH:D010190', (267, 284))	('tumor', 'Disease', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('increased', 'PosReg', (242, 251))	('pancreatic cancer', 'Disease', (267, 284))	('protein phosphatase 2 catalytic subunit alpha', 'Gene', (26, 71))	('rat', 'Species', '10116', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('protein phosphatase 2 catalytic subunit alpha', 'Gene', '5515', (26, 71))	('pancreatic cancer', 'Disease', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('sensitivity', 'MPA', (252, 263))	('activating', 'Var', (168, 178))	('PP2A', 'Gene', '5524', (20, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (267, 284))	('Penfluridol', 'Chemical', 'MESH:D010395', (230, 241))
47043	31620245	PP2A accounts for serine-threonine phosphatase activity in eukaryotic cells and studies have shown that inhibition of PP2A expression and/or function may contribute to leukemogenesis in several hematological malignancies.	('hematological malignancies', 'Disease', 'MESH:D019337', (194, 220))	('PP2A', 'Gene', '5524', (0, 4))	('PP2A', 'Gene', (118, 122))	('leukemogenesis', 'Disease', (168, 182))	('hematological malignancies', 'Phenotype', 'HP:0004377', (194, 220))	('contribute', 'Reg', (154, 164))	('PP2A', 'Gene', '5524', (118, 122))	('serine-threonine', 'Chemical', 'MESH:C061951', (18, 34))	('PP2A', 'Gene', (0, 4))	('function', 'MPA', (141, 149))	('inhibition', 'Var', (104, 114))	('hematological malignancies', 'Disease', (194, 220))
47056	31620245	org, Pathology atlas (https://www.proteinatlas.org/ENSG00000149131-SERPING1/pathology) showed that 5-year survival was 15% in patients with pancreatic cancer and high expression of Serping 1 (C1-INH), whereas those with a low expression had a 5-year survival of 56% (p-score 0.0059) (Figure 7).	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('SERPING1', 'Gene', (67, 75))	('Serping 1', 'Gene', '710', (181, 190))	('patients', 'Species', '9606', (126, 134))	('Serping 1', 'Gene', (181, 190))	('SERPING1', 'Gene', '710', (67, 75))	('high expression', 'Var', (162, 177))	('pancreatic cancer', 'Disease', (140, 157))
47071	31620245	Pancreatic cancer has been unresponsive to both anti-programmed death 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4).	('CTLA-4', 'Gene', (143, 149))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('anti-cytotoxic', 'Var', (88, 102))	('CTLA-4', 'Gene', '1493', (143, 149))	('anti-programmed', 'Var', (48, 63))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
47093	31620245	Here, protein expression of C1-INH in different cancer tissues was presented, where they had used two different antibodies, HPA048738 (polyclonal, Sigma-Aldrich) and CAB026161 (monoclonal, R&D Systems).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CAB026161', 'Var', (166, 175))	('HPA048738', 'Chemical', 'MESH:C047158', (124, 133))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('CAB026161', 'Chemical', 'MESH:C079661', (166, 175))
47097	30159429	Clinical significance of CRNDE transcript variants in glioblastoma multiforme The long non-coding RNA CRNDE is an oncogene that promotes tumor growth in glioblastoma multiforme (GBM).	('tumor', 'Disease', (137, 142))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (153, 176))	('glioblastoma multiforme', 'Disease', (54, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('variants', 'Var', (42, 50))	('CRNDE', 'Gene', '643911', (102, 107))	('CRNDE', 'Gene', (102, 107))	('promotes', 'PosReg', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (54, 77))	('CRNDE', 'Gene', '643911', (25, 30))	('CRNDE', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('glioblastoma multiforme', 'Disease', (153, 176))
47099	30159429	Here, we report our preliminary findings on the differential expressions of CRNDE transcript variants in GBM, and their prognostic significance.	('CRNDE', 'Gene', '643911', (76, 81))	('variants', 'Var', (93, 101))	('CRNDE', 'Gene', (76, 81))
47105	30159429	It is noteworthy that CRNDE has different transcript variants resulting from alternative splicing.	('alternative splicing', 'Var', (77, 97))	('CRNDE', 'Gene', '643911', (22, 27))	('CRNDE', 'Gene', (22, 27))
47123	30159429	The characterization of these tumor-specific variants may also allow for high specificity targeting therapies on cancerous tissues with only minimal impact on normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('variants', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancerous', 'Disease', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('cancerous', 'Disease', 'MESH:D009369', (113, 122))
47129	30159429	Researches that focus on the identification of tumor-specific variants are likely to become increasingly important for the development of biomarkers and effective therapeutic strategies.	('variants', 'Var', (62, 70))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
47132	29541171	Previous studies have indicated that long non-coding RNAs (lncRNAs) have a close association with glioma, suggesting that lncRNAs may be potential targets for the development of novel treatments for glioma.	('association', 'Interaction', (81, 92))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('ncRNA', 'Gene', (60, 65))	('long non-coding RNAs', 'Var', (37, 57))	('ncRNA', 'Gene', '54719', (60, 65))	('ncRNA', 'Gene', (123, 128))	('glioma', 'Disease', (98, 104))	('glioma', 'Disease', (199, 205))	('ncRNA', 'Gene', '54719', (123, 128))
47133	29541171	The present review summarized the latest studies on the dysregulation of lncRNAs in glioma, and discussed their potential use in the diagnosis, prognosis and therapies of glioma.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('ncRNA', 'Gene', (74, 79))	('glioma', 'Disease', (84, 90))	('ncRNA', 'Gene', '54719', (74, 79))	('glioma', 'Disease', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('dysregulation', 'Var', (56, 69))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
47146	29541171	Previously, the dysregulation of lncRNAs has been closely associated with carcinogenesis and cancer progression.	('cancer', 'Disease', (93, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('associated', 'Reg', (58, 68))	('ncRNA', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinogenesis', 'Disease', (74, 88))	('ncRNA', 'Gene', '54719', (34, 39))	('dysregulation', 'Var', (16, 29))
47148	29541171	For example, the variant genotypes of rs7763881 in the hepatocellular carcinoma up-regulated long non-coding RNA gene may be responsible for the decreased susceptibility to hepatitis B virus-associated carcinogenesis in liver, suggesting that genetic variations in lncRNAs are associated with cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('up-regulated', 'PosReg', (80, 92))	('decreased', 'NegReg', (145, 154))	('variant', 'Var', (17, 24))	('associated', 'Reg', (277, 287))	('hepatocellular carcinoma', 'Disease', (55, 79))	('ncRNA', 'Gene', (266, 271))	('rs7763881', 'Var', (38, 47))	('ncRNA', 'Gene', '54719', (266, 271))	('carcinogenesis', 'Disease', (202, 216))	('susceptibility to hepatitis B virus', 'Phenotype', 'HP:0410369', (155, 190))	('rs7763881', 'Mutation', 'rs7763881', (38, 47))	('cancer', 'Disease', (293, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('susceptibility', 'MPA', (155, 169))	('hepatitis B virus', 'Species', '10407', (173, 190))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('hepatitis', 'Phenotype', 'HP:0012115', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('long non-coding RNA', 'Gene', (93, 112))
47149	29541171	In addition, aberrant expression of lncRNAs has been employed in cancer diagnosis and monitoring.	('ncRNA', 'Gene', (37, 42))	('aberrant expression', 'Var', (13, 32))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ncRNA', 'Gene', '54719', (37, 42))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
47184	29541171	A previous study has demonstrated that H19 is upregulated in CD133+ glioblastoma cells compared with CD133- tumor cells.	('CD133+', 'Var', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('glioblastoma', 'Disease', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('tumor', 'Disease', (108, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('H19', 'Protein', (39, 42))	('upregulated', 'PosReg', (46, 57))
47188	29541171	The silencing of H19 may regulate drug resistance genes, including multidrug resistance protein 1, multidrug resistant associated protein 1 and ATP-binding cassette subfamily G member 2; and may promote apoptosis in sensitized tumor cells in drug-resistant glioma.	('H19', 'Gene', (17, 20))	('tumor', 'Disease', (227, 232))	('drug resistance', 'MPA', (34, 49))	('multidrug resistant associated protein 1', 'Gene', (99, 139))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('ATP-binding cassette subfamily G member 2', 'Gene', '9429', (144, 185))	('glioma', 'Disease', (257, 263))	('drug resistance', 'Phenotype', 'HP:0020174', (34, 49))	('glioma', 'Disease', 'MESH:D005910', (257, 263))	('apoptosis', 'CPA', (203, 212))	('multidrug resistance protein 1', 'Gene', '5243', (67, 97))	('silencing', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('glioma', 'Phenotype', 'HP:0009733', (257, 263))	('ATP-binding cassette subfamily G member 2', 'Gene', (144, 185))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('regulate', 'Reg', (25, 33))	('promote', 'PosReg', (195, 202))	('multidrug resistance protein 1', 'Gene', (67, 97))
47189	29541171	Furthermore, Jiang et al also demonstrated that the stable overexpression of H19 in U87MG and U373MG cell lines promoted tumor formation and induced tumor cell proliferation and angiogenesis in an in vivo murine xenograft model.	('U87MG', 'CellLine', 'CVCL:0022', (84, 89))	('U373MG', 'CellLine', 'CVCL:2219', (94, 100))	('murine', 'Species', '10090', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('induced', 'PosReg', (141, 148))	('tumor', 'Disease', (121, 126))	('promoted', 'PosReg', (112, 120))	('angiogenesis', 'CPA', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('overexpression', 'PosReg', (59, 73))	('U373MG', 'Var', (94, 100))	('H19', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
47194	29541171	Ma et al revealed that MALAT1 expression was associated with the malignant status of glioma and that high levels of MALAT1 expression were associated with poor prognosis in patients with glioma.	('MALAT1', 'Gene', (23, 29))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('expression', 'MPA', (30, 40))	('patients', 'Species', '9606', (173, 181))	('glioma', 'Disease', (187, 193))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('associated', 'Reg', (45, 55))	('glioma', 'Disease', (85, 91))	('malignant', 'Disease', (65, 74))	('associated', 'Reg', (139, 149))	('high levels', 'Var', (101, 112))	('MALAT1', 'Gene', '378938', (116, 122))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('MALAT1', 'Gene', '378938', (23, 29))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('MALAT1', 'Gene', (116, 122))
47195	29541171	Xiang et al identified that the level of MALAT1 was increased in tumor tissues compared with normal brain tissues in glioma, and the knockdown of MALAT1 resulted in the downregulation of cyclin D1 and MYC, the inhibition of tumor growth and induction of cell apoptosis in gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (272, 279))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cyclin D1', 'Gene', '595', (187, 196))	('MALAT1', 'Gene', (41, 47))	('induction', 'Reg', (241, 250))	('MALAT1', 'Gene', '378938', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('MYC', 'Gene', (201, 204))	('glioma', 'Disease', (272, 278))	('MALAT1', 'Gene', '378938', (41, 47))	('increased', 'PosReg', (52, 61))	('tumor', 'Disease', (65, 70))	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('cell apoptosis', 'CPA', (254, 268))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('MYC', 'Gene', '4609', (201, 204))	('gliomas', 'Disease', (272, 279))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('tumor', 'Disease', (224, 229))	('glioma', 'Disease', (117, 123))	('downregulation', 'NegReg', (169, 183))	('inhibition', 'NegReg', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('gliomas', 'Disease', 'MESH:D005910', (272, 279))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('cyclin D1', 'Gene', (187, 196))	('knockdown', 'Var', (133, 142))	('MALAT1', 'Gene', (146, 152))
47213	29541171	Furthermore, it was suggested that the knockdown of HOTAIR may lead to the inhibition of FGF1 by upregulating miR-326, which suppressed tumor growth in vitro and in vivo.	('miR-326', 'Gene', (110, 117))	('FGF1', 'Gene', (89, 93))	('knockdown', 'Var', (39, 48))	('inhibition', 'NegReg', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('miR-326', 'Gene', '442900', (110, 117))	('FGF1', 'Gene', '2246', (89, 93))	('suppressed', 'NegReg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('upregulating', 'PosReg', (97, 109))	('tumor', 'Disease', (136, 141))	('HOTAIR', 'Gene', (52, 58))
47217	29541171	These data suggest that the inhibition of HOTAIR activity may potentially be used as a novel therapy for the treatment of glioma.	('glioma', 'Disease', (122, 128))	('inhibition', 'Var', (28, 38))	('HOTAIR', 'Protein', (42, 48))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
47237	29541171	Furthermore, ectopic expression of MEG3 inhibited the growth of glioma cells by activation of the p53 signaling pathway.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('MEG3', 'Gene', (35, 39))	('inhibited', 'NegReg', (40, 49))	('MEG3', 'Gene', '55384', (35, 39))	('p53', 'Gene', (98, 101))	('glioma', 'Disease', (64, 70))	('ectopic expression', 'Var', (13, 31))	('p53', 'Gene', '7157', (98, 101))	('glioma', 'Disease', 'MESH:D005910', (64, 70))	('activation', 'PosReg', (80, 90))
47246	29541171	Gliomas with oxalosuccinate decarboxylase (IDH1) mutations exhibited a unique lncRNA gene expression signature that was different from that of tumors exhibiting the wild-type IDH1 gene.	('ncRNA', 'Gene', '54719', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('IDH1', 'Gene', (43, 47))	('ncRNA', 'Gene', (79, 84))	('IDH1', 'Gene', (175, 179))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('oxalosuccinate decarboxylase', 'Gene', '3417', (13, 41))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('oxalosuccinate decarboxylase', 'Gene', (13, 41))	('IDH1', 'Gene', '3417', (43, 47))	('Gliomas', 'Disease', (0, 7))	('IDH1', 'Gene', '3417', (175, 179))
47253	29541171	Preclinical studies have demonstrated the therapeutic efficacy of antisense oligonucleotides targeting cancer-associated lncRNAs, including MALAT-1 and H19.	('oligonucleotides', 'Chemical', 'MESH:D009841', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('antisense oligonucleotides', 'Var', (66, 92))	('ncRNA', 'Gene', (122, 127))	('MALAT-1', 'Gene', '378938', (140, 147))	('MALAT-1', 'Gene', (140, 147))	('ncRNA', 'Gene', '54719', (122, 127))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
47257	29541171	Similarly, Ke et al also reported that HOTAIR knockdown inhibited tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('knockdown', 'Var', (46, 55))	('tumor', 'Disease', (66, 71))	('inhibited', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('HOTAIR', 'Var', (39, 45))
47258	29541171	In addition, aberrant expression of growth arrest specific transcript 5 (GAS5) lncRNA has also been associated with chemoresistance in glioma.	('GAS5', 'Gene', '60674', (73, 77))	('growth arrest specific transcript 5', 'Gene', (36, 71))	('glioma', 'Disease', (135, 141))	('ncRNA', 'Gene', '54719', (80, 85))	('aberrant expression', 'Var', (13, 32))	('associated with', 'Reg', (100, 115))	('growth arrest specific transcript 5', 'Gene', '60674', (36, 71))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('growth arrest', 'Phenotype', 'HP:0001510', (36, 49))	('chemoresistance', 'CPA', (116, 131))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('GAS5', 'Gene', (73, 77))	('ncRNA', 'Gene', (80, 85))
47260	29541171	The knockdown of GAS5 sensitized U87MG cells to ERL treatment.	('U87MG', 'CellLine', 'CVCL:0022', (33, 38))	('GAS5', 'Gene', (17, 21))	('sensitized', 'Reg', (22, 32))	('knockdown', 'Var', (4, 13))	('GAS5', 'Gene', '60674', (17, 21))
47262	29541171	The silencing of H19 may decrease the half-maximal inhibitory concentration values for TMZ, and increase the apoptotic rate of glioma cells.	('H19', 'Gene', (17, 20))	('TMZ', 'Chemical', 'MESH:D000077204', (87, 90))	('half-maximal inhibitory concentration values', 'MPA', (38, 82))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('decrease', 'NegReg', (25, 33))	('glioma', 'Disease', (127, 133))	('increase', 'PosReg', (96, 104))	('apoptotic rate', 'CPA', (109, 123))	('silencing', 'Var', (4, 13))
47293	29203859	Further, inhibition of the EGFR tyrosine kinase activity by tyrphostin AG1478 increases IL-13 release after an injury, suggesting a negative feedback between EGFR and IL-13.	('IL-13', 'Gene', '3596', (88, 93))	('IL-13', 'Gene', '3596', (167, 172))	('EGFR', 'Gene', (27, 31))	('AG1478', 'Chemical', 'MESH:C101044', (71, 77))	('tyrosine kinase activity', 'MPA', (32, 56))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('tyrphostin', 'Chemical', 'MESH:D020032', (60, 70))	('increases', 'PosReg', (78, 87))	('IL-13', 'Gene', (88, 93))	('IL-13', 'Gene', (167, 172))	('inhibition', 'Var', (9, 19))
47307	29203859	In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Ralpha2 interacts with EGFRvIII to promotes GBM growth through upregulation of EGFRvIII tyrosine kinase activities and subsequently the RAS/RAF/MEK/ERK and STAT3 pathways.	('STAT3', 'Gene', '6774', (221, 226))	('MEK', 'Gene', (209, 212))	('upregulation', 'PosReg', (128, 140))	('MEK', 'Gene', '5609', (209, 212))	('GBM growth', 'CPA', (109, 119))	('tyrosine kinase', 'Enzyme', (153, 168))	('STAT3', 'Gene', (221, 226))	('ERK', 'Gene', '5594', (213, 216))	('RAF', 'Gene', (205, 208))	('promotes', 'PosReg', (100, 108))	('IL-13Ralpha2', 'Gene', (60, 72))	('activities', 'MPA', (169, 179))	('RAF', 'Gene', '22882', (205, 208))	('mutant', 'Var', (36, 42))	('EGFRvIII', 'Gene', (144, 152))	('ERK', 'Gene', (213, 216))	('tyrosine', 'Chemical', 'MESH:D014443', (153, 161))	('EGFR', 'Gene', (43, 47))
47313	29203859	Of the 274 patients evaluated, 94 patients expressing high levels of IL-13Ralpha2 (red) showed statistically significant decreased survival rate compared to 102 patients with low levels of IL-13Ralpha2 (green).	('IL-13Ralpha2', 'Var', (69, 81))	('survival rate', 'CPA', (131, 144))	('decreased', 'NegReg', (121, 130))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (11, 19))	('high levels', 'Var', (54, 65))
47315	29203859	Of the 137 GBM patients with twofold overexpression of EGFR mRNA, 62 patients with high levels of IL-13Ralpha2 (red) had a poor survival outcome when compared to 32 patients with low levels of IL-13Ralpha2 (green) (Fig.	('patients', 'Species', '9606', (15, 23))	('overexpression', 'PosReg', (37, 51))	('high levels', 'Var', (83, 94))	('IL-13Ralpha2', 'Var', (98, 110))	('patients', 'Species', '9606', (165, 173))	('EGFR mRNA', 'Gene', (55, 64))	('patients', 'Species', '9606', (69, 77))
47322	29203859	In an attempt to delineate the functional relationship between IL-13Ralpha2 and EGFRvIII in human gliomas, isogenic human glioma cell lines that expressed either IL-13Ralpha2, EGFRvIII, both or null were generated to recapitulate the heterogeneous nature of the human GBM tumors.	('EGFRvIII', 'Gene', (176, 184))	('glioma', 'Disease', (122, 128))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('human', 'Species', '9606', (262, 267))	('IL-13Ralpha2', 'Var', (162, 174))	('gliomas', 'Disease', (98, 105))	('IL-13Ralpha2 and EGFRvIII', 'Gene', '3598', (63, 88))	('glioma', 'Disease', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('GBM tumors', 'Disease', (268, 278))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('human', 'Species', '9606', (92, 97))	('human', 'Species', '9606', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('GBM tumors', 'Disease', 'MESH:D005910', (268, 278))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))
47327	29203859	Knockdown of IL-13Ralpha2 expression significantly reduced glioma migration in U87MG (Fig.	('glioma migration', 'Disease', 'MESH:D005910', (59, 75))	('reduced', 'NegReg', (51, 58))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('U87MG', 'CellLine', 'CVCL:0022', (79, 84))	('IL-13Ralpha2', 'Gene', (13, 25))	('U87MG', 'Var', (79, 84))	('glioma migration', 'Disease', (59, 75))
47329	29203859	In addition, knockdown of IL-13Ralpha2 inhibited basal, and IL-13- and CHI3L1/YKL40-induced migration of both U87MG (Fig.	('inhibited', 'NegReg', (39, 48))	('IL-13', 'Gene', '3596', (26, 31))	('CHI3L1', 'Gene', '1116', (71, 77))	('YKL40', 'Gene', (78, 83))	('U87MG', 'CellLine', 'CVCL:0022', (110, 115))	('migration', 'CPA', (92, 101))	('YKL40', 'Gene', '1116', (78, 83))	('IL-13', 'Gene', (60, 65))	('knockdown', 'Var', (13, 22))	('CHI3L1', 'Gene', (71, 77))	('IL-13', 'Gene', (26, 31))	('IL-13', 'Gene', '3596', (60, 65))
47350	29203859	To further confirm that IL-13Ralpha2 could induce tyrosine kinase activities in EGFRvIII-positive cells, targeted silencing of endogenous IL-13Ralpha2 was performed in EGFRvIII-positive U251-E18 and primary GBM culture derived from patients.	('patients', 'Species', '9606', (232, 240))	('silencing', 'Var', (114, 123))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('tyrosine kinase activities', 'MPA', (50, 76))	('induce', 'PosReg', (43, 49))
47353	29203859	The results demonstrated that AG1478 could significantly inhibit cell proliferation only in EGFRvIII-positive cells or in cells co-expressing EGFRvIII and IL-13Ralpha2.	('cell proliferation', 'CPA', (65, 83))	('AG1478', 'Chemical', 'MESH:C101044', (30, 36))	('inhibit', 'NegReg', (57, 64))	('AG1478', 'Var', (30, 36))
47375	29203859	The finding that IL-13Ralpha2 could enhance MAPK and STAT3 signaling in the presence of EGFRvIII was further confirmed using primary GBM from Mayo clinic that expressed endogenous EGFRvIII and IL-13Ralpha2.	('STAT3', 'Gene', '6774', (53, 58))	('Mayo', 'Species', '162683', (142, 146))	('STAT3', 'Gene', (53, 58))	('enhance', 'PosReg', (36, 43))	('IL-13Ralpha2', 'Var', (17, 29))
47379	29203859	To assess the potential of IL-13Ralpha2/EGFRvIII on Raf-ERK1/2 signaling, we transiently transfected the normal human astrocytes cells with IL-13Ralpha2, EGFRvIII, or both receptors under the serum-free medium.	('IL-13Ralpha2/EGFRvIII', 'Gene', (27, 48))	('ERK1/2', 'Gene', '5595;5594', (56, 62))	('ERK1/2', 'Gene', (56, 62))	('IL-13Ralpha2/EGFRvIII', 'Gene', '3598', (27, 48))	('Raf', 'Gene', '22882', (52, 55))	('Raf', 'Gene', (52, 55))	('human', 'Species', '9606', (112, 117))	('IL-13Ralpha2', 'Var', (140, 152))
47383	29203859	Taken together, IL-13Ralpha2 could only promote cellular proliferation in the presence of EGFRvIII through the activation of the RAS/RAF/MEK/ERK and STAT3 signaling cascades.	('EGFRvIII', 'Gene', (90, 98))	('promote', 'PosReg', (40, 47))	('activation', 'PosReg', (111, 121))	('MEK', 'Gene', (137, 140))	('ERK', 'Gene', (141, 144))	('MEK', 'Gene', '5609', (137, 140))	('STAT3', 'Gene', '6774', (149, 154))	('STAT3', 'Gene', (149, 154))	('IL-13Ralpha2', 'Var', (16, 28))	('cellular proliferation', 'CPA', (48, 70))	('RAF', 'Gene', '22882', (133, 136))	('ERK', 'Gene', '5594', (141, 144))	('RAF', 'Gene', (133, 136))
47387	29203859	Co-immunoprecipitation results showed that the EGFRvIII association with adapter proteins, Grb2, was enhanced in the presence of IL-13Ralpha2 compared to without (Fig.	('presence', 'Var', (117, 125))	('Grb2', 'Gene', '2885', (91, 95))	('EGFRvIII', 'Gene', (47, 55))	('association', 'Interaction', (56, 67))	('enhanced', 'PosReg', (101, 109))	('IL-13Ralpha2', 'Var', (129, 141))	('Grb2', 'Gene', (91, 95))
47390	29203859	Further, mutant IL-13Ralpha2 was incapable of further activating the MAPK, nor STAT and PI3K/AKT signaling cascades (Supplementary Fig.	('MAPK', 'Pathway', (69, 73))	('AKT', 'Gene', (93, 96))	('mutant', 'Var', (9, 15))	('IL-13Ralpha2', 'Gene', (16, 28))	('AKT', 'Gene', '207', (93, 96))
47393	29203859	Co-immunoprecipitation in Gli36.IL-13Ralpha2 cells transfected with the various EGFR constructs showed that the DK and DY3 mutant exhibited reduced binding ability when compared to EGFRvIII (Fig.	('Gli36', 'Chemical', '-', (26, 31))	('binding', 'Interaction', (148, 155))	('DY3 mutant', 'Var', (119, 129))	('reduced', 'NegReg', (140, 147))
47397	29203859	Next, we investigated whether IL-13Ralpha2 could provide a growth advantage in the presence of wtEGFR, using a tetracycline (Tet)-inducible wtEGFR (denoted as U251-E6) or mutant EGFRvIII (denoted as U251-E18) in the glioblastoma cell line U251MG.	('Tet', 'Chemical', 'MESH:D013752', (125, 128))	('U251MG', 'CellLine', 'CVCL:0021', (239, 245))	('tetracycline', 'Chemical', 'MESH:D013752', (111, 123))	('glioblastoma', 'Disease', (216, 228))	('glioblastoma', 'Disease', 'MESH:D005909', (216, 228))	('EGFRvIII', 'Gene', (178, 186))	('advantage', 'PosReg', (66, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('mutant', 'Var', (171, 177))	('growth', 'MPA', (59, 65))
47399	29203859	Targeted knockdown of IL-13Ralpha2 in primary wtEGFR-positive GBM patient tumor, as validated by western blot analysis (Supplementary Fig.	('GBM', 'Disease', (62, 65))	('knockdown', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patient', 'Species', '9606', (66, 73))	('tumor', 'Disease', (74, 79))	('IL-13Ralpha2', 'Gene', (22, 34))
47404	29203859	Targeted IL-13Ralpha2 knockdown showed only modestly reduced or no detectable change in STAT3 in wtEGFR-expressing cell line and primary glioma cultures derived from GBM patient tumors, respectively (Fig.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('tumors', 'Disease', (178, 184))	('STAT3', 'Gene', '6774', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('knockdown', 'Var', (22, 31))	('STAT3', 'Gene', (88, 93))	('IL-13Ralpha2', 'Gene', (9, 21))	('primary glioma', 'Disease', 'MESH:D005910', (129, 143))	('primary glioma', 'Disease', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('patient', 'Species', '9606', (170, 177))
47405	29203859	In contrast, silencing of IL-13Ralpha2 in EGFRvIII-positive glioma cells and primary culture caused a significant reduction in STAT3 activation (Fig.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('reduction', 'NegReg', (114, 123))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('glioma', 'Disease', (60, 66))	('STAT3', 'Gene', '6774', (127, 132))	('IL-13Ralpha2', 'Gene', (26, 38))	('STAT3', 'Gene', (127, 132))	('silencing', 'Var', (13, 22))
47409	29203859	The results showed that only tetracycline analogs fed mice, transplanted with U251-E18 cells expressing both IL-13Ralpha2 and mutant EGFR, had a significantly larger mean tumor volume (Fig.	('larger', 'PosReg', (159, 165))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tetracycline', 'Chemical', 'MESH:D013752', (29, 41))	('IL-13Ralpha2', 'Gene', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('EGFR', 'Gene', (133, 137))	('mutant', 'Var', (126, 132))
47412	29203859	Immunoblotting analysis of the excised tumors in representative animals revealed a slight decrease in the level of IL-13Ralpha2 when wtEGFR proteins were induced, and a remarkable increase when mutant EGFR proteins were induced (Fig.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('increase', 'PosReg', (180, 188))	('level of IL-13Ralpha2', 'MPA', (106, 127))	('mutant', 'Var', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('decrease', 'NegReg', (90, 98))	('tumors', 'Disease', (39, 45))
47413	29203859	We also inoculated mice with U251-E6 and U251-E18 cells intracranially.	('U251-E6', 'Var', (29, 36))	('mice', 'Species', '10090', (19, 23))	('U251-E18', 'Var', (41, 49))
47422	29203859	Targeted silencing of CHI3L1 has been shown to overcome temozolomide-resistance in GBM.	('CHI3L1', 'Gene', '1116', (22, 28))	('temozolomide', 'Chemical', 'MESH:D000077204', (56, 68))	('temozolomide-resistance', 'MPA', (56, 79))	('CHI3L1', 'Gene', (22, 28))	('Targeted silencing', 'Var', (0, 18))	('overcome', 'PosReg', (47, 55))
47425	29203859	IL-13Ralpha2 is also amongst the gene signatures that mediate breast cancer metastasis to the lung and to the brain, thus, indicating the importance of IL-13Ralpha2 in promoting the invasion and migration potential of cancer cells.	('promoting', 'PosReg', (168, 177))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('breast cancer metastasis to the lung', 'Disease', 'MESH:D009362', (62, 98))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IL-13Ralpha2', 'Var', (152, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('breast cancer metastasis to the lung', 'Disease', (62, 98))	('invasion', 'CPA', (182, 190))	('cancer', 'Disease', (69, 75))
47427	29203859	in that the overexpression of IL-13Ralpha2 proteins did not confer an added growth advantage in human breast and pancreatic cancer cell lines lacking the EGFRvIII receptors.	('human', 'Species', '9606', (96, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (102, 130))	('lacking', 'NegReg', (142, 149))	('IL-13Ralpha2', 'Var', (30, 42))
47448	29203859	Given that the co-expression of high levels of IL-13Ralpha2 and EGFRvIII/EGFR correlate with shorter patient survival by TGCA analysis, the activation of STAT3 by Y705 phosphorylation is linked with clinically more aggressive behavior in glioblastomas.	('IL-13Ralpha2 and EGFRvIII', 'Gene', '3598', (47, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('glioblastomas', 'Disease', 'MESH:D005909', (238, 251))	('glioblastomas', 'Disease', (238, 251))	('Y705', 'Var', (163, 167))	('STAT3', 'Gene', '6774', (154, 159))	('activation', 'PosReg', (140, 150))	('aggressive behavior', 'Phenotype', 'HP:0000718', (215, 234))	('shorter', 'NegReg', (93, 100))	('patient', 'Species', '9606', (101, 108))	('STAT3', 'Gene', (154, 159))	('glioblastomas', 'Phenotype', 'HP:0012174', (238, 251))
47467	29203859	Deen, Brain Tumor Research Centre, UCSF School of Medicine, CA, USA), U1242 (kind gift from Isa Hussaini, University of Virginia, Charlotesville, VA, USA), U87MG (American Type Culture Collection,Rockville, MD, USA) were cultured in 10% FBS containing DMEM supplemented with antibiotics and l-glutamine as described above.	('Brain Tumor', 'Phenotype', 'HP:0030692', (6, 17))	('U1242', 'Var', (70, 75))	('U87MG', 'CellLine', 'CVCL:0022', (156, 161))	('l-glutamine', 'Chemical', 'MESH:D005973', (291, 302))	('U87MG', 'Var', (156, 161))	('FBS', 'Disease', 'MESH:D005198', (237, 240))	('Tumor', 'Phenotype', 'HP:0002664', (12, 17))	('FBS', 'Disease', (237, 240))	('DMEM', 'Chemical', '-', (252, 256))
47481	29203859	Western blotting was performed using the following primary antibodies: anti-IL-13Ralpha2 (R&D systems, AF146; 1/1000), anti-EGFR clone 12 (Thermo Scientific/NeoMarker, NH, USA, MS-400-P; 1/1000), anti-EGFR (Cell Signaling Technology, MA, USA, #4267; 1/1000), anti-MMP2 (Santa Cruz Biotechnology, sc-10736; 1/1000), anti-vimentin (Epitomics, Burlingame, CA, USA, 2862-1; 1:1000), anti-Grb2 (BD Transduction Lab, NJ, USA, G16720; 1/1000), anti-phosphotyrosine (clone 4G10) (Upstate/Millipore, MA, USA, 05-321; 1/1000), anti-phosphotyrosine (p-Tyr-102) (Cell Signaling Technology, #9416; 1/1000), anti-pan Ras (Calbiochem, MA, USA, #OP-40; 1/1000), anti-C-Raf (BD Transduction Lab, R19120; 1/1000), anti-phospho-C-Raf (Ser338) (Cell Signaling Technology, #9427; 1/1000), anti-MEK1/2 (Cell Signaling Technology, #9122; 1/1000), anti-phospho-MEK1/2 (Ser217/221) (Cell Signaling Technology, #9121; 1/1000), anti-p42/44 MAPK (ERK1/2) (Cell Signaling Technology, #4695; 1/1000), anti-phospho-p42/44 MAPK (ERK1/2) (Thr-202/Tyr-204) (Cell Signaling Technology, #9101; 1/1000), anti-PTEN (Cell Signaling Technology, #9559; 1/1000), anti-PI3K p85alpha (Cell Signaling Technology, #4292; 1/1000), anti-phospho-PI3K p85alpha (Y458) (Cell Signaling Technology, #4228; 1/1000), anti-AKT (Cell Signaling Technology, #4691; 1/1000), anti-phospho-AKT (Ser-473) (Cell Signaling Technology, #9271; 1/1000), anti-STAT3 (Cell Signaling Technology, #9139; 1/1000), anti-phosho-STAT3 (Ser-727) (Cell Signaling Technology, #9136; 1/1000), anti-phospho-STAT3 (Tyr705) (Cell Signaling Technology, #9131; 1/1000), anti-TGFbeta (Cell Signaling Technology, #3711; 1/1000), anti-Hsp70 (System Biosciences, CA, USA, H53220; 1/1000), anti-pan-actin (Thermo Scientific/Neomarker, MS-1295-P; 1/ 20,000), anti-beta-tubulin (BD Biosciences, 556321; 1/5000) and anti-tubulin (Santa Cruz Biotechnology, sc-5286; 1/10,000).	('p85alpha', 'Gene', (1131, 1139))	('p85alpha', 'Gene', '5295', (1202, 1210))	('PTEN', 'Gene', '5728', (1072, 1076))	('C-Raf', 'Gene', '5894', (651, 656))	('STAT3', 'Gene', (1453, 1458))	('STAT3', 'Gene', '6774', (1526, 1531))	('C-Raf', 'Gene', (709, 714))	('AKT', 'Gene', '207', (1328, 1331))	('Grb2', 'Gene', '2885', (384, 388))	('p42', 'Gene', '2038', (984, 987))	('p85alpha', 'Gene', (1202, 1210))	('AKT', 'Gene', (1267, 1270))	('STAT3', 'Gene', '6774', (1453, 1458))	('vimentin', 'Gene', '7431', (320, 328))	('Thr-202/Tyr', 'Var', (1006, 1017))	('Ser338', 'Chemical', '-', (716, 722))	('vimentin', 'Gene', (320, 328))	('MMP2', 'Gene', (264, 268))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (522, 537))	('MEK1/2', 'Gene', '5604;5605', (837, 843))	('Grb2', 'Gene', (384, 388))	('MEK1/2', 'Gene', (837, 843))	('MEK1/2', 'Gene', '5604;5605', (773, 779))	('C-Raf', 'Gene', '5894', (709, 714))	('MEK1/2', 'Gene', (773, 779))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (442, 457))	('C-Raf', 'Gene', (651, 656))	('Tyr705', 'Chemical', '-', (1533, 1539))	('p42', 'Gene', (906, 909))	('TGFbeta', 'Gene', (1590, 1597))	('ERK1/2', 'Gene', (919, 925))	('AKT', 'Gene', '207', (1267, 1270))	('MMP2', 'Gene', '4313', (264, 268))	('AKT', 'Gene', (1328, 1331))	('ERK1/2', 'Gene', '5595;5594', (919, 925))	('Thr-202/Tyr', 'SUBSTITUTION', 'None', (1006, 1017))	('TGFbeta', 'Gene', '7040', (1590, 1597))	('PTEN', 'Gene', (1072, 1076))	('STAT3', 'Gene', (1391, 1396))	('p85alpha', 'Gene', '5295', (1131, 1139))	('p42', 'Gene', (984, 987))	('ERK1/2', 'Gene', (997, 1003))	('STAT3', 'Gene', (1526, 1531))	('ERK1/2', 'Gene', '5595;5594', (997, 1003))	('p42', 'Gene', '2038', (906, 909))	('STAT3', 'Gene', '6774', (1391, 1396))
47497	29203859	Details of the different animal models are as follow: Six to eight-week-old female immunodeficient NOD/SCID mice (Animal Resource Centre, Canning Vale, Western Australia) were injected subcutaneously with U251-E6 and U251-E18 cells (5 x 106 cell each, n = 4 per group) resuspended in a 1:1 mixture of PBS and Matrigel (BD Bioscience) in the right and left flanks, respectively.	('U251-E6', 'Var', (205, 212))	('immunodeficient NOD/SCID', 'Disease', (83, 107))	('immunodeficient NOD/SCID', 'Disease', 'MESH:D020191', (83, 107))	('PBS', 'Chemical', '-', (301, 304))	('mice', 'Species', '10090', (108, 112))	('U251-E18', 'Var', (217, 225))
47524	29203859	Endogenous peroxidase was quenched with 0.3% H2O2 for 20 min and then blocked with 5% BSA at RT.	('H2O2', 'Chemical', 'MESH:D006861', (45, 49))	('H2O2', 'Var', (45, 49))	('quenched', 'NegReg', (26, 34))
47546	29203859	Similar experiments were performed with Gli36.IL-13Ralpha2 cells transfected with full length EGFRvIII, DK and DY3 mutants.	('EGFRvIII', 'Gene', (94, 102))	('mutants', 'Var', (115, 122))	('DY3', 'Gene', (111, 114))	('Gli36', 'Chemical', '-', (40, 45))
47579	28279797	We have previously demonstrated that a dense polyethylene glycol (PEG) corona on NP eliminates adhesive trapping in the brain parenchyma, and that such particles rapidly penetrate healthy brain tissue if they are <114 nm in diameter and brain tumor tissue if they are <70 nm in diameter.	('polyethylene glycol', 'Chemical', 'MESH:D011092', (45, 64))	('brain tumor', 'Disease', (237, 248))	('adhesive trapping', 'MPA', (95, 112))	('rat', 'Species', '10116', (26, 29))	('brain tumor', 'Disease', 'MESH:D001932', (237, 248))	('<114', 'Var', (213, 217))	('rat', 'Species', '10116', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('brain tumor', 'Phenotype', 'HP:0030692', (237, 248))	('eliminates', 'NegReg', (84, 94))	('PEG', 'Chemical', 'MESH:D011092', (66, 69))	('brain parenchyma', 'Disease', (120, 136))	('brain parenchyma', 'Disease', 'MESH:D010195', (120, 136))
47628	28279797	Therefore, on Day 7, the burr holes were re-accessed and animals were treated via CED with 10 muL of the following treatment groups: normal saline (NS), CDDP, CDDP-UPN and CDDP-BPN.	('CDDP', 'Var', (153, 157))	('CDDP-UPN', 'Var', (159, 167))	('CDDP', 'Chemical', '-', (153, 157))	('CDDP', 'Chemical', '-', (159, 163))	('CDDP-UPN', 'Chemical', '-', (159, 167))	('CDDP-BPN', 'Var', (172, 180))	('CDDP-BPN', 'Chemical', '-', (172, 180))	('CDDP', 'Chemical', '-', (172, 176))
47645	28279797	In general, CDDP and CDDP-BPN treatments did not yield significant differences in cytotoxicity in either cell line, suggesting that delivering CDDP in BPN did not reduce the intrinsic potency of CDDP.	('cytotoxicity', 'Disease', (82, 94))	('CDDP', 'Var', (143, 147))	('CDDP', 'Chemical', '-', (12, 16))	('CDDP-BPN', 'Chemical', '-', (21, 29))	('intrinsic potency', 'MPA', (174, 191))	('BPN', 'Chemical', 'MESH:D001977', (26, 29))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('CDDP', 'Chemical', '-', (143, 147))	('CDDP', 'Chemical', '-', (195, 199))	('BPN', 'Chemical', 'MESH:D001977', (151, 154))	('CDDP', 'Chemical', '-', (21, 25))
47653	28279797	The diffusion rates of CDDP-BPN and CDDP-UPN in brain tissues were 285-fold and 17,000-fold lower, respectively, than their theoretical diffusion rates in ACSF at tau = 1 s (Table 1).	('CDDP-BPN', 'Var', (23, 31))	('rat', 'Species', '10116', (146, 149))	('CDDP-BPN', 'Chemical', '-', (23, 31))	('CDDP-UPN', 'Var', (36, 44))	('diffusion', 'MPA', (4, 13))	('CDDP-UPN', 'Chemical', '-', (36, 44))	('lower', 'NegReg', (92, 97))	('rat', 'Species', '10116', (14, 17))
47656	28279797	When administered as a manual co-injection, the Vd of CDDP-BPN in the striatum was 14-fold higher than that of CDDP-UPN (Fig.	('higher', 'PosReg', (91, 97))	('CDDP-BPN', 'Chemical', '-', (54, 62))	('CDDP-BPN', 'Var', (54, 62))	('CDDP-UPN', 'Chemical', '-', (111, 119))
47661	28279797	The Vd of CDDP-UPN was also enhanced by CED, albeit only by a factor of 3.	('CDDP-UPN', 'Chemical', '-', (10, 18))	('CED', 'Var', (40, 43))	('enhanced', 'PosReg', (28, 36))	('CDDP-UPN', 'Gene', (10, 18))
47667	28279797	Furthermore, 40% of rats treated with 48 mug CDDP-BPN were long-term survivors, representing an improvement in CDDP tolerability compared to animals treated with CDDP at half that dose.	('CDDP', 'Chemical', '-', (111, 115))	('CDDP', 'Chemical', '-', (162, 166))	('rats', 'Species', '10116', (20, 24))	('CDDP-BPN', 'Var', (45, 53))	('CDDP', 'Chemical', '-', (45, 49))	('CDDP-BPN', 'Chemical', '-', (45, 53))	('improvement', 'PosReg', (96, 107))
47676	28279797	F98 forms highly aggressive tumors that mimic many of the hallmarks of human GBM, including a highly invasive pattern of growth and overexpression of protein-based tumor markers such as PDGFbeta and EGFR.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (28, 33))	('overexpression', 'PosReg', (132, 146))	('aggressive tumors', 'Disease', (17, 34))	('PDGFbeta', 'Disease', (186, 194))	('EGFR', 'Gene', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('PDGFbeta', 'Disease', 'None', (186, 194))	('F98', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('aggressive tumors', 'Disease', 'MESH:D001523', (17, 34))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('human', 'Species', '9606', (71, 76))	('EGFR', 'Gene', '1956', (199, 203))
47707	28279797	However, less overall percentage of encapsulated CDDP was released from CDDP-BPN (~60%) compared to CDDP-CP (~80%).	('CDDP', 'Chemical', '-', (72, 76))	('CDDP-BPN', 'Chemical', '-', (72, 80))	('less', 'NegReg', (9, 13))	('released', 'MPA', (58, 66))	('CDDP-CP', 'Chemical', '-', (100, 107))	('CDDP-BPN', 'Var', (72, 80))	('CDDP', 'Chemical', '-', (49, 53))	('CDDP', 'Chemical', '-', (100, 104))
47714	28279797	When administered using a manual injection, CDDP-BPN achieved a higher Vd within the rat striatum as compared to that of the conventionally designed CDDP-UPN.	('CDDP-BPN', 'Var', (44, 52))	('higher', 'PosReg', (64, 70))	('CDDP-BPN', 'Chemical', '-', (44, 52))	('rat', 'Species', '10116', (85, 88))	('CDDP-UPN', 'Chemical', '-', (149, 157))
47726	28279797	Overall, we anticipate that local, intratumoral administration of CDDP-BPN via CED may provide a promising adjuvant therapy for patients diagnosed with high grade gliomas.	('gliomas', 'Disease', (163, 170))	('rat', 'Species', '10116', (56, 59))	('gliomas', 'Disease', 'MESH:D005910', (163, 170))	('gliomas', 'Phenotype', 'HP:0009733', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('CDDP-BPN', 'Var', (66, 74))	('tumor', 'Disease', (40, 45))	('rat', 'Species', '10116', (38, 41))	('patients', 'Species', '9606', (128, 136))	('CDDP-BPN', 'Chemical', '-', (66, 74))
47800	27690294	The incidences of total and >= grade 3 were higher in the CIK immunotherapy group than the control group.	('higher', 'PosReg', (44, 50))	('CIK', 'Chemical', '-', (58, 61))	('CIK', 'Var', (58, 61))
47818	27690294	Pre-informed stratification based upon the methylation status of O6-Methylguanine-DNA Methyltransferase (MGMT) gene promoter or isocitrate dehydrogenase 1 gene (IDH1) mutation must have enforced the power of the result in this study.	('IDH1', 'Gene', '3417', (161, 165))	('O6-Methylguanine-DNA Methyltransferase', 'Gene', '4255', (65, 103))	('mutation', 'Var', (167, 175))	('MGMT', 'Gene', '4255', (105, 109))	('IDH1', 'Gene', (161, 165))	('MGMT', 'Gene', (105, 109))	('O6-Methylguanine-DNA Methyltransferase', 'Gene', (65, 103))
47832	28234925	MMP-2 expression was associated with shorter overall survival in patients with grade II-IV astrocytic tumors (HR 1.60; 95% CI 1.03-2.48; p = 0.036).	('MMP-2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('shorter', 'NegReg', (37, 44))	('expression', 'Var', (6, 16))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (91, 107))	('II-IV astrocytic tumors', 'Disease', 'MESH:D001254', (85, 108))	('patients', 'Species', '9606', (65, 73))	('MMP-2', 'Gene', '4313', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('II-IV astrocytic tumors', 'Disease', (85, 108))	('overall survival', 'MPA', (45, 61))
47833	28234925	In glioblastoma, high MMP-2 was associated with poorer prognosis in patients who survived longer than 8.5 months independent of age and gender (HR 2.27; 95% CI 1.07-4.81; p = 0.033).	('high', 'Var', (17, 21))	('poorer', 'NegReg', (48, 54))	('MMP-2', 'Gene', '4313', (22, 27))	('glioblastoma', 'Disease', (3, 15))	('patients', 'Species', '9606', (68, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('MMP-2', 'Gene', (22, 27))
47860	28234925	The sections were then incubated overnight at 4 C with a MMP-2 antibody with affinity towards both latent MMP-2 (72 kDa) and active MMP-2 (66 kDa) (cloneVB3, Merck Millipore, Germany, diluted at 1:300).	('MMP-2', 'Gene', (57, 62))	('MMP-2', 'Gene', '4313', (132, 137))	('MMP-2', 'Gene', (106, 111))	('66 kDa', 'Var', (139, 145))	('MMP-2', 'Gene', '4313', (57, 62))	('MMP-2', 'Gene', '4313', (106, 111))	('MMP-2', 'Gene', (132, 137))
47865	28234925	Sections from patients with of DA, AA and GBM were stained with a mIDH1R132H antibody (mIDH1R132H, clone H14, Dionova, 1:100) to detect the most common isocitrate dehydrogenase (IDH) mutation using the BenchMark Ultra IHC/ISH staining system (Ventana Medical Systems, Inc, USA) as previously described.	('mIDH1', 'Gene', '15926', (66, 71))	('IDH', 'Gene', '3417', (178, 181))	('mIDH1', 'Gene', '15926', (87, 92))	('mIDH1', 'Gene', (87, 92))	('mIDH1', 'Gene', (66, 71))	('IDH', 'Gene', (67, 70))	('IDH', 'Gene', (88, 91))	('mutation', 'Var', (183, 191))	('IDH', 'Gene', '3417', (67, 70))	('IDH', 'Gene', '3417', (88, 91))	('IDH', 'Gene', (178, 181))	('patients', 'Species', '9606', (14, 22))
47908	28234925	High MMP-2 expression was significantly associated with poorer survival in patients with grade II-IV astrocytoma when dichotomized at the median intensity of 117.1 (HR 1.60; 95% CI 1.03-2.48; p = 0.036) (Fig 3C).	('High', 'Var', (0, 4))	('grade', 'Disease', (89, 94))	('MMP-2', 'Gene', '4313', (5, 10))	('expression', 'MPA', (11, 21))	('poorer', 'NegReg', (56, 62))	('patients', 'Species', '9606', (75, 83))	('astrocytoma', 'Disease', 'MESH:D001254', (101, 112))	('astrocytoma', 'Disease', (101, 112))	('astrocytoma', 'Phenotype', 'HP:0009592', (101, 112))	('MMP-2', 'Gene', (5, 10))	('survival', 'MPA', (63, 71))
47914	28234925	After 8.5 months, patients with high levels of MMP-2 had a significantly poorer overall survival compared to patients with low intensity (HR 2.18; 95% CI 1.05-4.56; p = 0.036) (Fig 3D).	('patients', 'Species', '9606', (109, 117))	('overall survival', 'MPA', (80, 96))	('MMP-2', 'Gene', '4313', (47, 52))	('poorer', 'NegReg', (73, 79))	('high levels', 'Var', (32, 43))	('patients', 'Species', '9606', (18, 26))	('MMP-2', 'Gene', (47, 52))
47922	28234925	In survival analysis, high MMP-2 expression was associated with poorer outcome in patients with grade II-IV astrocytomas (HR 2.54; 95% CI 1.86-3.48; p<0.001) (Fig 4D).	('II-IV astrocytomas', 'Disease', 'MESH:D005909', (102, 120))	('II-IV astrocytomas', 'Disease', (102, 120))	('MMP-2', 'Gene', (27, 32))	('high', 'Var', (22, 26))	('patients', 'Species', '9606', (82, 90))	('astrocytoma', 'Phenotype', 'HP:0009592', (108, 119))	('expression', 'MPA', (33, 43))	('MMP-2', 'Gene', '4313', (27, 32))	('poorer', 'NegReg', (64, 70))
47928	28234925	When combining MMP-2 and TIMP-1 into a sum score, high levels were significantly associated with shorter overall survival (HR 1.28; 95% CI 1.05-1.55; p = 0.011) (Fig 4H), also when accounting for GBM subtype, age, and gender (HR 1.32; 95% CI 1.06-1.65; p = 0.015).	('TIMP-1', 'Gene', (25, 31))	('MMP-2', 'Gene', '4313', (15, 20))	('overall survival', 'MPA', (105, 121))	('shorter', 'NegReg', (97, 104))	('high levels', 'Var', (50, 61))	('MMP-2', 'Gene', (15, 20))	('TIMP-1', 'Gene', '7076', (25, 31))
47930	28234925	In the TCGA dataset, high c-MET mRNA was significantly associated with shorter survival (HR 1.26; 95% CI 1.04-1.52; p = 0.018), but c-MET mRNA did not appear to be a time-dependent prognosticator (Fig 5A).	('c-MET', 'Gene', '4233', (26, 31))	('c-MET', 'Gene', (132, 137))	('high', 'Var', (21, 25))	('c-MET', 'Gene', (26, 31))	('shorter', 'NegReg', (71, 78))	('c-MET', 'Gene', '4233', (132, 137))	('survival', 'MPA', (79, 87))
47931	28234925	Stratifying TCGA patients into four groups based on c-MET and MMP-2/TIMP-1 sum score showed that patients with both high c-MET and high sum score had significantly reduced survival compared to patients with low c-MET and low sum score (HR 1.51; 95% CI 1.17-1.94; p = 0.001) (Fig 5B), and this was augmented when adjusting for GBM subtype, age, and gender in the multivariate analysis (HR 1.73; 95% CI 1.27-2.35; p<0.001) (Table 5).	('c-MET', 'Gene', (121, 126))	('patients', 'Species', '9606', (193, 201))	('c-MET', 'Gene', (52, 57))	('MMP-2', 'Gene', (62, 67))	('c-MET', 'Gene', '4233', (52, 57))	('c-MET', 'Gene', '4233', (211, 216))	('c-MET', 'Gene', (211, 216))	('high sum score', 'Var', (131, 145))	('patients', 'Species', '9606', (97, 105))	('c-MET', 'Gene', '4233', (121, 126))	('patients', 'Species', '9606', (17, 25))	('TIMP-1', 'Gene', (68, 74))	('TIMP-1', 'Gene', '7076', (68, 74))	('reduced', 'NegReg', (164, 171))	('MMP-2', 'Gene', '4313', (62, 67))	('survival', 'MPA', (172, 180))
47933	28234925	The MMP-2 level increased with malignancy grade, and high expression was associated with shorter survival in patients diagnosed with grade II-IV astrocytomas as well as in patients with GBM who lived longer than 8.5 months after initial diagnosis.	('malignancy', 'Disease', 'MESH:D009369', (31, 41))	('survival', 'MPA', (97, 105))	('MMP-2', 'Gene', (4, 9))	('patients', 'Species', '9606', (109, 117))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('malignancy', 'Disease', (31, 41))	('increased', 'PosReg', (16, 25))	('MMP-2', 'Gene', '4313', (4, 9))	('patients', 'Species', '9606', (172, 180))	('II-IV astrocytomas', 'Disease', 'MESH:D005909', (139, 157))	('high expression', 'Var', (53, 68))	('shorter', 'NegReg', (89, 96))	('II-IV astrocytomas', 'Disease', (139, 157))
47954	28234925	We further observed that patients with wtIDH1 tumors tended to have a higher MMP-2 expression than patients with mIDH1 tumors further supporting the idea that MMP-2 contributes to tumor aggressiveness as patients with mutations in IDH have a better prognosis, especially in WHO grade II-III.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('IDH', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MMP-2', 'Gene', '4313', (77, 82))	('IDH1 tumors', 'Disease', 'MESH:D009369', (41, 52))	('IDH', 'Gene', (231, 234))	('tumor aggressiveness', 'Disease', (180, 200))	('mIDH1 tumors', 'Disease', (113, 125))	('MMP-2', 'Gene', (159, 164))	('IDH', 'Gene', '3417', (114, 117))	('expression', 'MPA', (83, 93))	('higher', 'PosReg', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('patients', 'Species', '9606', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('IDH', 'Gene', '3417', (41, 44))	('IDH', 'Gene', '3417', (231, 234))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (180, 200))	('IDH1 tumors', 'Disease', (41, 52))	('MMP-2', 'Gene', (77, 82))	('mIDH1 tumors', 'Disease', 'MESH:D009369', (113, 125))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (25, 33))	('MMP-2', 'Gene', '4313', (159, 164))	('IDH', 'Gene', (114, 117))	('mutations', 'Var', (218, 227))	('IDH1 tumors', 'Disease', 'MESH:D009369', (114, 125))	('aggressiveness', 'Phenotype', 'HP:0000718', (186, 200))
47957	28234925	Further, in vitro knockdown or inhibition of LOX in GBM cells resulted in diminished migratory and invasive abilities.	('inhibition', 'NegReg', (31, 41))	('knockdown', 'Var', (18, 27))	('diminished', 'NegReg', (74, 84))	('LOX', 'Gene', '4015', (45, 48))	('LOX', 'Gene', (45, 48))
47958	28234925	showed that U87 cells transfected with a mutated IDH1 gene had lower invasive capabilities, and this was linked to reduced levels of MMP-2 and MMP-9.	('MMP-9', 'Gene', '4318', (143, 148))	('mutated', 'Var', (41, 48))	('IDH1', 'Gene', '3417', (49, 53))	('lower', 'NegReg', (63, 68))	('MMP-9', 'Gene', (143, 148))	('reduced', 'NegReg', (115, 122))	('IDH1', 'Gene', (49, 53))	('MMP-2', 'Gene', '4313', (133, 138))	('U87', 'CellLine', 'CVCL:0022', (12, 15))	('invasive capabilities', 'CPA', (69, 90))	('MMP-2', 'Gene', (133, 138))
47960	28234925	Overall, this suggests that a mutation in IDH reduces the intratumoral production of pro-invasive proteins, possibly due to the metabolic/oxidative changes that follow from the mutation.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('IDH', 'Gene', (42, 45))	('mutation', 'Var', (30, 38))	('IDH', 'Gene', '3417', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('oxidative changes', 'Phenotype', 'HP:0025464', (138, 155))	('reduces', 'NegReg', (46, 53))
47963	28234925	Classical GBMs are especially characterized by amplification in the epidermal growth factor receptor (EGFR), a receptor that has also been linked to tumor invasiveness.	('epidermal growth factor receptor', 'Gene', (68, 100))	('tumor invasiveness', 'Disease', (149, 167))	('linked', 'Reg', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('amplification', 'Var', (47, 60))	('epidermal growth factor receptor', 'Gene', '1956', (68, 100))	('tumor invasiveness', 'Disease', 'MESH:D009369', (149, 167))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
47965	28234925	This GBM subtype is characterized by mutations in the tumor suppressors: phosphatase and tensin homolog (PTEN) and p53.	('PTEN', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PTEN', 'Gene', '5728', (105, 109))	('p53', 'Gene', '7157', (115, 118))	('p53', 'Gene', (115, 118))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
47969	28234925	Interestingly, deletions in PTEN may be related to T cell anergy as well as tumor tolerance.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('related', 'Reg', (40, 47))	('T cell anergy', 'Disease', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('deletions', 'Var', (15, 24))	('T cell anergy', 'Disease', 'OMIM:616452', (51, 64))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
47980	28234925	We have previously reported that low TIMP-1 score predicts longer survival in patients with GBM.	('TIMP-1', 'Gene', '7076', (37, 43))	('patients', 'Species', '9606', (78, 86))	('low', 'Var', (33, 36))	('TIMP-1', 'Gene', (37, 43))	('longer', 'PosReg', (59, 65))
47985	28234925	We found that high levels of c-MET significantly worsened the prognosis for patients with high sum score.	('patients', 'Species', '9606', (76, 84))	('c-MET', 'Gene', (29, 34))	('high levels', 'Var', (14, 25))	('worsened', 'NegReg', (49, 57))	('prognosis', 'CPA', (62, 71))	('c-MET', 'Gene', '4233', (29, 34))
47990	28234925	In contrast, in a study testing the efficacy of bevacizumab in patients with recurrent high-grade gliomas, high MMP-2 plasma levels were associated with improved tumor control and survival.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('MMP-2', 'Gene', '4313', (112, 117))	('plasma levels', 'MPA', (118, 131))	('tumor', 'Disease', (162, 167))	('high', 'Var', (107, 111))	('gliomas', 'Disease', (98, 105))	('improved', 'PosReg', (153, 161))	('bevacizumab', 'Chemical', 'MESH:D000068258', (48, 59))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))	('patients', 'Species', '9606', (63, 71))	('survival', 'CPA', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('MMP-2', 'Gene', (112, 117))
47999	25557107	HDAC4, a prognostic and chromosomal instability marker, refines the predictive value of MGMT promoter methylation Chromosomal instability is a hallmark of human cancers and is closely linked to tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Chromosomal instability', 'Var', (114, 137))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('linked', 'Reg', (184, 190))	('human', 'Species', '9606', (155, 160))	('cancers', 'Disease', (161, 168))	('chromosomal instability', 'Phenotype', 'HP:0040012', (24, 47))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('MGMT', 'Gene', (88, 92))	('HDAC4', 'Gene', '9759', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('HDAC4', 'Gene', (0, 5))	('tumor', 'Disease', (194, 199))	('MGMT', 'Gene', '4255', (88, 92))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Disease', (161, 167))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (114, 137))
48027	25557107	The relationship between CIN and multi-drug resistance can be explained by the increased heterogeneity in malignant cancers resulting from CIN, which increases the probability of a drug-resistant subclone arising in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('malignant cancers', 'Disease', (106, 123))	('CIN', 'Var', (139, 142))	('drug-resistant subclone', 'MPA', (181, 204))	('CIN', 'Phenotype', 'HP:0040012', (139, 142))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('malignant cancers', 'Disease', 'MESH:D009369', (106, 123))	('CIN', 'Phenotype', 'HP:0040012', (25, 28))	('increases', 'PosReg', (150, 159))	('drug resistance', 'Phenotype', 'HP:0020174', (39, 54))
48048	24012342	The significance of this is the fact that the SCID is immunodeficient because of an inactivating mutation in the key DNA repair gene DNAPKcs (which is required for VDJ recombination during T and B cell development), and consequently all the tissues of the mouse are highly radiosensitive.	('SCID', 'Disease', (46, 50))	('immunodeficient', 'Disease', 'MESH:D007153', (54, 69))	('immunodeficient', 'Disease', (54, 69))	('inactivating mutation', 'Var', (84, 105))	('DNAPKcs', 'Gene', (133, 140))	('mouse', 'Species', '10090', (256, 261))	('SCID', 'Disease', 'MESH:D053632', (46, 50))
48070	24012342	We have shown that inhibition of HIF-1 (hypoxia inducible factor-1) abrogates this influx of macrophages into irradiated GBM xenografts and enhances the efficacy of radiation.	('hypoxia', 'Disease', (40, 47))	('influx of macrophages', 'MPA', (83, 104))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('inhibition', 'Var', (19, 29))	('HIF-1', 'Gene', '3091', (33, 38))	('efficacy of radiation', 'CPA', (153, 174))	('enhances', 'PosReg', (140, 148))	('HIF-1', 'Gene', (33, 38))	('abrogates', 'NegReg', (68, 77))
48081	24012342	Also mice that cannot mobilize bone marrow-derived EPCs due to defective Id genes (Id1+/- Id3-/- mice) show a marked inhibition of the growth of transplanted tumors, and normal tumor growth can be restored by transplanting normal bone marrow into these mice.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('inhibition', 'NegReg', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mice', 'Species', '10090', (5, 9))	('tumors', 'Disease', (158, 164))	('growth', 'CPA', (135, 141))	('tumor', 'Disease', (177, 182))	('Id3', 'Gene', '15903', (90, 93))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mice', 'Species', '10090', (97, 101))	('Id3', 'Gene', (90, 93))	('Id1', 'Gene', (83, 86))	('tumor', 'Disease', (158, 163))	('Id1', 'Gene', '15901', (83, 86))	('defective', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('Id genes', 'Gene', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mice', 'Species', '10090', (253, 257))
48086	24012342	The mobilization and trafficking of bone marrow derived cells to sites of ischemic injury has been shown to be regulated by HIF-1, and the recruitment of bone BMDCs is markedly reduced in HIF-1 knockout orthotopic GBM.	('HIF-1', 'Gene', '3091', (124, 129))	('knockout', 'Var', (194, 202))	('HIF-1', 'Gene', (124, 129))	('ischemic injury', 'Disease', (74, 89))	('reduced', 'NegReg', (177, 184))	('trafficking', 'CPA', (21, 32))	('mobilization', 'CPA', (4, 16))	('HIF-1', 'Gene', '3091', (188, 193))	('ischemic injury', 'Disease', 'MESH:D003324', (74, 89))	('recruitment', 'CPA', (139, 150))	('HIF-1', 'Gene', (188, 193))
48087	24012342	Further HIF-1 knockout sensitizes tumors to irradiation without any effect on the intrinsic radiosensitivity of the tumor cells and pharmacological HIF-1 inhibition also sensitizes tumors to irradiation.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('HIF-1 inhibition also sensitizes tumors', 'Disease', (148, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('HIF-1', 'Gene', '3091', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('HIF-1', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('HIF-1', 'Gene', '3091', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', (181, 187))	('HIF-1', 'Gene', (148, 153))	('sensitizes', 'Reg', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (34, 40))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('HIF-1 inhibition also sensitizes tumors', 'Disease', 'MESH:C565433', (148, 187))	('knockout', 'Var', (14, 22))
48088	24012342	Consistent with these results from the literature we showed that post-irradiation treatment of mice with the HIF-1 inhibitor NSC-134754 markedly sensitizes intracranial U251 GBM tumors to irradiation and blocks the radiation-induced uptake of CD11b+ monocytes into the tumors (Figure 3).	('sensitizes', 'Reg', (145, 155))	('U251', 'Gene', (169, 173))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('rat', 'Species', '10116', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('HIF-1', 'Gene', '3091', (109, 114))	('tumors', 'Disease', (269, 275))	('radiation-induced uptake of CD11b+ monocytes into', 'CPA', (215, 264))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('blocks', 'NegReg', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('HIF-1', 'Gene', (109, 114))	('NSC-134754', 'Var', (125, 135))
48096	24012342	Originally developed as a therapy against HIV, AMD3100 was unexpectedly found to mobilize CD34+ hematopoietic stem cells from the bone marrow into the blood stream.	('CD34', 'Gene', '12490', (90, 94))	('mobilize', 'CPA', (81, 89))	('AMD3100', 'Var', (47, 54))	('CD34', 'Gene', (90, 94))	('AMD3100', 'Chemical', 'MESH:C088327', (47, 54))
48104	24012342	We hypothesized therefore that blocking the interaction of SDF-1 with CXCR7 could also block vasculogenesis and improve tumor control by irradiation.	('improve', 'PosReg', (112, 119))	('SDF-1', 'Gene', (59, 64))	('block', 'NegReg', (87, 92))	('blocking', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CXCR7', 'Gene', (70, 75))	('vasculogenesis', 'CPA', (93, 107))	('interaction', 'Interaction', (44, 55))	('tumor', 'Disease', (120, 125))	('CXCR7', 'Gene', '12778', (70, 75))
48112	24012342	NOX-A12 inhibits SDF-1 with subnanomolar affinity and should therefore inhibit SDF-1 mediated activation of both receptors, CXCR4 and CXCR7.	('NOX-A12', 'Var', (0, 7))	('CXCR4', 'Gene', (124, 129))	('inhibit', 'NegReg', (71, 78))	('inhibits', 'NegReg', (8, 16))	('CXCR7', 'Gene', (134, 139))	('SDF-1', 'Gene', (79, 84))	('SDF-1', 'Gene', (17, 22))	('activation', 'MPA', (94, 104))	('CXCR7', 'Gene', '12778', (134, 139))	('CXCR4', 'Gene', '12767', (124, 129))
48129	23677714	Over expression of constitutive Cdc42 (Q61L) using transient transfection in U-87 MG cells induced a partial cell migration, but did not affected the degradation of the protein levels of Cdc42 after luteolin treatment.	('partial cell migration', 'CPA', (101, 123))	('Cdc42', 'Gene', '998', (187, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (77, 84))	('Cdc42', 'Gene', '998', (32, 37))	('Cdc42', 'Gene', (187, 192))	('Cdc42', 'Gene', (32, 37))	('Q61L', 'Var', (39, 43))	('Q61L', 'Mutation', 'p.Q61L', (39, 43))	('luteolin', 'Chemical', 'MESH:D047311', (199, 207))
48130	23677714	Moreover, inhibition of the proteaosome pathway by MG132 caused a significant recovery in the migration ability of U-87 MG cells and augmented the Cdc42 protein levels after luteolin treatment, suggesting that pharmacological inhibition of migration via luteolin treatment is likely to preferentially facilitate the protein degradation of Cdc42.	('Cdc42', 'Gene', (339, 344))	('protein degradation', 'MPA', (316, 335))	('inhibition', 'NegReg', (10, 20))	('Cdc42', 'Gene', (147, 152))	('MG132', 'Chemical', 'MESH:C072553', (51, 56))	('luteolin', 'Chemical', 'MESH:D047311', (254, 262))	('MG132', 'Var', (51, 56))	('U-87 MG', 'CellLine', 'CVCL:0022', (115, 122))	('Cdc42', 'Gene', '998', (339, 344))	('migration ability', 'CPA', (94, 111))	('Cdc42', 'Gene', '998', (147, 152))	('facilitate', 'PosReg', (301, 311))	('recovery', 'PosReg', (78, 86))	('luteolin', 'Chemical', 'MESH:D047311', (174, 182))	('migration', 'CPA', (240, 249))	('proteaosome', 'Enzyme', (28, 39))	('augmented', 'PosReg', (133, 142))
48155	23677714	Stock solutions of luteolin were prepared in DMSO and stored at -20  C. Cycloeximide (CHX) (#C4859) and MG132 (Z-Leu-Leu-Leu-al) (#C2211) from Sigma-Aldrich (USA).	('Cycloeximide', 'Chemical', '-', (72, 84))	('Leu', 'Chemical', 'MESH:D007930', (117, 120))	('Leu', 'Chemical', 'MESH:D007930', (121, 124))	('luteolin', 'Chemical', 'MESH:D047311', (19, 27))	('DMSO', 'Chemical', 'MESH:D004121', (45, 49))	('MG132', 'Chemical', 'MESH:C072553', (104, 109))	('#C2211', 'Var', (130, 136))	('#C4859', 'Var', (92, 98))	('Leu', 'Chemical', 'MESH:D007930', (113, 116))	('CHX', 'Chemical', 'MESH:D003513', (86, 89))
48157	23677714	Human glioblastoma cell line (U-87 MG and T98G), and HUVECs used in this study was obtained from the American type culture collection (ATCC, Manassas, VA).	('Human', 'Species', '9606', (0, 5))	('U-87 MG', 'CellLine', 'CVCL:0022', (30, 37))	('glioblastoma', 'Disease', (6, 18))	('T98G', 'CellLine', 'CVCL:0556', (42, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (6, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (6, 18))	('T98G', 'Var', (42, 46))
48197	23677714	These results suggested that although luteolin (30 muM) treatment did not significantly affect the cellular viability, the luteolin inhibited the cell migration and invasion in U-87 MG and T98G cells.	('luteolin', 'Chemical', 'MESH:D047311', (38, 46))	('inhibited', 'NegReg', (132, 141))	('luteolin', 'Var', (123, 131))	('muM', 'Gene', '56925', (51, 54))	('T98G', 'CellLine', 'CVCL:0556', (189, 193))	('muM', 'Gene', (51, 54))	('luteolin', 'Chemical', 'MESH:D047311', (123, 131))	('U-87 MG', 'CellLine', 'CVCL:0022', (177, 184))
48199	23677714	We noted that ERK1/2 was inactivated using the MEK inhibitor, U0126, the cell migration was significantly inhibited (Fig.	('MEK', 'Gene', (47, 50))	('MEK', 'Gene', '5609', (47, 50))	('U0126', 'Chemical', 'MESH:C113580', (62, 67))	('inhibited', 'NegReg', (106, 115))	('cell migration', 'CPA', (73, 87))	('U0126', 'Var', (62, 67))
48201	23677714	The quantification of migratory ability of U-87 MG cells treated with U0126 or luteolin was significant decreased to 37.5 and 31.5 %, respectively.	('migratory ability', 'CPA', (22, 39))	('U0126', 'Chemical', 'MESH:C113580', (70, 75))	('U-87 MG', 'CellLine', 'CVCL:0022', (43, 50))	('decreased', 'NegReg', (104, 113))	('U0126', 'Var', (70, 75))	('luteolin', 'Chemical', 'MESH:D047311', (79, 87))
48203	23677714	3c, the protein expressions of phosphorylated ERK1/2 (p-ERK) were significantly reduced after U0126 treatment.	('U0126', 'Var', (94, 99))	('ERK', 'Gene', '5594', (46, 49))	('ERK', 'Gene', (56, 59))	('ERK', 'Gene', (46, 49))	('U0126', 'Chemical', 'MESH:C113580', (94, 99))	('reduced', 'NegReg', (80, 87))	('protein expressions', 'MPA', (8, 27))	('ERK', 'Gene', '5594', (56, 59))
48207	23677714	3d, the single treatment of U0126 or luteolin have a significantly similar inhibitory of migration, and cotreatment showed a synergy inhibitory effect of migration in U-87 MG cells (Fig.	('U0126', 'Chemical', 'MESH:C113580', (28, 33))	('U-87 MG', 'CellLine', 'CVCL:0022', (167, 174))	('luteolin', 'Chemical', 'MESH:D047311', (37, 45))	('U0126', 'Var', (28, 33))	('migration', 'CPA', (89, 98))	('migration', 'CPA', (154, 163))	('inhibitory', 'NegReg', (75, 85))
48208	23677714	In addition, we also examined the cellular cytotoxicity of U0126 at 30 muMu concentration and did not significantly affected in the growth of U-87 MG cells (Fig.	('muM', 'Gene', (71, 74))	('U0126', 'Chemical', 'MESH:C113580', (59, 64))	('cytotoxicity', 'Disease', (43, 55))	('U0126', 'Var', (59, 64))	('muM', 'Gene', '56925', (71, 74))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('U-87 MG', 'CellLine', 'CVCL:0022', (142, 149))
48211	23677714	The results showed that filopodia assembly in U-87 MG was abolished by luteolin (30 muM) (Fig.	('U-87 MG', 'CellLine', 'CVCL:0022', (46, 53))	('abolished', 'NegReg', (58, 67))	('filopodia assembly', 'CPA', (24, 42))	('luteolin', 'Chemical', 'MESH:D047311', (71, 79))	('muM', 'Gene', '56925', (84, 87))	('U-87 MG', 'Var', (46, 53))	('muM', 'Gene', (84, 87))
48232	23677714	More specifically, MG132 provided a prevention to against the degradation of Cdc42 by luteolin treatment in U-87 MG cells, some similar to control group (Fig.	('Cdc42', 'Gene', '998', (77, 82))	('luteolin', 'Chemical', 'MESH:D047311', (86, 94))	('prevention', 'NegReg', (36, 46))	('Cdc42', 'Gene', (77, 82))	('MG132', 'Chemical', 'MESH:C072553', (19, 24))	('U-87 MG', 'CellLine', 'CVCL:0022', (108, 115))	('MG132', 'Var', (19, 24))	('degradation', 'MPA', (62, 73))
48258	23677714	In addition, AKT is downstream serine/threonine kinase in the RTK/PTEN/PI3K pathway and large scale genomic analysis of GBM has demonstrated that this pathway is mutated in the majority of GBMs.	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('mutated', 'Var', (162, 169))	('PI3', 'Gene', (71, 74))	('AKT', 'Gene', '207', (13, 16))	('PI3', 'Gene', '5266', (71, 74))	('AKT', 'Gene', (13, 16))
48272	23677714	Consequently, a novel luteolin-mediated inhibitory of migration pathway is proposed that luteolin inhibited the invasion and migration of glioblastoma cells is likely to inhibite PI3K/AKT activation and facilitate protein degradation of Cdc42 via the proteaosome degradation pathway.	('facilitate', 'PosReg', (203, 213))	('proteaosome degradation pathway', 'Pathway', (251, 282))	('Cdc42', 'Gene', (237, 242))	('inhibited', 'NegReg', (98, 107))	('luteolin', 'Var', (89, 97))	('AKT', 'Gene', '207', (184, 187))	('PI3', 'Gene', '5266', (179, 182))	('inhibite', 'NegReg', (170, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('glioblastoma', 'Disease', (138, 150))	('AKT', 'Gene', (184, 187))	('protein degradation', 'MPA', (214, 233))	('Cdc42', 'Gene', '998', (237, 242))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('luteolin', 'Chemical', 'MESH:D047311', (22, 30))	('luteolin', 'Chemical', 'MESH:D047311', (89, 97))	('PI3', 'Gene', (179, 182))
48296	32692442	Furthermore, gene annotation of binding peaks in promoter regions and integration with gene expression data of ZEB1 knockdown compared to control MDA-MB-231 cells (Lehmann et al, 2016) corroborated both direct repressive and direct activating functions of ZEB1 (Fig EV1D and E).	('ZEB1', 'Gene', (111, 115))	('knockdown', 'Var', (116, 125))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (146, 156))	('expression', 'Species', '29278', (92, 102))	('activating', 'MPA', (232, 242))
48324	32692442	We assessed their differential expression levels in the aforementioned transcriptome analysis of ZEB1 knockdown compared to control MDA-MB-231 cells (Lehmann et al, 2016).	('ZEB1', 'Gene', (97, 101))	('expression', 'Species', '29278', (31, 41))	('knockdown', 'Var', (102, 111))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (132, 142))
48333	32692442	Transient siRNA-mediated knockdown of ZEB1 and to a lesser extent also FOSL1 and YAP inhibited TGFbeta-mediated activation (Fig 4A).	('TGFbeta', 'Gene', (95, 102))	('inhibited', 'NegReg', (85, 94))	('YAP', 'Gene', '10413', (81, 84))	('TGFbeta', 'Gene', '7039', (95, 102))	('YAP', 'Gene', (81, 84))	('FOSL1', 'Gene', (71, 76))	('ZEB1', 'Gene', (38, 42))	('knockdown', 'Var', (25, 34))	('FOSL1', 'Gene', '8061', (71, 76))
48351	32692442	Neither deletion nor mutation of the ZEB1 motif resulted in altered luciferase activity after overexpression of different combinations of ZEB1, YAP, FOSL1 and JUN factors.	('activity', 'MPA', (79, 87))	('YAP', 'Gene', (144, 147))	('ZEB1', 'Gene', (37, 41))	('luciferase', 'Enzyme', (68, 78))	('mutation', 'Var', (21, 29))	('FOSL1', 'Gene', (149, 154))	('FOSL1', 'Gene', '8061', (149, 154))	('expression', 'Species', '29278', (98, 108))	('YAP', 'Gene', '10413', (144, 147))	('deletion', 'Var', (8, 16))
48354	32692442	Importantly, direct DNA binding of recombinant ZEB1 via its C-terminal zinc finger domain occurred only at the double Z-box motif but not at the TEAD or the AP-1 motif (Fig 5D).	('TE', 'Chemical', 'MESH:D013691', (145, 147))	('double', 'Var', (111, 117))	('DNA binding', 'Interaction', (20, 31))	('ZEB1', 'Gene', (47, 51))
48357	32692442	In order to assess how ZEB1 affects chromatin status, we performed ATAC-seq on wild-type, control and ZEB1 knockdown MDA-MB-231 cells.	('knockdown', 'Var', (107, 116))	('ZEB1', 'Gene', (102, 106))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (117, 127))
48374	32692442	In this context, high expression of ZEB1 was strongly associated with reduced distant metastasis-free survival (DMFS), the major cause of poor clinical outcome (Fig 8A).	('reduced', 'NegReg', (70, 77))	('ZEB1', 'Gene', (36, 40))	('distant metastasis-free survival', 'CPA', (78, 110))	('high expression', 'Var', (17, 32))	('expression', 'Species', '29278', (22, 32))
48402	32692442	Particularly, co-expression of ZEB1 and FOSL1 in breast cancer cells marks the highly aggressive claudin-low subtype, and importantly, the lack of one of the two factors is enough to classify them to another clinically established subtype (Fig 7A and B).	('ZEB1', 'Gene', (31, 35))	('expression', 'Species', '29278', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('claudin-low subtype', 'Disease', (97, 116))	('co-expression', 'Var', (14, 27))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('FOSL1', 'Gene', (40, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('FOSL1', 'Gene', '8061', (40, 45))
48403	32692442	In patient samples from hormone receptor negative breast cancers, which are in general associated with poor clinical outcome (Foulkes et al, 2010), high expression of ZEB1 predicts an additional increased risk for distant metastasis and therapy relapse, possibly by selecting for the claudin-low subtype.	('distant metastasis', 'CPA', (214, 232))	('breast cancers', 'Disease', 'MESH:D001943', (50, 64))	('hormone receptor', 'Gene', (24, 40))	('hormone receptor', 'Gene', '3164', (24, 40))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('patient', 'Species', '9606', (3, 10))	('ZEB1', 'Gene', (167, 171))	('expression', 'Species', '29278', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (50, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('therapy relapse', 'CPA', (237, 252))	('high expression', 'Var', (148, 163))	('breast cancers', 'Disease', (50, 64))
48426	32692442	The ANKRD1 luciferase reporter plasmids (wild type, del Z-box) were generated by amplifying the ANKRD1 promoter (-425 to +120 and +73, respectively, rel.	('ANKRD1', 'Gene', '27063', (4, 10))	('ANKRD1', 'Gene', (96, 102))	('ANKRD1', 'Gene', '27063', (96, 102))	('-425 to +120', 'Var', (113, 125))	('ANKRD1', 'Gene', (4, 10))
48427	32692442	Mutation of the Z-Box was introduced by QuickchangeII site-directed mutagenesis (Ambion) of the ANKRD1 wild-type promoter construct using the complementary primer pair as shown in Appendix Table S11.	('ANKRD1', 'Gene', (96, 102))	('mutagenesis', 'Var', (68, 79))	('ANKRD1', 'Gene', '27063', (96, 102))
48428	32692442	For the DOCK9 luciferase reporter vector, the chromosomal region chr13:99,719,488-99,719,923 (hg19) was amplified from BAC DNA (RPCIB753F20107Q, Source Bioscience).	('DOCK9', 'Gene', '23348', (8, 13))	('DOCK9', 'Gene', (8, 13))	('RPCIB753F20107Q', 'Var', (128, 143))	('chr13:99,719,488-99,719,923', 'STRUCTURAL_ABNORMALITY', 'None', (65, 92))
48434	32692442	Cells were washed twice with cold PBS, scraped off and centrifuged (300 g, 5 min, 4 C).	('cold PBS', 'Disease', (29, 37))	('cold PBS', 'Disease', 'MESH:D011535', (29, 37))	('300 g', 'Var', (68, 73))
48447	32692442	siRNAs were obtained from Ambion (Silencer Select siRNAs) with the following sequences: hs ZEB1, 5'-GGUAGAUGGUAAUGUAAUATT-3' (s229971); hs FOSL1, 5'-CCAUCUGCAAAAUCCCGGAtt-3' (s15585); hs siJUN, 5'-GGCACAGCUUAAACAGAAAtt-3' (s7658); hs siYAP, 5'-AGAGAUACUUCUUCUUAAAUCAtt-3'; Silencer Select Negative Control #1 siRNA (4390844).	('siJUN', 'Disease', 'None', (187, 192))	('YAP', 'Gene', '10413', (236, 239))	('s7658', 'Var', (223, 228))	('FOSL1', 'Gene', (139, 144))	('FOSL1', 'Gene', '8061', (139, 144))	('YAP', 'Gene', (236, 239))	('siJUN', 'Disease', (187, 192))
48451	32692442	Primary antibodies against ZEB1 (1:300, Sigma-Prestige, HPA027524), JUN (1:100, DB Biosciences, 610327), FOSL1 (1:100, Santa Cruz, sc-28310) and TAZ (1:200, BD Biosciences, 560235) were diluted in blocking solution and incubated for 1 h at RT.	('1:100', 'Var', (73, 78))	('1:100', 'Var', (112, 117))	('TAZ', 'Gene', '6901', (145, 148))	('TAZ', 'Gene', (145, 148))	('FOSL1', 'Gene', (105, 110))	('FOSL1', 'Gene', '8061', (105, 110))
48452	32692442	Cells were washed twice and subsequently incubated with Alexa 488- and Alexa 594-conjugated secondary antibodies (Life Technologies, A-11037, A-11029, A-11034, 1:500 in blocking buffer) for 1 h at RT protected from the light.	('A-11029', 'Var', (142, 149))	('Alexa 594', 'Chemical', 'MESH:C417664', (71, 80))	('A-11034', 'Var', (151, 158))	('Alexa 488', 'Chemical', '-', (56, 65))
48486	32692442	In brief, two stable MDA-MB-231 knockdown clones for ZEB1 (shZEB1) were compared to two control clones (shCtrl).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (21, 31))	('knockdown', 'Var', (32, 41))	('ZEB1', 'Gene', (53, 57))	('hZEB1', 'Gene', '6935', (60, 65))	('hZEB1', 'Gene', (60, 65))
48514	32692442	The following microarray probes were used for each gene: 212764_at for ZEB1, 204420_at for FOSL1, 201464_x_at for JUN, 212298_at for NRP1, 209101_at for CTGF, 201110_s_at for THBS1, 201289_at for CYR61, 212233_at for MAP1B, 201506_at for TGFBI, 200872_at for S100A10, 218995_s_at for EDN1 and 208112_x_at for EHD1.	('200872_at', 'Var', (245, 254))	('204420_at', 'Var', (77, 86))	('HD', 'Disease', 'MESH:D006816', (310, 312))	('201110_s_at', 'Var', (159, 170))	('201289_at', 'Var', (182, 191))	('212233_at', 'Var', (203, 212))	('218995_s_at', 'Var', (268, 279))	('EDN1', 'Gene', (284, 288))	('201464_x_at', 'Var', (98, 109))	('212764_at', 'Var', (57, 66))	('212298_at', 'Var', (119, 128))	('208112_x_at', 'Var', (293, 304))	('FOSL1', 'Gene', (91, 96))	('201506_at', 'Var', (224, 233))	('FOSL1', 'Gene', '8061', (91, 96))
48521	30976053	The examination of these mutations in the context of pathways and gene sets is an essential issue in cancer genome research.	('cancer', 'Disease', (101, 107))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
48546	30976053	1 illustrates coMut plots of the somatic mutations in the apoptosis pathway obtained from the breast cancer (BC) mutation data and in the ErbB pathway obtained from glioblastoma (GBM) mutation data.	('mutations', 'Var', (41, 50))	('mutation', 'Var', (113, 121))	('BC', 'Phenotype', 'HP:0003002', (109, 111))	('glioblastoma', 'Disease', (165, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (165, 177))	('GBM', 'Phenotype', 'HP:0012174', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (165, 177))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('apoptosis pathway', 'Pathway', (58, 75))	('ErbB', 'Gene', (138, 142))	('breast cancer', 'Disease', (94, 107))	('ErbB', 'Gene', '1956', (138, 142))
48557	30976053	Mutations in EGFR, KRAS, and TP53 are vital in lung cancer biology, and the molecular alterations associated with these mutation profiles have been widely investigated.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (29, 33))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
48560	30976053	For k = 10, we found that the gene set (ABL1, EGFR, KRAS, MKNK2, NF1, PAK6, PTEN, STK11, TERT, TP53) was mutated in 145 patients (Fig.	('KRAS', 'Gene', '3845', (52, 56))	('EGFR', 'Gene', '1956', (46, 50))	('ABL1', 'Gene', (40, 44))	('STK11', 'Gene', (82, 87))	('KRAS', 'Gene', (52, 56))	('PTEN', 'Gene', (76, 80))	('ABL1', 'Gene', '25', (40, 44))	('TP53', 'Gene', '7157', (95, 99))	('PAK6', 'Gene', (70, 74))	('STK11', 'Gene', '6794', (82, 87))	('PTEN', 'Gene', '5728', (76, 80))	('MKNK2', 'Gene', (58, 63))	('mutated', 'Var', (105, 112))	('EGFR', 'Gene', (46, 50))	('NF1', 'Gene', '4763', (65, 68))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('MKNK2', 'Gene', '2872', (58, 63))	('patients', 'Species', '9606', (120, 128))	('NF1', 'Gene', (65, 68))	('PAK6', 'Gene', '56924', (70, 74))	('TP53', 'Gene', (95, 99))
48562	30976053	The subset (KRAS, EGFR, STK11, PTEN, TP53) covering 133 patients is a subset of the PI3K-Akt signalling pathway, and PI3K-Akt pathway mutations involved in tumourigenesis have been reported for LUAD.	('PTEN', 'Gene', (31, 35))	('patients', 'Species', '9606', (56, 64))	('LUAD', 'Disease', (194, 198))	('KRAS', 'Gene', '3845', (12, 16))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('TP53', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (31, 35))	('EGFR', 'Gene', (18, 22))	('KRAS', 'Gene', (12, 16))	('mutations', 'Var', (134, 143))	('STK11', 'Gene', (24, 29))	('Akt', 'Gene', (89, 92))	('TP53', 'Gene', '7157', (37, 41))	('Akt', 'Gene', (122, 125))	('EGFR', 'Gene', '1956', (18, 22))	('Akt', 'Gene', '207', (89, 92))	('Akt', 'Gene', '207', (122, 125))	('LUAD', 'Phenotype', 'HP:0030078', (194, 198))	('STK11', 'Gene', '6794', (24, 29))
48569	30976053	The subset (ABL1, EGFR, KRAS, PAK6) which was mutated in 94 patients, forms part of the ErbB signalling pathway, which involves a family of tyrosine kinases and has been confirmed to be vital for the development of LUAD.	('KRAS', 'Gene', '3845', (24, 28))	('EGFR', 'Gene', '1956', (18, 22))	('ErbB', 'Gene', (88, 92))	('patients', 'Species', '9606', (60, 68))	('PAK6', 'Gene', '56924', (30, 34))	('mutated', 'Var', (46, 53))	('ErbB', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', (18, 22))	('PAK6', 'Gene', (30, 34))	('LUAD', 'Disease', (215, 219))	('ABL1', 'Gene', '25', (12, 16))	('LUAD', 'Phenotype', 'HP:0030078', (215, 219))	('ABL1', 'Gene', (12, 16))	('KRAS', 'Gene', (24, 28))
48573	30976053	For example, the co-mutation (overlaps) of TP53 and NF1 has been known to be the feature of the PI subtype of LUAD.	('co-mutation', 'Var', (17, 28))	('NF1', 'Gene', (52, 55))	('LUAD', 'Disease', (110, 114))	('NF1', 'Gene', '4763', (52, 55))	('LUAD', 'Phenotype', 'HP:0030078', (110, 114))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
48575	30976053	As expected, the robustness of AWRMP degenerated with increases in d. By observing the number of the times that ten genes of the optimal gene set were identified in the 100 runs of the disturbance test, we found that the subset (EGFR, KRAS, STK11, TP53, NF1) was always identified, even for d = 50 (Fig.	('TP53', 'Gene', '7157', (248, 252))	('d =', 'Var', (291, 294))	('TP53', 'Gene', (248, 252))	('STK11', 'Gene', (241, 246))	('KRAS', 'Gene', (235, 239))	('EGFR', 'Gene', '1956', (229, 233))	('EGFR', 'Gene', (229, 233))	('KRAS', 'Gene', '3845', (235, 239))	('NF1', 'Gene', (254, 257))	('STK11', 'Gene', '6794', (241, 246))	('NF1', 'Gene', '4763', (254, 257))
48580	30976053	For the BC mutation data, AWRMP identified the parsimonious set (AKT1, BRCA2, GATA3, MAP3K1, PIK3CA TP53, RGS1(A), where "(A)" refers to amplification) with a high coverage score of 0.86 and a low overlap score of 0.45 (Supplementary Fig.	('TP53', 'Gene', '7157', (100, 104))	('mutation', 'Var', (11, 19))	('PIK3CA', 'Gene', '5290', (93, 99))	('AKT1', 'Gene', '207', (65, 69))	('MAP3K1', 'Gene', (85, 91))	('RGS1', 'Gene', '5996', (106, 110))	('RGS1', 'Gene', (106, 110))	('TP53', 'Gene', (100, 104))	('BRCA2', 'Gene', (71, 76))	('AKT1', 'Gene', (65, 69))	('GATA3', 'Gene', (78, 83))	('MAP3K1', 'Gene', '4214', (85, 91))	('BRCA2', 'Gene', '675', (71, 76))	('PIK3CA', 'Gene', (93, 99))	('GATA3', 'Gene', '2625', (78, 83))	('BC', 'Phenotype', 'HP:0003002', (8, 10))
48581	30976053	Among these genes, BRCA2 truncating mutations have been associated with an increased risk of BC.	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('BRCA2', 'Gene', (19, 24))	('truncating mutations', 'Var', (25, 45))	('associated', 'Reg', (56, 66))	('BRCA2', 'Gene', '675', (19, 24))
48585	30976053	The relation between RGS1 mutation and BC has been discovered in.	('RGS1', 'Gene', '5996', (21, 25))	('RGS1', 'Gene', (21, 25))	('BC', 'Phenotype', 'HP:0003002', (39, 41))	('mutation', 'Var', (26, 34))
48587	30976053	Among these genes, NF1 is a human glioblastoma suppressor gene, and patients harbouring NF1 mutation or deletion tended to show decreased PKC pathway activity and elevated MAP kinase activity.	('elevated', 'PosReg', (163, 171))	('mutation', 'Var', (92, 100))	('NF1', 'Gene', (88, 91))	('NF1', 'Gene', (19, 22))	('human', 'Species', '9606', (28, 33))	('MAP kinase activity', 'MPA', (172, 191))	('NF1', 'Gene', '4763', (88, 91))	('PKC pathway', 'Pathway', (138, 149))	('NF1', 'Gene', '4763', (19, 22))	('patients', 'Species', '9606', (68, 76))	('glioblastoma', 'Disease', (34, 46))	('decreased', 'NegReg', (128, 137))	('glioblastoma', 'Disease', 'MESH:D005909', (34, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (34, 46))	('deletion', 'Var', (104, 112))	('activity', 'MPA', (150, 158))
48629	30583471	Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin.	('Original tumor', 'Disease', (0, 14))	('EGFR', 'Gene', '1956', (132, 136))	('CD56', 'Gene', '4684', (104, 108))	('vimentin', 'Gene', '7431', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('vimentin', 'Gene', (156, 164))	('EGFR', 'Gene', (132, 136))	('Ki67', 'Var', (138, 142))	('CD44', 'Gene', (98, 102))	('Ki67', 'Chemical', '-', (138, 142))	('CD56', 'Gene', (104, 108))	('Nestin', 'Gene', '10763', (144, 150))	('Nestin', 'Gene', (144, 150))	('Original tumor', 'Disease', 'MESH:D009369', (0, 14))
48637	30583471	Indeed, cyclin-dependent kinase inhibitors, including p15/INK4b, p16/INK4A, p21/Waf1, p27/Kip1, and Mouse double minute 2 homolog (MDM2), play a primordial role in this process.	('Mouse double minute 2 homolog', 'Gene', (100, 129))	('Kip1', 'Gene', (90, 94))	('INK4A', 'Gene', (69, 74))	('p15', 'Gene', '12579', (54, 57))	('INK4b', 'Gene', (58, 63))	('Kip1', 'Gene', '12576', (90, 94))	('p21/Waf1', 'Var', (76, 84))	('Mouse double minute 2 homolog', 'Gene', '17246', (100, 129))	('INK4A', 'Gene', '12578', (69, 74))	('INK4b', 'Gene', '12579', (58, 63))	('p15', 'Gene', (54, 57))
48638	30583471	Specific alterations affecting these pathways that include aberrant expression of oncogenes and tumor suppressor genes are shown to be correlated to tumor prognosis, disease progression, and cancer metastasis.	('cancer metastasis', 'Disease', 'MESH:D009362', (191, 208))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'MPA', (68, 78))	('correlated', 'Reg', (135, 145))	('aberrant', 'Var', (59, 67))	('oncogenes', 'Gene', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (96, 101))	('alterations', 'Var', (9, 20))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer metastasis', 'Disease', (191, 208))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
48639	30583471	Among them, amplification of several growth factor receptors, including EGFR, have been associated to a poor prognosis in GBM.	('EGFR', 'Gene', '1956', (72, 76))	('amplification', 'Var', (12, 25))	('EGFR', 'Gene', (72, 76))	('associated', 'Reg', (88, 98))	('GBM', 'Disease', (122, 125))
48651	30583471	Histone methylation involves specific lysine and arginine of H3 and H4 implied in the regulation of gene transcription and in the support of gene maintenance either on activation or on a repressive dynamic process.	('regulation', 'MPA', (86, 96))	('arginine', 'Var', (49, 57))	('lysine', 'Var', (38, 44))	('arginine', 'Chemical', 'MESH:D001120', (49, 57))	('lysine', 'Chemical', 'MESH:D008239', (38, 44))
48653	30583471	Concerning H3K9m2 level regulation, some KDM has been studied, such as LSD1 (KDM1), associated with demethylation of H3K9m1/m2, lysine-specific demethylase 4C (KDM4C/JMJD2C), and G9a, which demethylase H3K9m2/m3.	('KDM1', 'Gene', '23028', (77, 81))	('JMJD2C', 'Gene', (166, 172))	('KDM4C', 'Gene', '23081', (160, 165))	('KDM4C', 'Gene', (160, 165))	('G9a', 'Gene', '10919', (179, 182))	('lysine-specific demethylase 4C', 'Gene', (128, 158))	('JMJD2C', 'Gene', '23081', (166, 172))	('LSD1', 'Gene', (71, 75))	('associated', 'Reg', (84, 94))	('KDM1', 'Gene', (77, 81))	('G9a', 'Gene', (179, 182))	('LSD1', 'Gene', '23028', (71, 75))	('demethylation', 'MPA', (100, 113))	('H3K9m1/m2', 'Var', (117, 126))	('lysine-specific demethylase 4C', 'Gene', '23081', (128, 158))
48727	30583471	Furthermore, adherent R2J did not express CD56, a neuronal lineage marker, whereas the spheres expressed it, suggesting that R2J cells are more likely to differentiate into neurons than in astrocytes.	('CD56', 'Gene', (42, 46))	('CD56', 'Gene', '4684', (42, 46))	('R2J', 'Var', (125, 128))	('differentiate', 'CPA', (154, 167))
48740	30583471	Indeed, T98G is p53 mutation, has a positive MGMT status, and is resistant to TMZ.	('T98G', 'Var', (8, 12))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('TMZ', 'Chemical', 'MESH:D000077204', (78, 81))	('MGMT', 'Gene', (45, 49))	('MGMT', 'Gene', '4255', (45, 49))
48750	30583471	These results are essential as R2J cells expressed a high level of HDAC that plays an important role in gene expression associated to cell proliferation (p21/Waf1, p27/kip1, p16/ink4a) and apoptosis via Bad, Trail, and FasL in glioma cells.	('cell proliferation', 'CPA', (134, 152))	('Trail', 'Gene', (208, 213))	('p21/Waf1', 'Var', (154, 162))	('kip1', 'Gene', '1027', (168, 172))	('FasL', 'Gene', (219, 223))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('ink4a', 'Gene', (178, 183))	('Trail', 'Gene', '8743', (208, 213))	('FasL', 'Gene', '356', (219, 223))	('apoptosis', 'CPA', (189, 198))	('HDAC', 'Gene', (67, 71))	('ink4a', 'Gene', '1029', (178, 183))	('HDAC', 'Gene', '9734', (67, 71))	('kip1', 'Gene', (168, 172))	('glioma', 'Disease', (227, 233))
48753	30583471	To sustain an oxidative stress way of action and subsequent pathways, we showed that SS depleted thiol group concentration, in both R2J (p53 wild-type) and U251 (p53 mutant) cells, contrary to TMZ.	('depleted', 'NegReg', (88, 96))	('TMZ', 'Chemical', 'MESH:D000077204', (193, 196))	('SS', 'Chemical', 'MESH:D018038', (85, 87))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (137, 140))	('p53', 'Gene', '7157', (162, 165))	('oxidative stress', 'Phenotype', 'HP:0025464', (14, 30))	('thiol group concentration', 'MPA', (97, 122))	('mutant', 'Var', (166, 172))	('p53', 'Gene', (137, 140))	('thiol', 'Chemical', 'MESH:D013438', (97, 102))
48759	30583471	Epigenetic regulation of chromatin organization is a key regulator of gene expression that can significantly impact tumor biology and tumor response to therapies.	('impact', 'Reg', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Epigenetic regulation', 'Var', (0, 21))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (134, 139))
48760	30583471	In many tumor types, mutated or modified epigenetic regulators have been clearly associated to tumorigenesis because of their effects on gene expression (reviewed in), and this has led to the development of pharmacologic inhibitors specific of these actors.	('modified', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('epigenetic regulators', 'Protein', (41, 62))	('gene expression', 'MPA', (137, 152))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutated', 'Var', (21, 28))	('associated', 'Reg', (81, 91))	('effects', 'Reg', (126, 133))	('tumor', 'Disease', (95, 100))
48764	30583471	Therefore, our results led to the intriguing question: How do both these epigenetic modifications interact and would they be able to re-express suppressor tumor genes?	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('interact', 'Reg', (98, 106))	('tumor', 'Disease', (155, 160))	('epigenetic modifications', 'Var', (73, 97))
48766	30583471	Indeed, the pharmacologic inhibition or genetic depletion of G9a triggers the formation of LC3B-II, the aggregation of p62, and the formation of autophagosomes.	('p62', 'Gene', (119, 122))	('aggregation', 'CPA', (104, 115))	('autophagosomes', 'CPA', (145, 159))	('p62', 'Gene', '23636', (119, 122))	('G9a', 'Gene', (61, 64))	('triggers', 'Reg', (65, 73))	('G9a', 'Gene', '10919', (61, 64))	('LC3', 'Gene', '84557', (91, 94))	('LC3', 'Gene', (91, 94))	('genetic depletion', 'Var', (40, 57))	('formation', 'MPA', (78, 87))
48768	30583471	In addition, a recent study showed that BIX01294, an inhibitor of G9a, induced autophagy in glioma cells and stimulated differentiation of glioma stem cells (spheres cultivated without serum), associated with lower levels of H3K9m2 as the promoter of autophagy related genes.	('autophagy', 'CPA', (79, 88))	('differentiation', 'CPA', (120, 135))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Disease', (139, 145))	('lower', 'NegReg', (209, 214))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma', 'Disease', (92, 98))	('stimulated', 'PosReg', (109, 119))	('BIX01294', 'Var', (40, 48))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('BIX01294', 'Chemical', 'MESH:C518299', (40, 48))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('induced', 'PosReg', (71, 78))	('G9a', 'Gene', (66, 69))	('G9a', 'Gene', '10919', (66, 69))
48784	30583471	U251 was chosen due to its MGMT negative and p53 mutant status.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('mutant status', 'Var', (49, 62))	('MGMT', 'Gene', '4255', (27, 31))	('MGMT', 'Gene', (27, 31))
48821	30583471	Laser excitation and emission (adjusted with AOBS) were, respectively, 351-364/425-485 nm for Hoechst, 488/500-540 nm for FDA, and 543/600-650 nm for PI.	('488/500-540 nm', 'Var', (103, 117))	('351-364/425-485', 'Var', (71, 86))	('FDA', 'Chemical', 'MESH:C018506', (122, 125))	('AOBS', 'Disease', 'None', (45, 49))	('543/600-650 nm', 'Var', (131, 145))	('Hoechst', 'Chemical', '-', (94, 101))	('AOBS', 'Disease', (45, 49))
48871	29301607	Compared to GBM cells alone, invasion of GBM cells was increased by the presence of tMSLCs in the matrix (Fig.	('GBM', 'Phenotype', 'HP:0012174', (41, 44))	('increased', 'PosReg', (55, 64))	('tMSLCs', 'Chemical', '-', (84, 90))	('invasion of GBM cells', 'CPA', (29, 50))	('GBM', 'Phenotype', 'HP:0012174', (12, 15))	('tMSLCs', 'Var', (84, 90))
48881	29301607	After treatment with various chemical inhibitors against signaling pathways involved in GBM progression, we found that inhibition of JAK, SRC, or PIM1/2 suppresses the ability of tMSLCs to contract collagen gels (Fig.	('PIM1/2', 'Gene', '5292;11040', (146, 152))	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('suppresses', 'NegReg', (153, 163))	('tMSLCs', 'Chemical', '-', (179, 185))	('inhibition', 'Var', (119, 129))	('JAK', 'Gene', (133, 136))	('PIM1/2', 'Gene', (146, 152))	('SRC', 'Gene', '6714', (138, 141))	('SRC', 'Gene', (138, 141))
48883	29301607	Meanwhile, treatment with WP1066 inhibiting both JAK2 and STAT3 did not affect gel contraction (Fig.	('WP1066', 'Var', (26, 32))	('gel contraction', 'CPA', (79, 94))	('JAK2', 'Gene', '3717', (49, 53))	('STAT3', 'Gene', '6774', (58, 63))	('JAK2', 'Gene', (49, 53))	('inhibiting', 'NegReg', (33, 43))	('STAT3', 'Gene', (58, 63))
48888	29301607	However, targeting of STAT3 with siRNA or WP1066 consistently had no effect on gel contraction, proinvasive ECM remodeling, or collagen assembly (Fig.	('WP1066', 'Var', (42, 48))	('gel contraction', 'CPA', (79, 94))	('STAT3', 'Gene', '6774', (22, 27))	('proinvasive ECM remodeling', 'CPA', (96, 122))	('STAT3', 'Gene', (22, 27))	('collagen assembly', 'CPA', (127, 144))
48892	29301607	Abrogating JAK1 expression with two different siRNAs decreased MLC2 phosphorylation in tMSLCs (Fig.	('MLC2', 'Gene', (63, 67))	('Abrogating', 'Var', (0, 10))	('tMSLCs', 'Chemical', '-', (87, 93))	('decreased', 'NegReg', (53, 62))	('JAK1', 'Gene', (11, 15))	('expression', 'MPA', (16, 26))	('JAK1', 'Gene', '3716', (11, 15))	('MLC2', 'Gene', '4633', (63, 67))
48894	29301607	In view of these results, we further examined whether tMSLCs in GBM are also involved in actomyosin contractility by a similar regulatory mechanism that was seen in CAFs.	('tMSLCs', 'Var', (54, 60))	('involved', 'Reg', (77, 85))	('CAFs', 'Chemical', '-', (165, 169))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('GBM', 'Gene', (64, 67))	('tMSLCs', 'Chemical', '-', (54, 60))	('actomyosin contractility', 'MPA', (89, 113))
48895	29301607	Because ROCK activity is regulated by JAK1 in CAFs and participated in actomyosin contractility, we tested whether treatment with the ROCK inhibitor Y-27632 could diminish the effect of tMSLCs on gel contraction.	('gel contraction', 'CPA', (196, 211))	('diminish', 'NegReg', (163, 171))	('tMSLCs', 'Chemical', '-', (186, 192))	('participated in', 'Reg', (55, 70))	('actomyosin contractility', 'MPA', (71, 95))	('Y-27632', 'Var', (149, 156))	('Y-27632', 'Chemical', 'MESH:C108830', (149, 156))	('JAK1', 'Gene', (38, 42))	('tested', 'Reg', (100, 106))	('JAK1', 'Gene', '3716', (38, 42))	('CAFs', 'Chemical', '-', (46, 50))
48896	29301607	Importantly, the contractile force and p-MCL2 level in tMSLCs was decreased by treatment with Y-27632 in a dose-dependent manner (Fig.	('contractile force', 'CPA', (17, 34))	('Y-27632', 'Var', (94, 101))	('tMSLCs', 'Chemical', '-', (55, 61))	('decreased', 'NegReg', (66, 75))	('Y-27632', 'Chemical', 'MESH:C108830', (94, 101))	('p-MCL2 level', 'MPA', (39, 51))
48897	29301607	More importantly, treatment with Y-27632 diminished the ability of tMSLCs that assemble collagen and provide a proinvasive ECM condition (Fig.	('proinvasive', 'MPA', (111, 122))	('tMSLCs', 'Chemical', '-', (67, 73))	('diminished', 'NegReg', (41, 51))	('Y-27632', 'Var', (33, 40))	('Y-27632', 'Chemical', 'MESH:C108830', (33, 40))
48908	29301607	Because JAK1-mediated actomyosin contractility provided proinvasive ECM, we also examined whether inhibition of CCL2 attenuates the ability of tMSLCs that provide proinvasive ECM.	('tMSLCs', 'Chemical', '-', (143, 149))	('inhibition', 'Var', (98, 108))	('attenuates', 'NegReg', (117, 127))	('JAK1', 'Gene', (8, 12))	('JAK1', 'Gene', '3716', (8, 12))	('actomyosin contractility', 'MPA', (22, 46))	('CCL2', 'Gene', '6347', (112, 116))	('proinvasive ECM', 'MPA', (56, 71))	('CCL2', 'Gene', (112, 116))
48918	29301607	However, several strong lines of evidence have revealed that the mechanical aberrations could actively instruct malignant progression in cancer as well as providing physical track generation for migratory cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('migratory cancer', 'Disease', 'MESH:D010146', (195, 211))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('migratory cancer', 'Disease', (195, 211))	('cancer', 'Disease', (137, 143))	('instruct', 'NegReg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mechanical aberrations', 'Var', (65, 87))
48926	29301607	As further evidence, blocking JAK1 with either siRNA or pan-JAK inhibitor in tMSLCs effectively attenuated MLC2 phosphorylation and gel contraction, implicating that tMSLCs promote actomyosin contractility through JAK signaling.	('MLC2', 'Gene', '4633', (107, 111))	('attenuated', 'NegReg', (96, 106))	('blocking', 'Var', (21, 29))	('JAK1', 'Gene', (30, 34))	('MLC2', 'Gene', (107, 111))	('gel contraction', 'CPA', (132, 147))	('JAK1', 'Gene', '3716', (30, 34))	('tMSLCs', 'Chemical', '-', (77, 83))	('tMSLCs', 'Chemical', '-', (166, 172))	('promote', 'PosReg', (173, 180))	('actomyosin contractility', 'CPA', (181, 205))
48932	29301607	Aberrant cytokine signaling is a key feature of the tumor microenvironment.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Aberrant', 'Var', (0, 8))
48946	28379477	Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations.	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('FGFR3', 'Gene', '2261', (7, 12))	('FGFR3', 'Gene', '2261', (38, 43))	('fusions', 'Var', (44, 51))	('FGFR3', 'Gene', (7, 12))	('FGFR3', 'Gene', (38, 43))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))	('patients', 'Species', '9606', (185, 193))	('Inhibitors', 'Var', (71, 81))	('diffuse', 'Disease', (55, 62))
48950	28379477	Moderate to strong FGFR3 staining was detected in gliomas of all grades, was more common in females, and was associated with poor survival in diffuse astrocytomas.	('astrocytoma', 'Phenotype', 'HP:0009592', (150, 161))	('detected', 'Reg', (38, 46))	('astrocytomas', 'Disease', 'MESH:D001254', (150, 162))	('gliomas', 'Disease', (50, 57))	('astrocytomas', 'Disease', (150, 162))	('diffuse astrocytoma', 'Disease', 'MESH:D001254', (142, 161))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('FGFR3', 'Gene', '2261', (19, 24))	('diffuse astrocytoma', 'Disease', (142, 161))	('staining', 'Var', (25, 33))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('associated with', 'Reg', (109, 124))	('FGFR3', 'Gene', (19, 24))	('poor', 'NegReg', (125, 129))
48951	28379477	Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 15 strongly stained cases, whereas no fusions were found in 36 negatively to moderately stained cases.	('FGFR3', 'Gene', '2261', (58, 63))	('FGFR3', 'Gene', '2261', (31, 36))	('fusions', 'Var', (43, 50))	('FGFR3', 'Gene', (58, 63))	('TACC3', 'Gene', '10460', (37, 42))	('CAMK2A', 'Gene', '815', (64, 70))	('FGFR3', 'Gene', (31, 36))	('TACC3', 'Gene', (37, 42))	('CAMK2A', 'Gene', (64, 70))
48956	28379477	Strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a clinically applicable predictive marker for treatment regimens based on FGFR inhibitors.	('FGFR3', 'Gene', '2261', (7, 12))	('FGFR3', 'Gene', '2261', (49, 54))	('expression', 'MPA', (21, 31))	('FGFR3', 'Gene', (7, 12))	('FGFR3', 'Gene', (49, 54))	('protein', 'Protein', (13, 20))	('fusions', 'Var', (55, 62))
48957	28379477	FGFR3 gene fusions, initially discovered in glioblastoma, have since been reported in a wide spectrum of other malignancies.	('glioblastoma', 'Disease', (44, 56))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('FGFR3', 'Gene', '2261', (0, 5))	('FGFR3', 'Gene', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('fusions', 'Var', (11, 18))	('reported', 'Reg', (74, 82))	('malignancies', 'Disease', (111, 123))
48961	28379477	Fusions were only detected in aggressive isocitrate dehydrogenase wild-type tumors and were more common in female patients.	('Fusions', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('common', 'Reg', (97, 103))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('isocitrate dehydrogenase', 'Gene', '3417', (41, 65))	('isocitrate dehydrogenase', 'Gene', (41, 65))	('patients', 'Species', '9606', (114, 122))
48962	28379477	Interestingly, moderate to strong FGFR3 staining was associated with a lower MIB-1 proliferation index without any prognostic benefit.	('MIB-1', 'Gene', (77, 82))	('FGFR3', 'Gene', '2261', (34, 39))	('FGFR3', 'Gene', (34, 39))	('MIB-1', 'Gene', '57534', (77, 82))	('staining', 'Var', (40, 48))	('lower', 'NegReg', (71, 76))
48966	28379477	Diffuse gliomas can be currently stratified into 3 main categories based on isocitrate dehydrogenase (IDH) mutation status and the presence of 1p/19q codeletion.	('IDH', 'Gene', '3417', (102, 105))	('gliomas', 'Disease', (8, 15))	('isocitrate dehydrogenase', 'Gene', '3417', (76, 100))	('gliomas', 'Disease', 'MESH:D005910', (8, 15))	('gliomas', 'Phenotype', 'HP:0009733', (8, 15))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('IDH', 'Gene', (102, 105))	('mutation', 'Var', (107, 115))	('1p/19q codeletion', 'Var', (143, 160))	('isocitrate dehydrogenase', 'Gene', (76, 100))
48968	28379477	Since the discovery of recurrent fibroblast growth factor receptor (FGFR) gene fusions in glioblastoma (GBM),, targeted treatment regimens using FGFR inhibitors have arisen as a promising option for glioma patients with FGFR alterations.	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('glioma', 'Disease', 'MESH:D005910', (199, 205))	('patients', 'Species', '9606', (206, 214))	('GBM', 'Phenotype', 'HP:0012174', (104, 107))	('glioblastoma', 'Disease', (90, 102))	('glioma', 'Disease', (199, 205))	('fusions', 'Var', (79, 86))	('FGFR', 'Gene', (68, 72))
48969	28379477	Of those, oncogenic FGFR3 fusions and various FGFR1 alterations have been detected in brain tumors.	('FGFR3', 'Gene', '2261', (20, 25))	('alterations', 'Var', (52, 63))	('fusions', 'Var', (26, 33))	('FGFR3', 'Gene', (20, 25))	('detected', 'Reg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('FGFR1', 'Gene', (46, 51))	('brain tumors', 'Phenotype', 'HP:0030692', (86, 98))	('brain tumors', 'Disease', 'MESH:D001932', (86, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('FGFR1', 'Gene', '2260', (46, 51))	('brain tumors', 'Disease', (86, 98))
48970	28379477	In addition, FGFR fusions and other FGFR alterations have been detected in several extracranial malignancies., FGFR3 is most commonly fused to the transforming acidic coiled-coil protein 3 gene (TACC3), but other fusion partners also exist, such as recurrent FGFR3-BAIAP2L1 fusions in bladder cancer.	('TACC3', 'Gene', '10460', (195, 200))	('BAIAP2L1', 'Gene', (265, 273))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('TACC3', 'Gene', (195, 200))	('bladder cancer', 'Disease', (285, 299))	('BAIAP2L1', 'Gene', '55971', (265, 273))	('FGFR3', 'Gene', '2261', (111, 116))	('malignancies', 'Disease', (96, 108))	('fusions', 'Var', (274, 281))	('FGFR3', 'Gene', '2261', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('bladder cancer', 'Phenotype', 'HP:0009725', (285, 299))	('FGFR3', 'Gene', (111, 116))	('FGFR3', 'Gene', (259, 264))	('bladder cancer', 'Disease', 'MESH:D001749', (285, 299))
48971	28379477	Several FGFR inhibitors are currently being tested in clinical trials for different cancer types, and FGFR3 fusion-positive cells and tumors show the best treatment responses., Responses to FGFR inhibitor treatment have also been reported in GBM., Tumors that carry FGFR3 fusions or other responsive FGFR alterations represent a minority of cases in these malignancies, which emphasizes the need for efficient patient stratification tools, as also stated by others.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('FGFR3', 'Gene', (102, 107))	('alterations', 'Var', (305, 316))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Tumors', 'Disease', (248, 254))	('FGFR3', 'Gene', '2261', (102, 107))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))	('tumors', 'Disease', (134, 140))	('FGFR', 'Gene', (300, 304))	('Tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('malignancies', 'Disease', 'MESH:D009369', (356, 368))	('cancer', 'Disease', (84, 90))	('FGFR3', 'Gene', (266, 271))	('malignancies', 'Disease', (356, 368))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FGFR3', 'Gene', '2261', (266, 271))	('fusions', 'Var', (272, 279))	('patient', 'Species', '9606', (410, 417))	('Tumors', 'Phenotype', 'HP:0002664', (248, 254))
48973	28379477	High fusion protein levels have been reported in GBM,, most likely because the miR-99a binding site is removed by genomic rearrangements that generate FGFR3 fusions.	('removed', 'NegReg', (103, 110))	('FGFR3', 'Gene', '2261', (151, 156))	('GBM', 'Phenotype', 'HP:0012174', (49, 52))	('miR-99a', 'Gene', '407055', (79, 86))	('FGFR3', 'Gene', (151, 156))	('fusions', 'Var', (157, 164))	('miR-99a', 'Gene', (79, 86))
48974	28379477	The miR-99a-mediated suppression of FGFR3 may explain why activating FGFR3 mutations are not observed in diffuse gliomas.	('FGFR3', 'Gene', (36, 41))	('FGFR3', 'Gene', '2261', (69, 74))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('miR-99a', 'Gene', '407055', (4, 11))	('gliomas', 'Disease', (113, 120))	('FGFR3', 'Gene', (69, 74))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('mutations', 'Var', (75, 84))	('miR-99a', 'Gene', (4, 11))	('FGFR3', 'Gene', '2261', (36, 41))	('suppression', 'NegReg', (21, 32))
48978	28379477	Genetic alterations in FGFR3 and other glioma-associated genes were identified by targeted sequencing of selected cases.	('FGFR3', 'Gene', (23, 28))	('Genetic alterations', 'Var', (0, 19))	('glioma', 'Disease', (39, 45))	('FGFR3', 'Gene', '2261', (23, 28))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
48980	28379477	FGFR3 fusions involved several fusion partners, junctions, and breakpoints, rendering them difficult to detect in a comprehensive manner with PCR-based methods in a diagnostic context.	('FGFR3', 'Gene', '2261', (0, 5))	('involved', 'Reg', (14, 22))	('fusions', 'Var', (6, 13))	('FGFR3', 'Gene', (0, 5))
49007	28379477	Among samples with FGFR3 immunoreactivity, 68 (10%) showed weak, 21 (3.1%) moderate, and 12 (1.8%) strong positivity.	('FGFR3', 'Gene', '2261', (19, 24))	('immunoreactivity', 'Var', (25, 41))	('FGFR3', 'Gene', (19, 24))
49011	28379477	In the prognostic analysis, moderate and strong FGFR3 staining was associated with a significantly shorter cause-specific survival duration than weak and negative staining (P = .0417, n = 533, log-rank test) (Fig.	('shorter', 'NegReg', (99, 106))	('FGFR3', 'Gene', '2261', (48, 53))	('staining', 'Var', (54, 62))	('FGFR3', 'Gene', (48, 53))	('moderate', 'Var', (28, 36))	('cause-specific survival duration', 'CPA', (107, 139))
49012	28379477	Although the association remained significant after adjustment for grade, proliferation, and IDH1 p.R132H mutation status (P = .0422, Cox proportional hazards model) (Supplementary Table 3), no significant associations were observed when analysis was restricted to grade IV GBM (P = .203, n = 414, log-rank test) or cases lacking IDH1 p.R132H mutation (P = .119, n = 370 for grades II-IV astrocytomas and P = .525, n = 343 for GBMs, log-rank test) (Supplementary Figure 7), suggesting that the reduced survival of moderately to strongly stained cases is at least partly explained by their IDH1 mutation status and high proportion of glioblastoma tumors.	('IDH1', 'Gene', (589, 593))	('GBM', 'Phenotype', 'HP:0012174', (427, 430))	('reduced', 'NegReg', (494, 501))	('glioblastoma tumors', 'Disease', (633, 652))	('GBM', 'Phenotype', 'HP:0012174', (274, 277))	('glioblastoma', 'Phenotype', 'HP:0012174', (633, 645))	('survival', 'MPA', (502, 510))	('IDH1', 'Gene', '3417', (589, 593))	('astrocytomas', 'Disease', (388, 400))	('IDH1', 'Gene', (330, 334))	('IDH1', 'Gene', (93, 97))	('astrocytoma', 'Phenotype', 'HP:0009592', (388, 399))	('tumors', 'Phenotype', 'HP:0002664', (646, 652))	('p.R132H', 'Mutation', 'rs121913500', (98, 105))	('p.R132H', 'Mutation', 'rs121913500', (335, 342))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (633, 652))	('mutation status', 'Var', (594, 609))	('IDH1', 'Gene', '3417', (330, 334))	('tumor', 'Phenotype', 'HP:0002664', (646, 651))	('IDH1', 'Gene', '3417', (93, 97))	('astrocytomas', 'Disease', 'MESH:D001254', (388, 400))
49013	28379477	Indeed, moderate to strong FGFR3 staining was only observed in patients who lacked IDH1 p.R132H mutation, and all except one of them suffered from GBM in the survival analysis (Supplementary Figure 8).	('p.R132H mutation', 'Var', (88, 104))	('IDH1', 'Gene', '3417', (83, 87))	('FGFR3', 'Gene', '2261', (27, 32))	('p.R132H', 'Mutation', 'rs121913500', (88, 95))	('GBM', 'Phenotype', 'HP:0012174', (147, 150))	('FGFR3', 'Gene', (27, 32))	('suffered', 'Reg', (133, 141))	('patients', 'Species', '9606', (63, 71))	('IDH1', 'Gene', (83, 87))
49014	28379477	In the whole diffuse glioma cohort, we found only 3 IDH1 p.R132H-positive cases with moderate and none with strong FGFR3 staining (P = .0063, Fisher's exact test, for the IDH1 p.R132H staining association) (Fig.	('IDH1', 'Gene', '3417', (52, 56))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('p.R132H-positive', 'Var', (57, 73))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('p.R132H', 'Mutation', 'rs121913500', (57, 64))	('FGFR3', 'Gene', '2261', (115, 120))	('IDH1', 'Gene', (171, 175))	('glioma', 'Disease', (21, 27))	('FGFR3', 'Gene', (115, 120))	('IDH1', 'Gene', '3417', (171, 175))	('IDH1', 'Gene', (52, 56))	('p.R132H', 'Mutation', 'rs121913500', (176, 183))
49021	28379477	We analyzed all the patients with moderate to strong FGFR3 staining in whole-mount tissue slides and with enough tumor material for sequencing, but the cohort included also negatively to weakly stained cases.	('staining', 'Var', (59, 67))	('tumor', 'Disease', (113, 118))	('FGFR3', 'Gene', '2261', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('FGFR3', 'Gene', (53, 58))
49023	28379477	FGFR3 rearrangements that generated gene fusions were detected in 10 cases (Fig.	('gene fusions', 'MPA', (36, 48))	('FGFR3', 'Gene', (0, 5))	('rearrangements', 'Var', (6, 20))	('FGFR3', 'Gene', '2261', (0, 5))
49024	28379477	3A, Supplementary Table 4), including 9 FGFR3-TACC3 fusions and 1 FGFR3-CAMK2A fusion.	('CAMK2A', 'Gene', (72, 78))	('FGFR3', 'Gene', (40, 45))	('CAMK2A', 'Gene', '815', (72, 78))	('FGFR3', 'Gene', '2261', (66, 71))	('TACC3', 'Gene', '10460', (46, 51))	('FGFR3', 'Gene', (66, 71))	('TACC3', 'Gene', (46, 51))	('FGFR3', 'Gene', '2261', (40, 45))	('fusions', 'Var', (52, 59))
49025	28379477	In addition, case GBM-19 harbored an FGFR3 copy number gain (Fig.	('FGFR3', 'Gene', (37, 42))	('gain', 'PosReg', (55, 59))	('copy number', 'Var', (43, 54))	('FGFR3', 'Gene', '2261', (37, 42))	('GBM', 'Phenotype', 'HP:0012174', (18, 21))
49028	28379477	3C, Supplementary Figure 11), but the coiled-coil domain of TACC3 was conserved in FGFR3-TACC3 fusions.	('TACC3', 'Gene', '10460', (89, 94))	('TACC3', 'Gene', (60, 65))	('FGFR3', 'Gene', '2261', (83, 88))	('TACC3', 'Gene', (89, 94))	('fusions', 'Var', (95, 102))	('FGFR3', 'Gene', (83, 88))	('coiled-coil domain', 'MPA', (38, 56))	('TACC3', 'Gene', '10460', (60, 65))
49036	28379477	All cases with FGFR3 fusions were IDH wild-type, which is concordant with the results of previous reports.,  In addition, FGFR3 fusion events were mutually exclusive with amplification or mutation of epidermal growth factor receptor (EGFR)/platelet derived growth factor receptor alpha (PDGFRA)/MET (Fig.	('FGFR3', 'Gene', (15, 20))	('IDH', 'Gene', (34, 37))	('EGFR', 'Gene', (234, 238))	('platelet derived growth factor receptor alpha', 'Gene', '5156', (240, 285))	('IDH', 'Gene', '3417', (34, 37))	('mutation', 'Var', (188, 196))	('platelet derived growth factor receptor alpha', 'Gene', (240, 285))	('epidermal growth factor receptor', 'Gene', (200, 232))	('FGFR3', 'Gene', (122, 127))	('PDGFRA', 'Gene', (287, 293))	('amplification', 'Var', (171, 184))	('FGFR3', 'Gene', '2261', (15, 20))	('PDGFRA', 'Gene', '5156', (287, 293))	('epidermal growth factor receptor', 'Gene', '1956', (200, 232))	('EGFR', 'Gene', '1956', (234, 238))	('FGFR3', 'Gene', '2261', (122, 127))
49037	28379477	Mutual exclusivity between EGFR amplification and FGFR3-TACC3 fusions has been previously reported by us and others., Nearly all patients (7 of 8) with FGFR3-TACC3 fusions were female, the sole exception being a male patient with grade II oligoastrocytoma.	('EGFR', 'Gene', '1956', (27, 31))	('grade', 'Disease', (230, 235))	('II oligoastrocytoma', 'Disease', (236, 255))	('FGFR3', 'Gene', (50, 55))	('TACC3', 'Gene', (158, 163))	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (129, 137))	('FGFR3', 'Gene', '2261', (152, 157))	('patient', 'Species', '9606', (217, 224))	('TACC3', 'Gene', '10460', (158, 163))	('TACC3', 'Gene', '10460', (56, 61))	('TACC3', 'Gene', (56, 61))	('astrocytoma', 'Phenotype', 'HP:0009592', (244, 255))	('fusions', 'Var', (164, 171))	('FGFR3', 'Gene', (152, 157))	('FGFR3', 'Gene', '2261', (50, 55))	('II oligoastrocytoma', 'Disease', 'MESH:D001254', (236, 255))	('patient', 'Species', '9606', (129, 136))
49047	28379477	4A), suggesting that positive staining in the whole malignant tissue further supports the presence of FGFR3 fusion.	('FGFR3', 'Gene', (102, 107))	('FGFR3', 'Gene', '2261', (102, 107))	('fusion', 'Var', (108, 114))
49051	28379477	Surprisingly, astrocytoma cases with moderate to strong FGFR3 staining exhibited lower proliferation rates than negatively or weakly stained cases independently of tumor grade (P < .05, Kruskal-Wallis test) (Supplementary Figure 15a).	('staining', 'Var', (62, 70))	('tumor', 'Disease', (164, 169))	('lower', 'NegReg', (81, 86))	('FGFR3', 'Gene', '2261', (56, 61))	('Supplementary Figure 15a', 'Disease', (208, 232))	('astrocytoma', 'Disease', 'MESH:D001254', (14, 25))	('moderate', 'Var', (37, 45))	('astrocytoma', 'Disease', (14, 25))	('Supplementary Figure 15a', 'Disease', 'MESH:D017034', (208, 232))	('astrocytoma', 'Phenotype', 'HP:0009592', (14, 25))	('proliferation rates', 'CPA', (87, 106))	('FGFR3', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
49055	28379477	More detailed inspection of intratumoral FGFR3 staining patterns revealed that stronger FGFR3 staining was observed in less cellular tumor areas with higher differentiation state in a large proportion of fusion-negative cases but not in fusion-positive cases (P = .024, Fisher's exact test) (Fig.	('fusion-negative', 'Var', (204, 219))	('FGFR3', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('FGFR3', 'Gene', '2261', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('stronger', 'PosReg', (79, 87))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (33, 38))	('FGFR3', 'Gene', (41, 46))	('FGFR3', 'Gene', '2261', (88, 93))
49057	28379477	Our results demonstrate that FGFR3 staining, as detected using IHC, is indicative of FGFR3 gene fusion, which can be further confirmed by PCR- or sequencing-based technologies.	('FGFR3', 'Gene', (29, 34))	('FGFR3', 'Gene', (85, 90))	('fusion', 'Var', (96, 102))	('FGFR3', 'Gene', '2261', (29, 34))	('FGFR3', 'Gene', '2261', (85, 90))
49060	28379477	FGFR3 alterations will not be informative if the altered protein is not expressed.	('alterations', 'Var', (6, 17))	('FGFR3', 'Gene', (0, 5))	('FGFR3', 'Gene', '2261', (0, 5))
49065	28379477	Atypical oncogenic rearrangements, such as intragenic rearrangements in FGFR1, may also be difficult to detect, which might cause false negatives in sequencing analysis.	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', '2260', (72, 77))	('rearrangements', 'Var', (54, 68))
49072	28379477	In this study, FGFR3 fusions always involved 3' fusion partners with dimerization domains, and no FGFR3 staining was detected in the majority of samples (Fig.	('FGFR3', 'Gene', (15, 20))	('FGFR3', 'Gene', (98, 103))	("3' fusion partners", 'MPA', (45, 63))	('dimerization domains', 'MPA', (69, 89))	('FGFR3', 'Gene', '2261', (15, 20))	('fusions', 'Var', (21, 28))	('FGFR3', 'Gene', '2261', (98, 103))	('involved', 'Reg', (36, 44))
49077	28379477	), and funding from the US National Cancer Institute (R01 CA183153 to W.Z.).	('R01 CA183153', 'Var', (54, 66))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('Cancer', 'Disease', (36, 42))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))
49159	27145367	BIS depletion resulted in notable decreases in sphere-forming activity and was accompanied with decreases in SOX-2 expression.	('sphere-forming activity', 'CPA', (47, 70))	('decreases', 'NegReg', (34, 43))	('decreases', 'NegReg', (96, 105))	('SOX-2', 'Gene', (109, 114))	('depletion', 'Var', (4, 13))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('expression', 'MPA', (115, 125))	('SOX-2', 'Gene', '6657', (109, 114))	('BIS', 'Chemical', 'MESH:D001729', (0, 3))
49163	27145367	BIS depletion also affected epithelial-to-mesenchymal transition-related genes as evidenced by decrease in SNAIL and MMP-2 expression and increase in E-cadherin expression in GSC-like cells.	('decrease', 'NegReg', (95, 103))	('increase', 'PosReg', (138, 146))	('MMP-2', 'Gene', '4313', (117, 122))	('affected', 'Reg', (19, 27))	('expression', 'MPA', (123, 133))	('epithelial-to-mesenchymal', 'CPA', (28, 53))	('expression', 'MPA', (161, 171))	('MMP-2', 'Gene', (117, 122))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('E-cadherin', 'Gene', (150, 160))	('depletion', 'Var', (4, 13))	('E-cadherin', 'Gene', '999', (150, 160))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('SNAIL', 'Gene', '6615', (107, 112))	('SNAIL', 'Gene', (107, 112))	('BIS', 'Chemical', 'MESH:D001729', (0, 3))
49173	27145367	Constitutive activation of STAT3 by phosphorylation has been reported in 70% of human cancers, including glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('STAT3', 'Gene', (27, 32))	('phosphorylation', 'Var', (36, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activation', 'PosReg', (13, 23))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('glioblastoma', 'Disease', (105, 117))	('STAT3', 'Gene', '6774', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
49177	27145367	Numerous in vitro and in vivo animal studies have indicated that modulation of BIS expression conferred sensitization or protection of cancer cells to chemotherapeutic agents, indicating the possibility that BIS could be a potential therapeutic target.	('BIS', 'Chemical', 'MESH:D001729', (79, 82))	('sensitization', 'MPA', (104, 117))	('cancer', 'Disease', (135, 141))	('modulation', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BIS', 'Chemical', 'MESH:D001729', (208, 211))	('si', 'Chemical', 'MESH:D012825', (194, 196))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('BIS', 'Gene', (79, 82))	('protection', 'CPA', (121, 131))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
49179	27145367	also demonstrated that BIS knockdown consistently inhibited metastasis, as well as reversal of the epithelial-to-mesenchymal transition (EMT) pathway, in hepatocellular carcinoma.	('knockdown', 'Var', (27, 36))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (154, 178))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (154, 178))	('BIS', 'Chemical', 'MESH:D001729', (23, 26))	('metastasis', 'CPA', (60, 70))	('hepatocellular carcinoma', 'Disease', (154, 178))	('epithelial-to-mesenchymal transition', 'Pathway', (99, 135))	('inhibited', 'NegReg', (50, 59))
49193	27145367	A172 and U87 cells were transfected with small interfering RNA (siRNA) for BIS (si-BIS) or control siRNA (si-CTL) for 48 h, followed by incubation under sphere-forming conditions for a subsequent 72 h. As shown in Figure 2A, the size and the number of spheres notably decreased in si-BIS-treated cells as compared to si-CTL-treated cells in both A172 and U87 cells.	('BIS', 'Chemical', 'MESH:D001729', (83, 86))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('U87', 'Gene', '677775', (9, 12))	('si', 'Chemical', 'MESH:D012825', (281, 283))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('U87', 'Gene', (9, 12))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('si-BIS-treated', 'Var', (281, 295))	('si', 'Chemical', 'MESH:D012825', (317, 319))	('si-BIS', 'Chemical', '-', (281, 287))	('decreased', 'NegReg', (268, 277))	('si', 'Chemical', 'MESH:D012825', (229, 231))	('BIS', 'Chemical', 'MESH:D001729', (284, 287))	('U87', 'Gene', '677775', (355, 358))	('U87', 'Gene', (355, 358))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('si-BIS', 'Chemical', '-', (80, 86))	('BIS', 'Chemical', 'MESH:D001729', (75, 78))	('size', 'CPA', (229, 233))
49194	27145367	The quantitation of colony numbers after attachment to normal plates revealed that BIS depletion reduced sphere-forming activity by ~50% relative to that of the control group (Figure 2B-2D).	('sphere-forming activity', 'CPA', (105, 128))	('depletion', 'Var', (87, 96))	('BIS', 'Chemical', 'MESH:D001729', (83, 86))	('reduced', 'NegReg', (97, 104))
49195	27145367	Additionally, BIS knockdown attenuated induction of the representative stemness marker SOX-2 in spheres (Figure 3A).	('knockdown', 'Var', (18, 27))	('induction', 'MPA', (39, 48))	('attenuated', 'NegReg', (28, 38))	('BIS knockdown', 'Var', (14, 27))	('BIS', 'Chemical', 'MESH:D001729', (14, 17))	('SOX-2', 'Gene', '6657', (87, 92))	('SOX-2', 'Gene', (87, 92))
49198	27145367	We performed western blot assays for phosphorylated STAT3 (p-STAT3), which is the active form of STAT3 as a transcription factor, using specific antibodies targeting p-S727 and p-Y705 sites.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('si', 'Chemical', 'MESH:D012825', (184, 186))	('STAT3', 'Gene', (52, 57))	('STAT3', 'Gene', (97, 102))	('STAT3', 'Gene', '6774', (61, 66))	('STAT3', 'Gene', (61, 66))	('p-S727', 'Var', (166, 172))	('STAT3', 'Gene', '6774', (97, 102))	('STAT3', 'Gene', '6774', (52, 57))	('p-Y705 sites', 'Var', (177, 189))
49199	27145367	In the spheres of A172 and U87 cells treated with si-BIS, p-STAT3 levels associated with both sites decreased relative to control cells (Figure 3A).	('U87', 'Gene', '677775', (27, 30))	('si-BIS', 'Var', (50, 56))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('STAT3', 'Gene', '6774', (60, 65))	('decreased', 'NegReg', (100, 109))	('U87', 'Gene', (27, 30))	('STAT3', 'Gene', (60, 65))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('si-BIS', 'Chemical', '-', (50, 56))
49207	27145367	These results suggested that BIS depletion regulates STAT3 expression at post-transcriptional levels under sphere-forming conditions, resulting in decreased STAT3 phosphorylation and subcellular localization.	('regulates', 'Reg', (43, 52))	('STAT3', 'Gene', '6774', (53, 58))	('decreased', 'NegReg', (147, 156))	('STAT3', 'Gene', (53, 58))	('BIS', 'Var', (29, 32))	('STAT3', 'Gene', '6774', (157, 162))	('subcellular localization', 'MPA', (183, 207))	('STAT3', 'Gene', (157, 162))	('BIS', 'Chemical', 'MESH:D001729', (29, 32))	('si', 'Chemical', 'MESH:D012825', (65, 67))
49219	27145367	As shown in Figure 5, sphere numbers were recovered by ectopic STAT3 expression in BIS-depleted A172 and U87 cells.	('BIS', 'Chemical', 'MESH:D001729', (83, 86))	('U87', 'Gene', '677775', (105, 108))	('U87', 'Gene', (105, 108))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('STAT3', 'Gene', '6774', (63, 68))	('ectopic', 'Var', (55, 62))	('sphere numbers', 'CPA', (22, 36))	('STAT3', 'Gene', (63, 68))
49220	27145367	In addition, SOX-2 expression was partially rescued by ectopic expression of STAT3 (from 37% to 69 % compared to the value in si-CTL -treated A172 cells, data not shown).	('expression', 'MPA', (19, 29))	('SOX-2', 'Gene', '6657', (13, 18))	('SOX-2', 'Gene', (13, 18))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('STAT3', 'Gene', '6774', (77, 82))	('STAT3', 'Gene', (77, 82))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('ectopic expression', 'Var', (55, 73))
49225	27145367	Among EMT markers, SNAIL was significantly downregulated by BIS depletion, as was TWIST induction, though to a lesser extent than that observed with SNAIL.	('downregulated', 'NegReg', (43, 56))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('SNAIL', 'Gene', '6615', (149, 154))	('SNAIL', 'Gene', (149, 154))	('TWIST', 'Gene', '7291', (82, 87))	('SNAIL', 'Gene', (19, 24))	('SNAIL', 'Gene', '6615', (19, 24))	('TWIST', 'Gene', (82, 87))	('BIS', 'Chemical', 'MESH:D001729', (60, 63))	('BIS depletion', 'Var', (60, 73))
49227	27145367	Since BIS enhances the activities of MMP-2 and MMP-9, which are representative STAT3 targets, we measured the mRNA levels of these genes.	('BIS', 'Chemical', 'MESH:D001729', (6, 9))	('MMP-9', 'Gene', '4318', (47, 52))	('MMP-2', 'Gene', '4313', (37, 42))	('STAT3', 'Gene', '6774', (79, 84))	('enhances', 'PosReg', (10, 18))	('MMP-9', 'Gene', (47, 52))	('MMP-2', 'Gene', (37, 42))	('STAT3', 'Gene', (79, 84))	('activities', 'MPA', (23, 33))	('BIS', 'Var', (6, 9))
49229	27145367	Consistently, MMP-2 activity, but not MMP-9, was inhibited by BIS depletion as determined by gelatin zymography using supernatants from culture media associated with A172 spheres (Figure 6C).	('activity', 'MPA', (20, 28))	('MMP-9', 'Gene', (38, 43))	('BIS depletion', 'MPA', (62, 75))	('MMP-2', 'Gene', '4313', (14, 19))	('MMP-2', 'Gene', (14, 19))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('MMP-9', 'Gene', '4318', (38, 43))	('A172', 'Var', (166, 170))	('BIS', 'Chemical', 'MESH:D001729', (62, 65))	('inhibited', 'NegReg', (49, 58))
49230	27145367	Since targeting BIS alters the expression patterns of several genes associated with CSC and EMT properties, we hypothesized that BIS knockdown altered comprehensive expression profiles associated with STAT3 and EMT-related pathways.	('expression patterns', 'MPA', (31, 50))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('STAT3', 'Gene', '6774', (201, 206))	('alters', 'Reg', (20, 26))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('STAT3', 'Gene', (201, 206))	('knockdown', 'Var', (133, 142))	('CSC', 'Disease', (84, 87))	('BIS', 'Chemical', 'MESH:D001729', (16, 19))	('BIS', 'Chemical', 'MESH:D001729', (129, 132))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('altered', 'Reg', (143, 150))	('expression profiles', 'MPA', (165, 184))
49231	27145367	To test this hypothesis, we performed microarray analysis using Affymetrix arrays to assess the overall mRNA expression patterns in si-BIS-treated spheres as compared to si-CTL-treated spheres.	('si', 'Chemical', 'MESH:D012825', (132, 134))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('si-BIS-treated', 'Var', (132, 146))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('si-BIS', 'Chemical', '-', (132, 138))	('mRNA expression', 'MPA', (104, 119))	('si', 'Chemical', 'MESH:D012825', (59, 61))
49239	27145367	In the present study, we described, to our knowledge, for the first time, the role of BIS in a GSC subpopulation based on the following aspects: 1) BIS expression significantly increased under sphere-forming culture conditions as compared to monolayer conditions; 2) BIS depletion resulted in reduced stemness, as evidenced by decreases in sphere-forming activity and the expression of stemness-related genes, such as SOX-2 and NESTIN; 3) BIS knockdown decreased STAT3 levels, while STAT3 overexpression rescued sphere-forming activity; and 4) BIS depletion negatively affected EMT-related genes, such as SNAIL and MMP-2, displaying an association between stemness and EMT progression.	('NESTIN', 'Gene', (428, 434))	('STAT3', 'Gene', (483, 488))	('BIS', 'Chemical', 'MESH:D001729', (544, 547))	('NESTIN', 'Gene', '10763', (428, 434))	('reduced stemness', 'Disease', (293, 309))	('reduced stemness', 'Disease', 'MESH:D020295', (293, 309))	('decreased STAT3 levels', 'Phenotype', 'HP:0031037', (453, 475))	('sphere-forming activity', 'CPA', (512, 535))	('STAT3', 'Gene', '6774', (483, 488))	('sphere-forming activity', 'CPA', (340, 363))	('decreased', 'NegReg', (453, 462))	('negatively', 'NegReg', (558, 568))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('MMP-2', 'Gene', '4313', (615, 620))	('SNAIL', 'Gene', '6615', (605, 610))	('SNAIL', 'Gene', (605, 610))	('si', 'Chemical', 'MESH:D012825', (499, 501))	('BIS', 'Chemical', 'MESH:D001729', (86, 89))	('decreases', 'NegReg', (327, 336))	('affected', 'Reg', (569, 577))	('si', 'Chemical', 'MESH:D012825', (378, 380))	('si', 'Chemical', 'MESH:D012825', (680, 682))	('STAT3', 'Gene', (463, 468))	('SOX-2', 'Gene', '6657', (418, 423))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('SOX-2', 'Gene', (418, 423))	('EMT', 'CPA', (669, 672))	('BIS', 'Chemical', 'MESH:D001729', (148, 151))	('MMP-2', 'Gene', (615, 620))	('EMT-related genes', 'Gene', (578, 595))	('BIS', 'Chemical', 'MESH:D001729', (267, 270))	('BIS', 'Chemical', 'MESH:D001729', (439, 442))	('knockdown', 'Var', (443, 452))	('STAT3', 'Gene', '6774', (463, 468))
49244	27145367	As an essential molecular mechanism through which BIS regulates GSC properties, we demonstrated that BIS depletion was linked to decreased STAT3 stability, and subsequently, nuclear translocation of active p-STAT3 under sphere-forming conditions.	('nuclear translocation', 'MPA', (174, 195))	('STAT3', 'Gene', '6774', (139, 144))	('depletion', 'Var', (105, 114))	('STAT3', 'Gene', '6774', (208, 213))	('STAT3', 'Gene', (139, 144))	('BIS', 'Chemical', 'MESH:D001729', (101, 104))	('BIS', 'MPA', (101, 104))	('STAT3', 'Gene', (208, 213))	('BIS', 'Chemical', 'MESH:D001729', (50, 53))	('decreased', 'NegReg', (129, 138))
49259	27145367	On the other hands, even though BIS has no enzymatic domain, the BIS interactome and bioinformatics analysis revealed that BIS interacts with several proteins functioning in the proteasome-ubiquitination process.	('BIS', 'Chemical', 'MESH:D001729', (65, 68))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('BIS', 'Chemical', 'MESH:D001729', (32, 35))	('BIS', 'Var', (123, 126))	('BIS', 'Chemical', 'MESH:D001729', (123, 126))	('interacts', 'Reg', (127, 136))	('proteins', 'Protein', (150, 158))
49263	27145367	Through binding with multiple proteins to subsequently confer stabilization, BIS contributes to the preservation of various cellular functions, including pro-survival activity, muscle contraction, and cancer cell stemness.	('BIS', 'Var', (77, 80))	('cellular functions', 'CPA', (124, 142))	('BIS', 'Chemical', 'MESH:D001729', (77, 80))	('binding', 'Interaction', (8, 15))	('stabilization', 'MPA', (62, 75))	('cancer cell stemness', 'Disease', (201, 221))	('pro-survival activity', 'CPA', (154, 175))	('cancer cell stemness', 'Disease', 'MESH:D020295', (201, 221))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('muscle contraction', 'CPA', (177, 195))
49266	27145367	In summary, the present study demonstrated that BIS depletion suppressed the stemness phenotypes associated with glioblastoma cells as evidenced by decreases in the sphere-forming activity and the expression of stemness- and EMT-related genes, likely following STAT3 destabilization.	('glioblastoma', 'Disease', (113, 125))	('STAT3', 'Gene', (261, 266))	('BIS', 'Chemical', 'MESH:D001729', (48, 51))	('stemness', 'CPA', (77, 85))	('stemness- and', 'Gene', (211, 224))	('sphere-forming activity', 'CPA', (165, 188))	('decreases', 'NegReg', (148, 157))	('STAT3', 'Gene', '6774', (261, 266))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('suppressed', 'NegReg', (62, 72))	('depletion', 'Var', (52, 61))	('si', 'Chemical', 'MESH:D012825', (203, 205))	('expression', 'MPA', (197, 207))	('BIS', 'Var', (48, 51))
49277	27145367	The membranes were incubated for 1 h with 5% dry skim milk in Tris-buffered saline and Tween 20 (20 mM Tris, 137 mM NaCl, 0.1% Tween 20) and incubated with antibodies against BIS (1: 5000), p-STAT3 (1:1000; Y705, S727; Cell Signaling, Danvers, MA, USA), STAT3 (1:1000, Cell Signaling), SOX-2 (1: 500; Santa Cruz Biotechnology, Dallas, CA, USA), or beta-actin (1:5000, Sigma-Aldrich).	('beta-actin', 'Gene', '728378', (348, 358))	('STAT3', 'Gene', (254, 259))	('beta-actin', 'Gene', (348, 358))	('NaCl', 'Chemical', 'MESH:D012965', (116, 120))	('SOX-2', 'Gene', '6657', (286, 291))	('Tris', 'Chemical', '-', (103, 107))	('Tris', 'Chemical', '-', (62, 66))	('Y705', 'Var', (207, 211))	('SOX-2', 'Gene', (286, 291))	('STAT3', 'Gene', '6774', (192, 197))	('STAT3', 'Gene', '6774', (254, 259))	('BIS', 'Chemical', 'MESH:D001729', (175, 178))	('STAT3', 'Gene', (192, 197))
49303	23649683	After dosing of oral TMZ only, ECF-TMZ mean-Cmax and area under the concentration curve(AUC0- ) within the tumor were 0.59mug/mL and 1.82mug hr/mL, respectively.	('TMZ', 'Chemical', 'MESH:D000077204', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('rat', 'Species', '10116', (75, 78))	('ECF-TMZ', 'Var', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))
49356	23649683	The SPIO-induced changes in relaxation rates (DeltaR2* and DeltaR2) provide information on the underlying vascular morphology: DeltaR2* is proportional to total blood volume, DeltaR2 is proportional to microvascular blood volume, and (DeltaR2*/DeltaR2)3/2 is proportional to average blood vessel size.	('DeltaR2', 'DELETION', 'None', (235, 242))	('relaxation', 'MPA', (28, 38))	('DeltaR2', 'DELETION', 'None', (46, 53))	('DeltaR2', 'Var', (235, 242))	('DeltaR2', 'Var', (46, 53))	('DeltaR2', 'DELETION', 'None', (127, 134))	('rat', 'Species', '10116', (39, 42))	('DeltaR2', 'DELETION', 'None', (175, 182))	('DeltaR2', 'DELETION', 'None', (59, 66))	('DeltaR2', 'Var', (127, 134))	('DeltaR2', 'Var', (175, 182))	('DeltaR2', 'DELETION', 'None', (244, 251))	('DeltaR2', 'Var', (244, 251))	('DeltaR2', 'Var', (59, 66))
49357	23649683	Using the Analysis of Functional NeuroImages (AFNI) software package, voxel-wise pre- and post-contrast R2* and R2 maps were calculated by fitting the GE and SE signal intensity vs. TE curves to the following mono-exponential plus constant noise model: Maps were then calculated by subtracting pre-contrast DeltaR2(*) from post-contrast DeltaR2(*).	('DeltaR2', 'DELETION', 'None', (307, 314))	('DeltaR2', 'Var', (337, 344))	('DeltaR2', 'Var', (307, 314))	('SE', 'Disease', 'None', (158, 160))	('DeltaR2', 'DELETION', 'None', (337, 344))
49367	23649683	microvascular blood volume), and (DeltaR2*/DeltaR2)3/2 (i.e.	('DeltaR2', 'DELETION', 'None', (43, 50))	('DeltaR2', 'Var', (43, 50))	('microvascular', 'MPA', (0, 13))	('DeltaR2', 'DELETION', 'None', (34, 41))	('DeltaR2', 'Var', (34, 41))
49369	23649683	Both the total (DeltaR2*) and microvascular and (DeltaR2) blood volume of the control tumor was comparable to that of the contralateral ROI at D12, but were markedly elevated at D21.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('DeltaR2', 'DELETION', 'None', (16, 23))	('DeltaR2', 'Var', (16, 23))	('microvascular and', 'CPA', (30, 47))	('tumor', 'Disease', (86, 91))	('DeltaR2', 'DELETION', 'None', (49, 56))	('DeltaR2', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('elevated', 'PosReg', (166, 174))
49371	23649683	The average vessel size for both tumor and contralateral ROIs were similar in the D12 control, but the vessel size in the treated D12 tumor was lower compared to the contralateral ROI.	('D12', 'Var', (130, 133))	('vessel size', 'MPA', (103, 114))	('lower', 'NegReg', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
49372	23649683	Additionally, pooled histograms of DeltaR2*, DeltaR2, and (DeltaR2*/DeltaR2)3/2 from tumor and contralateral ROIs (Figure 3) show that for the D12 control group, the tumor and contralateral distributions were similar for all three in vivo MRI vascular parameters (Figure 3a-c), while for the D12 treated group, the distributions for all three parameters were shifted toward lower values (Figure 3d-f).	('D12', 'Var', (143, 146))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (166, 171))	('DeltaR2', 'DELETION', 'None', (68, 75))	('DeltaR2', 'DELETION', 'None', (59, 66))	('DeltaR2', 'Var', (45, 52))	('DeltaR2', 'Var', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('DeltaR2', 'DELETION', 'None', (45, 52))	('DeltaR2', 'DELETION', 'None', (35, 42))	('DeltaR2', 'Var', (35, 42))	('MRI vascular', 'MPA', (239, 251))	('DeltaR2', 'Var', (59, 66))
49373	23649683	In contrast, DeltaR2* and DeltaR2 were elevated in the control D21 tumors compared to the contralateral ROIs (Figure 3g-h).	('DeltaR2', 'DELETION', 'None', (26, 33))	('DeltaR2', 'Var', (26, 33))	('elevated', 'PosReg', (39, 47))	('DeltaR2', 'DELETION', 'None', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('DeltaR2', 'Var', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
49374	23649683	The treated D21 tumor exhibited DeltaR2* and DeltaR2 distributions that were shifted toward the lower contralateral values (Figure 3j-k).	('DeltaR2', 'DELETION', 'None', (32, 39))	('DeltaR2', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('DeltaR2', 'DELETION', 'None', (45, 52))	('DeltaR2', 'Var', (45, 52))
49375	23649683	Both control and treated D21 tumors exhibited (DeltaR2*/DeltaR2)3/2 distributions similar to the contralateral ROIs.	('DeltaR2', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('DeltaR2', 'DELETION', 'None', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('DeltaR2', 'Var', (47, 54))	('tumors', 'Disease', (29, 35))	('DeltaR2', 'DELETION', 'None', (56, 63))
49389	23649683	The treated D21 tumor also exhibited DeltaR2* and DeltaR2 distributions that were shifted toward the lower contralateral values.	('DeltaR2', 'DELETION', 'None', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('DeltaR2', 'Var', (50, 57))	('DeltaR2', 'DELETION', 'None', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('DeltaR2', 'Var', (37, 44))	('tumor', 'Disease', (16, 21))
49407	24022702	Mutations in many of the known cancer genes, so-called 'mountains' (genes altered in a high percentage of tumors), were discovered by focused sanger sequencing or cytogenetic analyses, some of which express mutated proteins that have become successful drug targets.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutated', 'Var', (207, 214))	('Mutations', 'Var', (0, 9))	('proteins', 'Protein', (215, 223))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', (31, 37))
49409	24022702	These pioneering studies led to the identification of a highly recurrent mutation in a novel oncogene, isocitrate dehydrogenase 1 (IDH1), involved in both cell metabolism and DNA methylation, reinforcing the promise of unbiased genomic sequencing in the identification of novel genetic driving events in human cancers.	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('IDH1', 'Gene', (131, 135))	('cancers', 'Disease', (310, 317))	('IDH1', 'Gene', '3417', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('isocitrate dehydrogenase 1', 'Gene', (103, 129))	('isocitrate dehydrogenase 1', 'Gene', '3417', (103, 129))	('mutation', 'Var', (73, 81))	('human', 'Species', '9606', (304, 309))
49410	24022702	The advancement in NGS technology has allowed the cancer research community to employ systematic sequencing to identify additional 'mountains', which include the discovery of frequent mutations in epigenetic regulators and pre-mRNA splicing machinery in many cancers (Figure 1 and described in detail below), and so-called 'hills' (genes altered less frequently in cancer).	('cancer', 'Disease', (365, 371))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('epigenetic regulators', 'Gene', (197, 218))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('mutations', 'Var', (184, 193))	('cancers', 'Disease', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', (259, 265))
49416	24022702	We review WES and WGS studies that have provided the clearest landscape of somatic mutations in major adult tumor types (majority of which involve deep sequencing analyses of the coding exomes and whole genomes of 20 or more samples per study), TCGA and ICGC publications, as well as a few examples of rare malignancies and cancers more prevalent in diverse geographical regions (a selection of studies is summarized in Table 1).	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('malignancies and cancers', 'Disease', 'MESH:D009369', (307, 331))	('adult tumor', 'Disease', 'MESH:C538052', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('adult tumor', 'Disease', (102, 113))	('cancers', 'Phenotype', 'HP:0002664', (324, 331))
49420	24022702	For example, the mutation rates for pediatric and haematological cancers possess the lowest mutation rates (~1 mutations/Mb for chronic lymphocytic leukemia (CLL)), compared to cancers where environmental mutagens are known to increase the mutation burden, such as melanoma and lung cancer (~15 mutations/Mb for melanoma).	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (128, 156))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('chronic lymphocytic leukemia', 'Disease', (128, 156))	('cancers', 'Disease', (65, 72))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('lowest', 'NegReg', (85, 91))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (128, 156))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('melanoma', 'Disease', 'MESH:D008545', (312, 320))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (278, 289))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('haematological cancers', 'Disease', (50, 72))	('melanoma', 'Disease', (265, 273))	('haematological cancers', 'Disease', 'MESH:D009369', (50, 72))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (265, 289))	('mutation', 'MPA', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('melanoma', 'Disease', (312, 320))
49421	24022702	In addition, mutation rates can vary tremendously within a cancer type, often due to the degree of exposure to an environmental mutagen, or dependent on which genes are mutated (e.g.	('mutation', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('due', 'Reg', (78, 81))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
49422	24022702	tumors possessing mutations in mismatch repair genes).	('tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', (0, 6))	('mismatch repair genes', 'Gene', (31, 52))	('tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (18, 27))
49424	24022702	For example, clustering analysis on all possible mutations (considering context of flanking residues) demonstrated natural groupings of mutation spectrum and cancer types consistent with known signatures of carcinogenesis mechanisms: lung tumors possess a high fraction of G>T transversions, attributable to exposure of polycyclic aromatic hydrocarbons from tobacco smoke; melanomas possess a high fraction of C>T transitions in dipyrimidines caused by UV-induced DNA damage and misrepair; gastrointestinal tumors (oesophageal, colorectal and gastric) possess a high frequency of transition mutations at CpG dinucleotides that may be a reflection of elevated methylation levels in these tumors; cervical, bladder, some head-and-neck and breast cancers possess frequent mutations at Cs in the context of TpC, characteristic mutations caused by the APOBEC family of cytidine deaminases; and leukemic samples (acute myeloid leukaemia (AML) and CLL) possess A to T mutations in the TpA context.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('leukemic', 'Disease', 'MESH:D007938', (889, 897))	('breast cancer', 'Phenotype', 'HP:0003002', (737, 750))	('AML', 'Disease', 'MESH:D015470', (932, 935))	('cancer', 'Disease', 'MESH:D009369', (744, 750))	('melanoma', 'Phenotype', 'HP:0002861', (373, 381))	('leukemic', 'Disease', (889, 897))	('lung tumors', 'Disease', (234, 245))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (907, 930))	('melanomas', 'Phenotype', 'HP:0002861', (373, 382))	('tumor', 'Phenotype', 'HP:0002664', (507, 512))	('AML', 'Phenotype', 'HP:0004808', (932, 935))	('tumors', 'Disease', (507, 513))	('AML', 'Disease', (932, 935))	('tumors', 'Disease', (239, 245))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (490, 513))	('dipyrimidines', 'Chemical', '-', (429, 442))	('colorectal', 'Disease', 'MESH:D015179', (528, 538))	('tumors', 'Phenotype', 'HP:0002664', (687, 693))	('cancer', 'Disease', (158, 164))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (907, 930))	('mutations', 'Var', (769, 778))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (687, 692))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (507, 513))	('cancers', 'Phenotype', 'HP:0002664', (744, 751))	('tumors', 'Disease', (687, 693))	('cancer', 'Disease', (744, 750))	('acute myeloid leukaemia', 'Disease', (907, 930))	('breast cancers', 'Disease', 'MESH:D001943', (737, 751))	('tobacco', 'Species', '4097', (358, 365))	('breast cancers', 'Disease', (737, 751))	('melanomas', 'Disease', 'MESH:D008545', (373, 382))	('cancer', 'Phenotype', 'HP:0002664', (744, 750))	('gastrointestinal tumors', 'Disease', (490, 513))	('lung tumors', 'Disease', 'MESH:D008175', (234, 245))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (604, 621))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (490, 513))	('carcinogenesis', 'Disease', (207, 221))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('melanomas', 'Disease', (373, 382))	('tumors', 'Disease', 'MESH:D009369', (687, 693))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('colorectal', 'Disease', (528, 538))	('lung tumors', 'Phenotype', 'HP:0100526', (234, 245))	('breast cancers', 'Phenotype', 'HP:0003002', (737, 751))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (913, 930))	('carcinogenesis', 'Disease', 'MESH:D063646', (207, 221))	('tumors', 'Phenotype', 'HP:0002664', (507, 513))
49426	24022702	Identifying which mutations are likely to be 'drivers' in pathogenesis and elucidating how mutated genes affect the biology of a given tumor, are fundamental challenges in cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('affect', 'Reg', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('mutations', 'Var', (18, 27))
49431	24022702	The Sanger-sequencing of 20,661 protein coding genes from 22 glioblastoma samples mentioned above revealed a recurrent heterozygous IDH1 mutation targeting amino acid R132 in 12% of samples, which correlated with improved patient survival.	('IDH1', 'Gene', (132, 136))	('improved', 'PosReg', (213, 221))	('IDH1', 'Gene', '3417', (132, 136))	('glioblastoma', 'Disease', (61, 73))	('patient', 'Species', '9606', (222, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('mutation targeting amino acid R132', 'Var', (137, 171))
49432	24022702	In parallel, glioblastoma was the first cancer to undergo comprehensive genomic characterization by TCGA Research Network, which used a targeted approach consisting of Sanger-based capillary sequencing of 601 selected genes in 91 glioblastoma tumor-normal pairs to identify somatic mutations, which revealed frequent mutations in the phosphatidylinositol 3-kinase (PI3K) regulatory subunit, PIK3R1.	('mutations', 'Var', (317, 326))	('PIK3R1', 'Gene', '5295', (391, 397))	('glioblastoma', 'Disease', (13, 25))	('PIK3R1', 'Gene', (391, 397))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('glioblastoma', 'Disease', (230, 242))	('cancer', 'Disease', (40, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (230, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (230, 242))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (230, 248))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('glioblastoma tumor', 'Disease', (230, 248))
49435	24022702	Investigation of RNA sequencing (RNA-seq) data from glioblastomas also revealed translocations involving fibroblast growth factor receptor (FGFR) genes to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, in approximately 3% (3/97) of cases.	('translocations', 'Var', (80, 94))	('FGFR', 'Gene', (140, 144))	('TACC3', 'Gene', '10460', (225, 230))	('TACC1', 'Gene', (216, 221))	('TACC3', 'Gene', (225, 230))	('glioblastomas', 'Phenotype', 'HP:0012174', (52, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (52, 65))	('glioblastomas', 'Disease', (52, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('TACC1', 'Gene', '6867', (216, 221))
49437	24022702	Somatic or germline inactivating mutations in the tumor suppressor gene, von Hippel-Lindau (VHL), a master regulator of HIF transcription factors and the hypoxia response, are found in most clear-cell renal-cell carcinoma (ccRCC) cases (somatic mutations reported in >55% of sporadic ccRCC).	('renal-cell carcinoma', 'Disease', (201, 221))	('renal-cell carcinoma', 'Disease', 'MESH:C538614', (201, 221))	('clear-cell renal-cell carcinoma', 'Phenotype', 'HP:0006770', (190, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (284, 289))	('hypoxia', 'Disease', (154, 161))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('VHL', 'Gene', (92, 95))	('germline inactivating mutations', 'Var', (11, 42))	('von Hippel-Lindau', 'Gene', (73, 90))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('VHL', 'Gene', '7428', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('von Hippel-Lindau', 'Gene', '7428', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (201, 221))	('found', 'Reg', (176, 181))	('tumor', 'Disease', (50, 55))
49439	24022702	Indeed, focused Sanger sequencing revealed mutations in neurofibromin 2 (NF2) and in genes involved in histone methylation and demethylation: SETD2, JARID1c (also known as KDM5C) and UTX (also known as KMD6A) (Box 3 and Figure 1a).	('neurofibromin 2', 'Gene', (56, 71))	('UTX', 'Gene', (183, 186))	('NF2', 'Gene', (73, 76))	('UTX', 'Gene', '7403', (183, 186))	('JARID1c', 'Gene', '8242', (149, 156))	('mutations', 'Var', (43, 52))	('KDM5C', 'Gene', (172, 177))	('SETD2', 'Gene', '29072', (142, 147))	('neurofibromin 2', 'Gene', '4771', (56, 71))	('NF2', 'Gene', '4771', (73, 76))	('KDM5C', 'Gene', '8242', (172, 177))	('JARID1c', 'Gene', (149, 156))	('SETD2', 'Gene', (142, 147))
49442	24022702	The importance of the PBAF complex was initially suggested from studies that found inactivating mutations in its core component, SMARCB1 (SNF5), in rhabdoid tumors.	('inactivating mutations', 'Var', (83, 105))	('SNF5', 'Gene', (138, 142))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (148, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('SMARCB1', 'Gene', '6598', (129, 136))	('SNF5', 'Gene', '6598', (138, 142))	('SMARCB1', 'Gene', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('rhabdoid tumors', 'Disease', (148, 163))
49444	24022702	A second WES study identified frequent mutations in the two-hit tumor suppressor BRCA1-associated protein-1 (BAP1) in ccRCC, previously found to be frequently mutated in uveal melanoma and pleural mesothelioma, that functions as a deubiquitinating enzyme and regulator of histone H2A lysine 119 ubiquitination (Figure 1a).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('tumor', 'Disease', (64, 69))	('ccRCC', 'Disease', (118, 123))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('BAP1', 'Gene', (109, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('uveal melanoma', 'Disease', (170, 184))	('BRCA1-associated protein-1', 'Gene', (81, 107))	('BAP1', 'Gene', '8314', (109, 113))	('mutations', 'Var', (39, 48))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (189, 209))	('lysine', 'Chemical', 'MESH:D008239', (284, 290))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (189, 209))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('pleural mesothelioma', 'Disease', (189, 209))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('BRCA1-associated protein-1', 'Gene', '8314', (81, 107))
49445	24022702	Interestingly, mutations in BAP1 and PBRM1 were anti-correlated, and tumors possessing BAP1 mutations were associated with high tumor grade.	('PBRM1', 'Gene', (37, 42))	('BAP1', 'Gene', '8314', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('BAP1', 'Gene', '8314', (28, 32))	('PBRM1', 'Gene', '55193', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('associated', 'Reg', (107, 117))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('BAP1', 'Gene', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
49446	24022702	Recent efforts from a larger WES/WGS study and TCGA confirmed PBRM1, SETD2, KDM5C and BAP1 to be significantly mutated in a cohort of 417 ccRCC tumors, as well as a novel hotspot mutation in a component the VHL E3 ligase complex, TCEB1.	('tumors', 'Disease', (144, 150))	('KDM5C', 'Gene', '8242', (76, 81))	('mutated', 'Var', (111, 118))	('VHL', 'Gene', '7428', (207, 210))	('BAP1', 'Gene', '8314', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('PBRM1', 'Gene', '55193', (62, 67))	('KDM5C', 'Gene', (76, 81))	('TCEB1', 'Gene', (230, 235))	('BAP1', 'Gene', (86, 90))	('PBRM1', 'Gene', (62, 67))	('SETD2', 'Gene', (69, 74))	('ccRCC', 'Disease', (138, 143))	('TCEB1', 'Gene', '6921', (230, 235))	('VHL', 'Gene', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('SETD2', 'Gene', '29072', (69, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
49447	24022702	Importantly, TCGA was able to show widespread DNA hypomethylation in SETD2-mutant tumors and transcriptional network analysis suggest mutations in the chromatin remodeling complex (PBRM1, ARID1A, and SMARCA4) are linked to RAS signaling, immune function, DNA repair, beta-catenin and TGF-beta signaling.	('linked', 'Reg', (213, 219))	('beta-catenin', 'Gene', '1499', (267, 279))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('ARID1A', 'Gene', '8289', (188, 194))	('ARID1A', 'Gene', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('PBRM1', 'Gene', (181, 186))	('PBRM1', 'Gene', '55193', (181, 186))	('SETD2', 'Gene', '29072', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SMARCA4', 'Gene', (200, 207))	('beta-catenin', 'Gene', (267, 279))	('mutations', 'Var', (134, 143))	('SETD2', 'Gene', (69, 74))	('SMARCA4', 'Gene', '6597', (200, 207))
49448	24022702	RNA-seq analysis also revealed recurrent SFPQ-TEF3 fusions found by in 5/416 samples, all five lacking a VHL mutation.	('VHL', 'Gene', (105, 108))	('TEF3', 'Gene', '7004', (46, 50))	('VHL', 'Gene', '7428', (105, 108))	('SFPQ', 'Gene', '6421', (41, 45))	('TEF3', 'Gene', (46, 50))	('fusions', 'Var', (51, 58))	('SFPQ', 'Gene', (41, 45))
49449	24022702	A first global view of the somatic mutations in HNSCC was published in two studies in 2011, based on WES characterization of 32 and 74 HNSCC tumor-normal pairs, respectively.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('HNSCC tumor', 'Disease', (135, 146))	('HNSCC', 'Gene', (48, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))	('mutations', 'Var', (35, 44))
49454	24022702	also looked for enrichment in functional gene sets among the list of SMGs and discovered that the highest scoring set was involved in epidermal development, particularly in squamous cell differentiation, pointing to disruption of the stratified squamous differentiation program as a candidate route to HNSCC.	('involved', 'Reg', (122, 130))	('squamous cell', 'Disease', (173, 186))	('disruption', 'Var', (216, 226))	('epidermal development', 'CPA', (134, 155))	('SMG', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (304, 307))	('SMG', 'Gene', '23034', (69, 72))
49455	24022702	Both studies identified previously unrecognized NOTCH1 mutations in HNSCC in approximately 10-15% of samples.	('mutations', 'Var', (55, 64))	('HNSCC', 'Gene', (68, 73))	('NOTCH1', 'Gene', '4851', (48, 54))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('NOTCH1', 'Gene', (48, 54))
49456	24022702	Although oncogenic activating NOTCH1 mutations have been observed in a number of hematological malignancies, the mutations in NOTCH1 identified in HNSCC possessed characteristics indicative of loss of function (LOF) mutations, hence suggesting a tumor-suppressive role in this cancer.	('a tumor', 'Disease', (244, 251))	('hematological malignancies', 'Disease', (81, 107))	('NOTCH1', 'Gene', '4851', (30, 36))	('cancer', 'Disease', (277, 283))	('hematological malignancies', 'Disease', 'MESH:D019337', (81, 107))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('NOTCH1', 'Gene', (126, 132))	('NOTCH1', 'Gene', '4851', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('hematological malignancies', 'Phenotype', 'HP:0004377', (81, 107))	('a tumor', 'Disease', 'MESH:D009369', (244, 251))	('loss of function', 'NegReg', (193, 209))	('HNSCC', 'Disease', (147, 152))
49459	24022702	This example highlights the increasingly recognized context-dependent nature of cancer gene functions and that different mutations of the same gene likely confer different cancer-relevant biological activities (Box 4), adding to the complexity of applying genomic information in therapeutic decisions.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (121, 130))	('confer', 'Reg', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (80, 86))
49461	24022702	Although 9 SMGs were identified using two algorithms (MutSig and MuSiC), the landscape of somatic mutations in this cancer type was dominated by near universal presence of TP53 mutations (found in 96% of samples).	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (177, 186))	('SMG', 'Gene', (11, 14))	('presence', 'Reg', (160, 168))	('SMG', 'Gene', '23034', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
49464	24022702	The discovery of the BRAF V600E mutation in over 50% of melanomas in 2002 and the subsequent development of an inhibitor to treat patients with BRAF-mutant metastatic disease is the proof-of-concept for genomics-informed personalized therapy.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('BRAF', 'Gene', '673', (21, 25))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', '673', (144, 148))	('patients', 'Species', '9606', (130, 138))	('melanomas', 'Disease', (56, 65))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', (144, 148))	('V600E', 'Var', (26, 31))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
49465	24022702	It is known that an additional 20% of melanomas are characterized by recurrent NRAS hotspot mutations; however, the driver mutations in the remaining melanoma cases remain poorly understood.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('NRAS', 'Gene', '4893', (79, 83))	('melanomas', 'Disease', (38, 47))	('mutations', 'Var', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanoma', 'Disease', (150, 158))	('melanomas', 'Disease', 'MESH:D008545', (38, 47))	('melanoma', 'Disease', (38, 46))	('NRAS', 'Gene', (79, 83))
49466	24022702	The search for additional driver mutations in melanoma has been complicated by the fact that melanoma has the highest basal mutation rate of any cancer sequenced to date, which can be almost entirely attributable to the abundance of UV-induced C>T transitions in dipyrimidines.	('cancer', 'Disease', (145, 151))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('basal', 'MPA', (118, 123))	('dipyrimidines', 'Chemical', '-', (263, 276))	('C>T transitions', 'Var', (244, 259))
49470	24022702	This method led to the identification of several novel SMGs, many of which harbored hotspot mutations, a pattern of mutation that signifies strong biological selection.	('SMG', 'Gene', (55, 58))	('SMG', 'Gene', '23034', (55, 58))	('harbored', 'Reg', (75, 83))	('mutations', 'Var', (92, 101))
49475	24022702	Significant progress in personalized treatment for this disease has been made in recent years with the demonstration that epidermal growth factor receptor (EGFR)-activating mutations or gene fusion events involving the receptor tyrosine kinase gene ALK identify NSCLC patients who are responsive to inhibitors of these tyrosine kinases (reviewed in).	('NSCLC', 'Disease', (262, 267))	('epidermal growth factor receptor', 'Gene', (122, 154))	('ALK', 'Gene', (249, 252))	('EGFR', 'Gene', '1956', (156, 160))	('epidermal growth factor receptor', 'Gene', '1956', (122, 154))	('mutations', 'Var', (173, 182))	('NSCLC', 'Disease', 'MESH:D002289', (262, 267))	('EGFR', 'Gene', (156, 160))	('gene fusion', 'Var', (186, 197))	('ALK', 'Gene', '238', (249, 252))	('patients', 'Species', '9606', (268, 276))
49478	24022702	G>T transversions and C>T transitions in the setting of CpG dinucleotides).	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (56, 73))	('C>T transitions', 'Var', (22, 37))	('G>T transversions', 'Var', (0, 17))
49480	24022702	The authors found that mutations in U2 small nuclear RNA auxiliary factor 1 (U2AF1) (Figure 1b) and TP53 correlated negatively with progression-free survival.	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('progression-free survival', 'CPA', (132, 157))	('mutations', 'Var', (23, 32))	('U2AF1', 'Gene', (77, 82))	('negatively', 'NegReg', (116, 126))	('U2AF1', 'Gene', '7307', (77, 82))
49481	24022702	Together with frequent mutations in RNA binding motif protein 10 (RBM10), the mutations in U2AF1 point towards a role for RNA splicing deregulation in lung cancer as seen in a number of hematological malignancies (Figure 1b and described in detail below).	('RBM10', 'Gene', '8241', (66, 71))	('RNA binding motif protein 10', 'Gene', '8241', (36, 64))	('hematological malignancies', 'Phenotype', 'HP:0004377', (186, 212))	('RBM10', 'Gene', (66, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('RNA binding motif protein 10', 'Gene', (36, 64))	('lung cancer', 'Disease', (151, 162))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('U2AF1', 'Gene', (91, 96))	('U2AF1', 'Gene', '7307', (91, 96))	('hematological malignancies', 'Disease', (186, 212))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('hematological malignancies', 'Disease', 'MESH:D019337', (186, 212))	('RNA', 'MPA', (122, 125))
49483	24022702	These included previously unreported LOF mutations in HLA-A and widespread TP53 mutations in nearly all samples analyzed.	('mutations', 'Var', (41, 50))	('HLA-A', 'Gene', '3105', (54, 59))	('mutations', 'Var', (80, 89))	('HLA-A', 'Gene', (54, 59))	('LOF', 'NegReg', (37, 40))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
49484	24022702	Integrative analysis identified pathways frequently deregulated in lung SCC, which included confirmation of the oxidative stress response due to frequent mutations and SCNAs in the CUL3 and KEAP1 components of an E3 ubiquitin ligase and its target substrate, NFE2L2, in 34% of samples (Box 3).	('KEAP1', 'Gene', (190, 195))	('deregulated', 'Reg', (52, 63))	('lung SCC', 'Disease', (67, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (112, 128))	('CUL3', 'Gene', '8452', (181, 185))	('oxidative stress response', 'MPA', (112, 137))	('CUL3', 'Gene', (181, 185))	('E3 ubiquitin ligase', 'Enzyme', (213, 232))	('KEAP1', 'Gene', '9817', (190, 195))	('NFE2L2', 'Gene', '4780', (259, 265))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('mutations', 'Var', (154, 163))	('NFE2L2', 'Gene', (259, 265))
49485	24022702	took into account gene expression levels in their significance analysis to identify 22 SMGs (Supplementary Figure 1), including frequent mutations and SCNAs in SOX family members not previously recognized in SCLC.	('SCLC', 'Disease', (208, 212))	('SCLC', 'Disease', 'MESH:D018288', (208, 212))	('mutations', 'Var', (137, 146))	('SMG', 'Gene', (87, 90))	('SMG', 'Gene', '23034', (87, 90))
49489	24022702	An analysis of WES data from 112 treatment-naive prostate adenocarcinoma-normal pairs identified 12 SMGs (Supplementary Figure 1); notably, SPOP, a substrate-binding subunit of a Cullin-based E3 ubiquitin ligase complex, was mutated in ~13% of samples.	('SPOP', 'Gene', (140, 144))	('prostate adenocarcinoma', 'Disease', (49, 72))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (49, 72))	('mutated', 'Var', (225, 232))	('SMG', 'Gene', (100, 103))	('SPOP', 'Gene', '8405', (140, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('SMG', 'Gene', '23034', (100, 103))
49495	24022702	These were characterized by high levels of microsatellite instability (MSI), frequent epigenetic silencing of the DNA mismatch-repair pathway gene, MLH1, mutations in other mismatch repair genes or a DNA polymerase catalytic subunit, POLE, providing molecular insights into the underlying causes for the elevated mutation rate.	('MSI', 'Disease', (71, 74))	('MLH1', 'Gene', (148, 152))	('MSI', 'Disease', 'None', (71, 74))	('mutations', 'Var', (154, 163))	('MLH1', 'Gene', '4292', (148, 152))	('epigenetic', 'MPA', (86, 96))	('microsatellite instability', 'MPA', (43, 69))
49496	24022702	Interestingly, the hypermutated samples possessed few SCNAs and harbored frequent concurrent BRAF V600E mutations.	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (93, 97))	('V600E', 'Var', (98, 103))	('V600E', 'Mutation', 'rs113488022', (98, 103))
49498	24022702	The two signature genes of CRC, TP53 and the WNT signaling pathway antagonist APC, were found to be more frequently mutated in the non-hypermutated tumors.	('CRC', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('APC', 'Disease', 'MESH:D011125', (78, 81))	('TP53', 'Gene', '7157', (32, 36))	('APC', 'Disease', (78, 81))	('TP53', 'Gene', (32, 36))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CRC', 'Phenotype', 'HP:0030731', (27, 30))	('mutated', 'Var', (116, 123))
49501	24022702	The RSPO fusions were found to be mutually exclusive with APC mutations, and exogenous expression of plasmids encoding fusions were shown to activate WNT signaling in a human colon cancer cell line.	('WNT signaling', 'Pathway', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('APC', 'Disease', 'MESH:D011125', (58, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (175, 187))	('RSPO', 'Gene', '284654', (4, 8))	('fusions', 'Var', (119, 126))	('APC', 'Disease', (58, 61))	('colon cancer', 'Disease', 'MESH:D015179', (175, 187))	('activate', 'PosReg', (141, 149))	('RSPO', 'Gene', (4, 8))	('human', 'Species', '9606', (169, 174))	('colon cancer', 'Disease', (175, 187))
49502	24022702	In a separate WGS study, a recurrent fusion of VTI1A and TCF7L2 (encodes a WNT signaling effector, TCF4 transcription factor) was found in 3/97 of colorectal cancer samples, and a colorectal carcinoma cell line harboring the fusion was shown to be dependent on its expression for anchorage-independent growth.	('TCF7L2', 'Gene', (57, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colorectal cancer', 'Disease', (147, 164))	('colorectal carcinoma', 'Disease', (180, 200))	('TCF7L2', 'Gene', '6934', (57, 63))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (180, 200))	('VTI1A', 'Gene', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('VTI1A', 'Gene', '143187', (47, 52))	('found', 'Reg', (130, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('fusion', 'Var', (37, 43))	('TCF4', 'Gene', (99, 103))	('TCF4', 'Gene', '6925', (99, 103))
49506	24022702	Interestingly, a member of the SWI/SNF chromatin remodeling family, ARID1A, was found to be mutated more frequently and had decreased expression in MSI (83%) and Epstein-Barr virus (EBV)-infected MSS (73%) gastric cancers, compared to non-EBV-infected MSS cancers (11%).	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('expression', 'MPA', (134, 144))	('ARID1A', 'Gene', '8289', (68, 74))	('MSI', 'Disease', (148, 151))	('ARID1A', 'Gene', (68, 74))	('non-EBV-infected MSS cancers', 'Disease', 'MESH:D013132', (235, 263))	('Epstein-Barr virus (EBV)-infected MSS', 'Disease', 'MESH:D020031', (162, 199))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('gastric cancers', 'Disease', 'MESH:D013274', (206, 221))	('decreased', 'NegReg', (124, 133))	('MSI', 'Disease', 'None', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('gastric cancers', 'Disease', (206, 221))	('gastric cancers', 'Phenotype', 'HP:0012126', (206, 221))	('mutated', 'Var', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('non-EBV-infected MSS cancers', 'Disease', (235, 263))
49507	24022702	Alterations in ARID1A were also predictive of improved disease-free survival, suggesting deregulation of the SWI/SNF complex represents a unique mechanism of carcinogenesis associated with a distinct clinical behavior.	('ARID1A', 'Gene', (15, 21))	('deregulation', 'Var', (89, 101))	('Alterations', 'Var', (0, 11))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('improved', 'PosReg', (46, 54))	('disease-free survival', 'CPA', (55, 76))	('carcinogenesis', 'Disease', (158, 172))	('SWI/SNF', 'Gene', (109, 116))	('ARID1A', 'Gene', '8289', (15, 21))
49509	24022702	Recently, a number of large-scale WES and WGS studies of breast cancer have developed new algorithms to reconstruct the clonal evolution of the tumors (Box 5), shedding light on the mutational processes responsible for the generation of somatic mutations in breast cancer in addition to identifying SMGs that correlated with well-established clinically relevant subtypes.	('tumors', 'Disease', (144, 150))	('breast cancer', 'Disease', (57, 70))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('mutations', 'Var', (245, 254))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('breast cancer', 'Disease', (258, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('SMG', 'Gene', (299, 302))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('SMG', 'Gene', '23034', (299, 302))
49511	24022702	Clonal frequency analysis provided evidence that somatic mutations in TP53, PIK3CA and PTEN are clonally dominant in most tumors in which they are found, consistent with a founder mutation status role in most, but not all TNBCs.	('tumors', 'Disease', (122, 128))	('PTEN', 'Gene', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('PTEN', 'Gene', '5728', (87, 91))	('TP53', 'Gene', '7157', (70, 74))	('PIK3CA', 'Gene', (76, 82))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('PIK3CA', 'Gene', '5290', (76, 82))
49515	24022702	The authors identified 18 SMGs by MuSiC, and found that GATA3 mutations correlated with response to aromatase inhibitor treatment.	('correlated', 'Reg', (72, 82))	('mutations', 'Var', (62, 71))	('GATA3', 'Gene', '2625', (56, 61))	('SMG', 'Gene', (26, 29))	('SMG', 'Gene', '23034', (26, 29))	('response to aromatase', 'MPA', (88, 109))	('GATA3', 'Gene', (56, 61))
49520	24022702	Forward genetics (in the form of a Sleeping Beauty transposon mutagenesis screen in a mouse model of PDAC) and functional genomics (in the form of a shRNA screen in pancreatic cell lines) were also leveraged to explore the functional relevance of SMGs identified by sequencing.	('PDAC', 'Phenotype', 'HP:0006725', (101, 105))	('mutagenesis', 'Var', (62, 73))	('mouse', 'Species', '10090', (86, 91))	('SMG', 'Gene', (247, 250))	('SMG', 'Gene', '23034', (247, 250))
49524	24022702	All the studies confirmed previously known mutations in TP53 in HCC, but they also shed light on the importance of deregulation by somatic mutations of genes involved in chromatin remodeling, the WNT-beta-catenin pathway, cell cycle control, the PI3K pathway, and oxidative and endoplasmic reticulum stress pathway (Supplementary Figure 1).	('HCC', 'Gene', (64, 67))	('mutations', 'Var', (139, 148))	('TP53', 'Gene', '7157', (56, 60))	('PI3K pathway', 'Pathway', (246, 258))	('HCC', 'Gene', '619501', (64, 67))	('beta-catenin', 'Gene', (200, 212))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (43, 52))	('beta-catenin', 'Gene', '1499', (200, 212))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))
49525	24022702	Although most of the mutations were not associated with a specific type of chronic liver disease, in one study, mutations in interferon regulatory factor 2 (IRF2) were exclusively found in hepatitis B virus (HBV)-related tumors.	('IRF2', 'Gene', (157, 161))	('hepatitis', 'Phenotype', 'HP:0012115', (189, 198))	('hepatitis B virus', 'Species', '10407', (189, 206))	('HBV', 'Species', '10407', (208, 211))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('hepatitis B virus', 'Disease', (189, 206))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('liver disease', 'Disease', 'MESH:D008107', (83, 96))	('mutations', 'Var', (112, 121))	('IRF2', 'Gene', '3660', (157, 161))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (221, 227))	('liver disease', 'Phenotype', 'HP:0001392', (83, 96))	('liver disease', 'Disease', (83, 96))	('found', 'Reg', (180, 185))
49526	24022702	WGS has also revealed that the number of HBV integration sites in HCC tumors was associated with poor survival, and identified recurrent integration events in the TERT, MLL4 and CCNE1 loci, which resulted in concurrent increase in gene expression, reaffirming the powerful analytical capacity of NGS to investigate the potential role of pathogens in human cancers.	('gene expression', 'MPA', (231, 246))	('integration sites', 'Var', (45, 62))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (356, 363))	('human', 'Species', '9606', (350, 355))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HCC tumors', 'Disease', (66, 76))	('TERT', 'Gene', (163, 167))	('increase', 'PosReg', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('poor', 'NegReg', (97, 101))	('TERT', 'Gene', '7015', (163, 167))	('HBV', 'Gene', (41, 44))	('CCNE1', 'Gene', (178, 183))	('HBV', 'Species', '10407', (41, 44))	('cancers', 'Phenotype', 'HP:0002664', (356, 363))	('HCC tumors', 'Disease', 'MESH:D006528', (66, 76))	('cancers', 'Disease', (356, 363))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('MLL', 'Gene', '4297', (169, 172))	('MLL', 'Gene', (169, 172))	('associated', 'Reg', (81, 91))
49531	24022702	Identification of gene fusions as the predominant drivers of certain leukemias has led to the development and clinical success of targeted therapies, including imatinib in chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) cases with the BCR-ABL1 fusion and all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL) cases with PML-RARA fusion.	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (309, 337))	('leukemias', 'Disease', 'MESH:D007938', (69, 78))	('chronic myeloid leukemia', 'Disease', (172, 196))	('acute lymphocytic leukemia', 'Disease', (207, 233))	('leukemias', 'Phenotype', 'HP:0001909', (69, 78))	('leukemia', 'Phenotype', 'HP:0001909', (188, 196))	('trans-retinoic acid', 'Chemical', 'MESH:D014212', (279, 298))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('BCR-ABL1', 'Gene', (255, 263))	('CML', 'Disease', 'MESH:D015464', (198, 201))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (180, 196))	('leukemias', 'Disease', (69, 78))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (309, 337))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (207, 233))	('CML', 'Disease', (198, 201))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (207, 233))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (172, 196))	('fusion', 'Var', (264, 270))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (172, 196))	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('ATRA', 'Chemical', 'MESH:D014212', (300, 304))	('acute promyelocytic leukemia', 'Disease', (309, 337))	('BCR-ABL1', 'Gene', '613;25', (255, 263))	('ALL', 'Phenotype', 'HP:0006721', (235, 238))	('leukemia', 'Phenotype', 'HP:0001909', (329, 337))	('APL', 'Phenotype', 'HP:0004836', (339, 342))	('imatinib', 'Chemical', 'MESH:D000068877', (160, 168))	('CML', 'Phenotype', 'HP:0005506', (198, 201))
49532	24022702	However, substantial numbers of leukemias do not possess such gene fusions, and the search for other genetic drivers led to the identification of somatic mutations in genes such as FLT3, RAS, CEBPA, KIT, JAK2, RUNX1, TET2, ASXL1, EZH2, and TP53 prior to the era of NGS-based studies.	('TP53', 'Gene', '7157', (240, 244))	('leukemias', 'Phenotype', 'HP:0001909', (32, 41))	('FLT3', 'Gene', '2322', (181, 185))	('CEBPA', 'Gene', '1050', (192, 197))	('TET2', 'Gene', '54790', (217, 221))	('EZH2', 'Gene', (230, 234))	('EZH2', 'Gene', '2146', (230, 234))	('RAS', 'Gene', (187, 190))	('leukemias', 'Disease', (32, 41))	('CEBPA', 'Gene', (192, 197))	('JAK2', 'Gene', '3717', (204, 208))	('TET2', 'Gene', (217, 221))	('TP53', 'Gene', (240, 244))	('RUNX1', 'Gene', (210, 215))	('RUNX1', 'Gene', '861', (210, 215))	('ASXL1', 'Gene', '171023', (223, 228))	('KIT', 'Gene', (199, 202))	('JAK2', 'Gene', (204, 208))	('ASXL1', 'Gene', (223, 228))	('leukemia', 'Phenotype', 'HP:0001909', (32, 40))	('mutations', 'Var', (154, 163))	('FLT3', 'Gene', (181, 185))	('leukemias', 'Disease', 'MESH:D007938', (32, 41))
49533	24022702	The first WGS of a patient with French-American-British (FAB) classification M1 acute myeloid leukemia (AML) not only confirmed mutations in previously known genes, but led to the subsequent identification of new somatic mutations in genes involved in DNA methylation, such as DNA methyltransferase 3A (DNMT3A), IDH1, and IDH2 (Figure 1a).	('acute myeloid leukemia', 'Disease', (80, 102))	('patient', 'Species', '9606', (19, 26))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('AML', 'Disease', 'MESH:D015470', (104, 107))	('IDH1', 'Gene', '3417', (312, 316))	('DNMT3A', 'Gene', '1788', (303, 309))	('mutations', 'Var', (221, 230))	('IDH2', 'Gene', (322, 326))	('AML', 'Phenotype', 'HP:0004808', (104, 107))	('AML', 'Disease', (104, 107))	('mutations', 'Var', (128, 137))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (80, 102))	('IDH2', 'Gene', '3418', (322, 326))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (80, 102))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('DNA methyltransferase 3A', 'Gene', '1788', (277, 301))	('DNA methyltransferase 3A', 'Gene', (277, 301))	('DNMT3A', 'Gene', (303, 309))	('IDH1', 'Gene', (312, 316))
49536	24022702	In this study, MuSiC identified 23 SMGs that included known mutations in AML, as well as mutations in the mRNA splicing machinery (U2AF1) (Figure 1b) or cohesin complex (SMC1A, SMC3.	('U2AF1', 'Gene', '7307', (131, 136))	('SMC3', 'Gene', '9126', (177, 181))	('AML', 'Disease', (73, 76))	('SMC1A', 'Gene', '8243', (170, 175))	('SMC3', 'Gene', (177, 181))	('AML', 'Phenotype', 'HP:0004808', (73, 76))	('U2AF1', 'Gene', (131, 136))	('SMC1A', 'Gene', (170, 175))	('mutations', 'Var', (89, 98))	('SMG', 'Gene', (35, 38))	('mutations', 'Var', (60, 69))	('SMG', 'Gene', '23034', (35, 38))	('AML', 'Disease', 'MESH:D015470', (73, 76))
49540	24022702	For example, mutations in spliceosome complex genes are more abundant in MDS than AML and approximately 40% of MDS cases are found to have mutations in one of the spliceosome complex genes (SF3B1, SRSF2, U2AF1, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1) in a mutually exclusive manner, suggesting that deregulation in pre-mRNA splicing plays a crucial role in MDS pathogenesis (Figure 1b).	('MDS', 'Phenotype', 'HP:0002863', (73, 76))	('AML', 'Disease', 'MESH:D015470', (82, 85))	('U2AF1', 'Gene', '7307', (204, 209))	('AML', 'Disease', (82, 85))	('SRSF2', 'Gene', '6427', (197, 202))	('AML', 'Phenotype', 'HP:0004808', (82, 85))	('MDS', 'Disease', 'MESH:D009190', (73, 76))	('SRSF2', 'Gene', (197, 202))	('MDS', 'Phenotype', 'HP:0002863', (111, 114))	('PRPF40B', 'Gene', '25766', (225, 232))	('ZRSR2', 'Gene', (211, 216))	('SF3B1', 'Gene', (190, 195))	('MDS', 'Phenotype', 'HP:0002863', (356, 359))	('U2AF2', 'Gene', (234, 239))	('MDS', 'Disease', (73, 76))	('SF3A1', 'Gene', '10291', (218, 223))	('MDS', 'Disease', 'MESH:D009190', (111, 114))	('U2AF2', 'Gene', '11338', (234, 239))	('SF1', 'Gene', (245, 248))	('mutations', 'Var', (13, 22))	('SF1', 'Gene', '7536', (245, 248))	('MDS', 'Disease', 'MESH:D009190', (356, 359))	('spliceosome complex genes', 'Gene', (26, 51))	('SF3B1', 'Gene', '23451', (190, 195))	('PRPF40B', 'Gene', (225, 232))	('MDS', 'Disease', (111, 114))	('mutations', 'Var', (139, 148))	('U2AF1', 'Gene', (204, 209))	('SF3A1', 'Gene', (218, 223))	('ZRSR2', 'Gene', '8233', (211, 216))	('MDS', 'Disease', (356, 359))
49541	24022702	Recently, sequencing of longitudinal samples from MDS patients identified hotspot mutations in SET binding protein 1 (SETBP1) that was acquired during leukemic evolution to AML.	('SETBP1', 'Gene', '26040', (118, 124))	('patients', 'Species', '9606', (54, 62))	('AML', 'Phenotype', 'HP:0004808', (173, 176))	('AML', 'Disease', (173, 176))	('leukemic', 'Disease', (151, 159))	('MDS', 'Disease', (50, 53))	('MDS', 'Disease', 'MESH:D009190', (50, 53))	('MDS', 'Phenotype', 'HP:0002863', (50, 53))	('mutations', 'Var', (82, 91))	('SET binding protein 1', 'Gene', '26040', (95, 116))	('SETBP1', 'Gene', (118, 124))	('SET binding protein 1', 'Gene', (95, 116))	('AML', 'Disease', 'MESH:D015470', (173, 176))	('leukemic', 'Disease', 'MESH:D007938', (151, 159))
49544	24022702	Examples of findings for CLL include three independent WES and WGS studies that revealed known mutations in TP53 and ATM, and previously unknown SMGs in NOTCH1, myeloid differentiation primary response gene 88 (MYD88), and the splicing factor SF3B1 (Figure 1b).	('NOTCH1', 'Gene', '4851', (153, 159))	('NOTCH1', 'Gene', (153, 159))	('ATM', 'Gene', '472', (117, 120))	('SF3B1', 'Gene', (243, 248))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('SF3B1', 'Gene', '23451', (243, 248))	('MYD88', 'Gene', '4615', (211, 216))	('mutations', 'Var', (95, 104))	('MYD88', 'Gene', (211, 216))	('SMG', 'Gene', (145, 148))	('SMG', 'Gene', '23034', (145, 148))	('ATM', 'Gene', (117, 120))
49546	24022702	For example, RNA-seq has identified hotspot mutations in NOTCH1 in some cases of MCL, suggesting a common role of NOTCH signaling deregulation in B cell malignancies.	('MCL', 'Disease', 'MESH:C535516', (81, 84))	('hotspot', 'PosReg', (36, 43))	('malignancies', 'Disease', (153, 165))	('NOTCH1', 'Gene', (57, 63))	('NOTCH1', 'Gene', '4851', (57, 63))	('MCL', 'Disease', (81, 84))	('mutations', 'Var', (44, 53))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))
49547	24022702	MYD88 mutations were also observed in DLBCL and Waldenstrom macroglobulinemia.	('Waldenstrom macroglobulinemia', 'Phenotype', 'HP:0005508', (48, 77))	('macroglobulinemia', 'Disease', (60, 77))	('DLBCL', 'Disease', (38, 43))	('MYD88', 'Gene', '4615', (0, 5))	('observed', 'Reg', (26, 34))	('macroglobulinemia', 'Disease', 'MESH:D008258', (60, 77))	('mutations', 'Var', (6, 15))	('MYD88', 'Gene', (0, 5))
49548	24022702	The landscape of somatic mutations has also been characterized in multiple myeloma in two recent WES/WGS studies, confirming known deregulation of RAS, NF-kappaB, and histone methyltransferase activity, while revealing previously unknown mutations in genes involved in RNA processing and protein homeostasis.	('mutations', 'Var', (25, 34))	('NF-kappaB', 'Protein', (152, 161))	('multiple myeloma', 'Phenotype', 'HP:0006775', (66, 82))	('multiple myeloma', 'Disease', 'MESH:D009101', (66, 82))	('multiple myeloma', 'Disease', (66, 82))	('RAS', 'Protein', (147, 150))	('histone methyltransferase', 'Gene', '56979', (167, 192))	('activity', 'MPA', (193, 201))	('deregulation', 'PosReg', (131, 143))	('histone methyltransferase', 'Gene', (167, 192))
49549	24022702	The pattern of somatic mutations in DLBCL is more complex, but a significant number of cases harbor mutations in regulators of histone and chromatin modification including MLL2, CREBBP, EP300 and activating mutation in EZH2 (Figure 1a).	('mutations', 'Var', (100, 109))	('EZH2', 'Gene', '2146', (219, 223))	('activating mutation', 'Var', (196, 215))	('EZH2', 'Gene', (219, 223))	('MLL2', 'Gene', '9757', (172, 176))	('CREBBP', 'Gene', (178, 184))	('EP300', 'Gene', (186, 191))	('EP300', 'Gene', '2033', (186, 191))	('CREBBP', 'Gene', '1387', (178, 184))	('MLL2', 'Gene', (172, 176))
49551	24022702	NGS also has the potential to reveal major actionable genetic alterations in rare cancers, such as the discovery of NOTCH2 mutations in 25% of splenic marginal zone lymphoma (SMZL), mutations in signal transducer and activator of transcription 3 (STAT3) in 40% of large granular lymphocytic leukemia (LGL), and BRAF V600E mutation present in 100% of hairy-cell leukemia (HCL) samples tested to date.	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('BRAF', 'Gene', (311, 315))	('BRAF', 'Gene', '673', (311, 315))	('NOTCH2', 'Gene', (116, 122))	('STAT3', 'Gene', '6774', (247, 252))	('granular lymphocytic leukemia', 'Disease', (270, 299))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hairy-cell leukemia', 'Disease', (350, 369))	('splenic marginal zone lymphoma', 'Disease', (143, 173))	('splenic marginal zone lymphoma', 'Disease', 'MESH:D018442', (143, 173))	('granular lymphocytic leukemia', 'Disease', 'MESH:D054066', (270, 299))	('mutations', 'Var', (182, 191))	('leukemia', 'Phenotype', 'HP:0001909', (291, 299))	('mutations', 'Var', (123, 132))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (165, 173))	('signal transducer and activator of transcription 3', 'Gene', '6774', (195, 245))	('leukemia', 'Phenotype', 'HP:0001909', (361, 369))	('NOTCH2', 'Gene', '4853', (116, 122))	('V600E', 'Mutation', 'rs113488022', (316, 321))	('STAT3', 'Gene', (247, 252))	('hairy-cell leukemia', 'Disease', 'MESH:D007943', (350, 369))
49554	24022702	In addition to the examples described above, TP53 is mutated in 96% of HGS-OvCa samples, but clear-cell and endometrioid ovarian cancer tumors have lower rates of TP53 mutations and instead possess frequent recurrent mutations in PIK3CA and ARID1A, which were identified using NGS technology.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('endometrioid ovarian cancer tumors', 'Disease', 'MESH:D010051', (108, 142))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (163, 167))	('PIK3CA', 'Gene', (230, 236))	('ARID1A', 'Gene', '8289', (241, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('ARID1A', 'Gene', (241, 247))	('lower', 'NegReg', (148, 153))	('TP53', 'Gene', (163, 167))	('endometrioid ovarian cancer tumors', 'Disease', (108, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PIK3CA', 'Gene', '5290', (230, 236))	('clear-cell', 'Disease', (93, 103))	('mutations', 'Var', (217, 226))	('TP53', 'Gene', '7157', (45, 49))	('mutations', 'Var', (168, 177))
49555	24022702	Most cutaneous melanomas are driven by BRAF or NRAS mutations; by contrast ocular melanomas, have frequent hotspot mutations in the G-proteins GNA11, GNAQ, and LOF mutations in deubiquitinating enzyme, BAP1.	('cutaneous melanomas', 'Disease', (5, 24))	('ocular melanomas', 'Disease', (75, 91))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('GNAQ', 'Gene', (150, 154))	('GNA11', 'Gene', (143, 148))	('NRAS', 'Gene', '4893', (47, 51))	('BRAF', 'Gene', '673', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('BRAF', 'Gene', (39, 43))	('BAP1', 'Gene', '8314', (202, 206))	('LOF', 'NegReg', (160, 163))	('NRAS', 'Gene', (47, 51))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('ocular melanomas', 'Phenotype', 'HP:0025534', (75, 91))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (5, 24))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (5, 24))	('GNA11', 'Gene', '2767', (143, 148))	('mutations', 'Var', (164, 173))	('ocular melanomas', 'Disease', 'MESH:D008545', (75, 91))	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', (202, 206))	('mutations', 'Var', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('GNAQ', 'Gene', '2776', (150, 154))
49556	24022702	Recent glioblastoma studies support the notion that pediatric and adult cancers need to be characterized separately at the molecular level, as pediatric and adult glioblastoma tumors possess distinct genetic driving events, which includes mutations in ATRX, DAXX, and the replication-independent histone variant, H3F3A, which were much more prevalent in the pediatric setting (Figure 1a and Supplementary Figure 1).	('mutations', 'Var', (239, 248))	('glioblastoma', 'Disease', (163, 175))	('glioblastoma', 'Disease', (7, 19))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (7, 19))	('ATRX', 'Gene', (252, 256))	('ATRX', 'Gene', '546', (252, 256))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('DAXX', 'Gene', (258, 262))	('glioblastoma tumors', 'Disease', (163, 182))	('adult cancers', 'Disease', (66, 79))	('DAXX', 'Gene', '1616', (258, 262))	('H3F3A', 'Gene', '3020', (313, 318))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('adult cancers', 'Disease', 'MESH:C535836', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (163, 182))	('H3F3A', 'Gene', (313, 318))	('glioblastoma', 'Disease', 'MESH:D005909', (7, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))
49558	24022702	One example of this is the V617F mutation in Janus kinase 2 (JAK2) in the diagnosis of the myeloproliferative neoplasm, polycythemia vera (PV), the incidence of which is estimated at 95% and is currently incorporated as one of the diagnostic criteria for PV.	('V617F', 'SUBSTITUTION', 'None', (27, 32))	('JAK2', 'Gene', '3717', (61, 65))	('polycythemia vera', 'Disease', (120, 137))	('V617F', 'Var', (27, 32))	('Janus kinase 2', 'Gene', '3717', (45, 59))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (91, 118))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('myeloproliferative neoplasm', 'Disease', (91, 118))	('polycythemia', 'Phenotype', 'HP:0001901', (120, 132))	('JAK2', 'Gene', (61, 65))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (91, 118))	('polycythemia vera', 'Disease', 'MESH:D011087', (120, 137))	('Janus kinase 2', 'Gene', (45, 59))
49561	24022702	Chromosomal alterations remain the strongest prognostic factor in both AML and MDS, but recent efforts incorporating somatic mutations have shown promise in creating more sophisticated prognostic models.	('AML', 'Disease', 'MESH:D015470', (71, 74))	('Chromosomal alterations', 'Var', (0, 23))	('AML', 'Disease', (71, 74))	('AML', 'Phenotype', 'HP:0004808', (71, 74))	('MDS', 'Phenotype', 'HP:0002863', (79, 82))	('MDS', 'Disease', (79, 82))	('MDS', 'Disease', 'MESH:D009190', (79, 82))
49562	24022702	For instance, in intermediate-risk AML identified by the conventional prognostic model, by incorporating information of additional genetic alterations, which include the internal tandem duplication in fms-related tyrosine kinase 3 gene (FLT3-ITD) and mutations in NPM1, CEBPA, and MLL genes, physicians are able to identify patients that will benefit from stem cell transplant during the first complete remission.	('AML', 'Disease', (35, 38))	('FLT3', 'Gene', (237, 241))	('mutations', 'Var', (251, 260))	('MLL', 'Gene', '4297', (281, 284))	('patients', 'Species', '9606', (324, 332))	('NPM1', 'Gene', '4869', (264, 268))	('MLL', 'Gene', (281, 284))	('CEBPA', 'Gene', (270, 275))	('tyrosine kinase 3', 'Gene', (213, 230))	('CEBPA', 'Gene', '1050', (270, 275))	('tyrosine kinase 3', 'Gene', '2241', (213, 230))	('internal tandem duplication', 'Var', (170, 197))	('FLT3', 'Gene', '2322', (237, 241))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('NPM1', 'Gene', (264, 268))	('AML', 'Phenotype', 'HP:0004808', (35, 38))
49564	24022702	In this regard, two groups have recently shown recurrent mutations in the TERT promoter in approximately 70% of melanomas, which highlights the discovery potential in examining somatic mutations in non-coding regions in cancer.	('melanomas', 'Disease', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TERT', 'Gene', '7015', (74, 78))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('mutations', 'Var', (57, 66))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cancer', 'Disease', (220, 226))	('TERT', 'Gene', (74, 78))
49565	24022702	Third, we need to begin to systematically explore the interaction of host genome variation with the somatic genome of the tumor in ultimately influencing outcomes.	('tumor', 'Disease', (122, 127))	('variation', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
49571	24022702	Driver mutations Somatic mutations in a gene that confer a selective advantage to cancer cells as reflected in statistical evidence of positive selection.	('Somatic mutations', 'Var', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('advantage', 'PosReg', (69, 78))	('mutations Somatic', 'Var', (7, 24))
49573	24022702	Hotspot mutations Recurrent mutations resulting in the same amino acid change in a gene observed in cancer, signifying strong positive selection.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('amino acid change', 'MPA', (60, 77))
49575	24022702	Two-hit tumor suppressor The Knudson two-hit hypothesis was proposed to explain the early onset of cancer in hereditary syndromes whereby inheritance of one germline copy of a mutated gene in all cells substantially increases the likelihood any cell undergoing mutation of the other allele, thus giving rise to earlier onset disease compared to sporadic forms of the disease.	('inheritance', 'Var', (138, 149))	('giving rise to', 'Reg', (296, 310))	('earlier onset disease', 'Disease', (311, 332))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Disease', (99, 105))	('mutation', 'Var', (261, 269))	('tumor', 'Disease', (8, 13))	('increases', 'PosReg', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
49576	24022702	It specifically relates to the necessity to inactivate both alleles of a recessive cancer gene.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('inactivate', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))
49579	24022702	CpG island methylator phenotype A classification of cancers by their degree of methylation at CpG rich promoter regions, first characterized in human colorectal cancers, and often associated with distinct epidemiology, histological and molecular distinct features.	('CpG', 'Gene', (94, 97))	('colorectal cancers', 'Disease', 'MESH:D015179', (150, 168))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (144, 149))	('colorectal cancers', 'Disease', (150, 168))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('methylation', 'Var', (79, 90))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (161, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
49590	24022702	A phenomenon, identified in breast cancers, of localized hypermutations almost exclusively involving C base pair substitutions at TpC dinucleotides.	('breast cancers', 'Phenotype', 'HP:0003002', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancers', 'Disease', 'MESH:D001943', (28, 42))	('TpC dinucleotides', 'Chemical', '-', (130, 147))	('breast cancers', 'Disease', (28, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('C base pair substitutions', 'Var', (101, 126))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('involving', 'Reg', (91, 100))
49591	24022702	Actionable genetic alterations A genetic alteration with sufficient scientific evidence supporting its use to inform a treatment decision Briefly, to identify mutated cancer-relevant genes, the first step is to generate high quality NGS data covering the genomic regions of interest (e.g.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (167, 173))	('genetic alterations', 'Var', (11, 30))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
49594	24022702	Once aligned, sophisticated analytical algorithms are used to call sequence variants in the tumor DNA compared to the human reference genome, and to determine whether a variant is "somatic" by comparison with the germline DNA.	('variant', 'Var', (169, 176))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('variants', 'Var', (76, 84))	('human', 'Species', '9606', (118, 123))
49599	24022702	Controlling for type I errors (false positives) is difficult as mutations in a gene can occur in excess of the calculated BMR if resident in a hypermutable region of the genome (a vs b).	('type I errors', 'Disease', 'MESH:D005776', (16, 29))	('type I errors', 'Disease', (16, 29))	('mutations', 'Var', (64, 73))
49602	24022702	Based on the assumption that mutations in intronic and UTR sequences are more likely under neutral selective pressure, whereas coding mutations will undergo selection during tumor progression, InVEx employs a permutation-based framework to determine whether the observed coding mutations experience positive selection against the inferred gene-specific BMR.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('UTR', 'Gene', (55, 58))
49605	24022702	However, given driver mutations can be present at low frequency in many cancer genes, the ICGC calculated that 500 tumor samples are needed to detect, with 80% power, genes mutated in 3% of samples assuming a typical BMR of 1.5 mutations/Mb.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutated', 'Var', (173, 180))	('tumor', 'Disease', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cancer', 'Disease', (72, 78))
49606	24022702	Distinguishing driver from passenger mutations A major challenge in interpreting and translating genomic discoveries is determining whether SMGs prioritized based on statistical significance truly play functional roles in processes important for tumorigenesis, and which mutations are modulating what gene functions.	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('SMG', 'Gene', (140, 143))	('SMG', 'Gene', '23034', (140, 143))	('tumor', 'Disease', (246, 251))
49608	24022702	The same mutations may be found as drivers in other cancers.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (9, 18))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
49609	24022702	Algorithms that score mutational impact by amino acid conservation can infer likely functional mutations in cancer genes.	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
49613	24022702	Integration with copy number and mutation data showed that the classical subtype is enriched for EGFR alterations, whereas the mesenchymal subtype contains cases with NF1 loss, and the proneural subtype has specific alterations in PDGFRA and IDH1.	('alterations', 'Var', (102, 113))	('EGFR', 'Gene', '1956', (97, 101))	('IDH1', 'Gene', (242, 246))	('NF1', 'Gene', (167, 170))	('EGFR', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (242, 246))	('NF1', 'Gene', '4763', (167, 170))	('PDGFRA', 'Gene', (231, 237))	('alterations', 'Reg', (216, 227))	('loss', 'NegReg', (171, 175))	('PDGFRA', 'Gene', '5156', (231, 237))
49614	24022702	Similarly, analysis of promoter methylation alterations in 272 glioblastoma tumors identified a subset of patient samples with characteristic promoter DNA methylation classified as glioma CpG island methylator phenotype (G-CIMP) which is associated with IDH1 mutations.	('IDH1', 'Gene', '3417', (254, 258))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('mutations', 'Var', (259, 268))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (63, 82))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('patient', 'Species', '9606', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('G-CIMP', 'Chemical', '-', (221, 227))	('glioblastoma tumors', 'Disease', (63, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('IDH1', 'Gene', (254, 258))	('glioma', 'Disease', (181, 187))
49617	24022702	For example, NF2 mutations were found in tumors possessing a non-hypoxic signature and were mutually exclusive with VHL mutations, suggesting mutations in NF2 is a key driver event in this ccRCC subgroup.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (142, 151))	('NF2', 'Gene', '4771', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('NF2', 'Gene', (155, 158))	('non-hypoxic signature', 'MPA', (61, 82))	('found', 'Reg', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('VHL', 'Gene', (116, 119))	('NF2', 'Gene', '4771', (155, 158))	('ccRCC', 'Disease', (189, 194))	('VHL', 'Gene', '7428', (116, 119))	('NF2', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
49618	24022702	Conversely, significant co-occurrence of mutations in epigenetic regulators, SETD2, JARID1C and PBRM1 were found in tumor possessing VHL mutations or hypoxic expression signature, supporting the notion that mutations in this class of genes may act as the second hit to widespread inactivation of VHL in ccRCC.	('SETD2', 'Gene', '29072', (77, 82))	('VHL', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('inactivation', 'NegReg', (280, 292))	('PBRM1', 'Gene', '55193', (96, 101))	('mutations', 'Var', (41, 50))	('ccRCC', 'Disease', (303, 308))	('VHL', 'Gene', '7428', (133, 136))	('mutations', 'Var', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('VHL', 'Gene', (296, 299))	('PBRM1', 'Gene', (96, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (303, 308))	('JARID1C', 'Gene', '8242', (84, 91))	('VHL', 'Gene', '7428', (296, 299))	('SETD2', 'Gene', (77, 82))	('mutations', 'Var', (137, 146))	('JARID1C', 'Gene', (84, 91))	('tumor', 'Disease', (116, 121))
49619	24022702	The authors of the TCGA lung squamous cell carcinoma (SQCC) study observed many of the genes involved in oxidative stress and squamous cell differentiation pathways frequently altered by mutations, SCNAs, and identified genomic alterations associated with reported lung SQCC gene signatures (classical, primitive, basal, and secretory).	('oxidative stress', 'Phenotype', 'HP:0025464', (105, 121))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (24, 52))	('primitive', 'Disease', (303, 312))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (24, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('altered', 'Reg', (176, 183))	('mutations', 'Var', (187, 196))	('lung squamous cell carcinoma', 'Disease', (24, 52))	('SQCC', 'Phenotype', 'HP:0002860', (270, 274))	('lung SQCC', 'Disease', (265, 274))	('SQCC', 'Phenotype', 'HP:0002860', (54, 58))
49621	24022702	Such associations include GATA3, high frequency of PIK3CA, and likely inactivating MAP3K1 and MAP2K4 mutations in the luminal A expression subtype, enrichment of TP53 and PIK3CA mutations in the HER2 expression subtype, and a high frequency of TP53 mutations in the basal-like expression tumors.	('PIK3CA', 'Gene', (171, 177))	('TP53', 'Gene', (244, 248))	('GATA3', 'Gene', (26, 31))	('HER2', 'Gene', (195, 199))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('MAP2K4', 'Gene', '6416', (94, 100))	('MAP2K4', 'Gene', (94, 100))	('TP53', 'Gene', (162, 166))	('PIK3CA', 'Gene', (51, 57))	('inactivating', 'NegReg', (70, 82))	('TP53', 'Gene', '7157', (244, 248))	('mutations', 'Var', (101, 110))	('PIK3CA', 'Gene', '5290', (171, 177))	('HER2', 'Gene', '2064', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('GATA3', 'Gene', '2625', (26, 31))	('TP53', 'Gene', '7157', (162, 166))	('mutations', 'Var', (249, 258))	('MAP3K1', 'Gene', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('mutations', 'Var', (178, 187))	('PIK3CA', 'Gene', '5290', (51, 57))	('MAP3K1', 'Gene', '4214', (83, 89))	('tumors', 'Disease', (288, 294))
49624	24022702	One example is the mutually exclusive mutations in the CUL3-KEAP1 E3 ligase complex and its target substrate NFE2L2 in the oxidative response pathway in lung squamous carcinomas.	('NFE2L2', 'Gene', '4780', (109, 115))	('KEAP1', 'Gene', (60, 65))	('NFE2L2', 'Gene', (109, 115))	('lung squamous carcinomas', 'Disease', (153, 177))	('CUL3', 'Gene', '8452', (55, 59))	('lung squamous carcinomas', 'Disease', 'MESH:D002294', (153, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('CUL3', 'Gene', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('mutations', 'Var', (38, 47))	('KEAP1', 'Gene', '9817', (60, 65))	('oxidative response pathway', 'Pathway', (123, 149))
49626	24022702	The utility of testing whether known pathways are enriched in SMG lists has been demonstrated in many studies, including the WES analysis of HNSCC that observed deregulation of squamous cell differentiation via somatic mutations, and the recent ICGC pancreatic study that observed enrichment of mutations in genes in the axon guidance pathway.	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('squamous cell differentiation', 'CPA', (177, 206))	('axon guidance pathway', 'Pathway', (321, 342))	('deregulation', 'MPA', (161, 173))	('SMG', 'Gene', (62, 65))	('mutations', 'Var', (295, 304))	('SMG', 'Gene', '23034', (62, 65))	('mutations', 'Var', (219, 228))
49628	24022702	Functional validation of SMGs and candidate driver mutations requires equal consideration in the selection and interpretation of biological assays employed to determine cancer relevance.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('SMG', 'Gene', (25, 28))	('SMG', 'Gene', '23034', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
49630	24022702	The example of NOTCH1, which acts as a tumor suppressor with loss-of-function mutations in some tumor types (a) and as an oncogene with activating mutation in another tumor type (b), highlights the challenges in functional validation of SMGs and candidate driver mutations identified by cancer genomics.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('a tumor', 'Disease', (37, 44))	('NOTCH1', 'Gene', (15, 21))	('mutations', 'Var', (78, 87))	('SMG', 'Gene', '23034', (237, 240))	('tumor', 'Disease', (167, 172))	('NOTCH1', 'Gene', '4851', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('a tumor', 'Disease', 'MESH:D009369', (37, 44))	('SMG', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('loss-of-function', 'NegReg', (61, 77))
49632	24022702	For example, if functional assays are performed in primary cells that have been immortalized by engineering specific genetic alterations, or cancer lines possessing inactivation of a tumor suppressor or activation of an oncogene that a candidate SMG may function through, a phenotype may not be observed due to prior deregulation.	('a tumor', 'Disease', (181, 188))	('SMG', 'Gene', (246, 249))	('function', 'Reg', (254, 262))	('inactivation', 'NegReg', (165, 177))	('SMG', 'Gene', '23034', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('alterations', 'Var', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('a tumor', 'Disease', 'MESH:D009369', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('oncogene', 'Gene', (220, 228))	('activation', 'PosReg', (203, 213))	('cancer', 'Disease', (141, 147))
49634	24022702	An example is the lineage-specific melanoma oncogene, MITF, which, when overexpressed alone, did not affect the proliferation or colony-formation of immortalized melanocytes in two-dimensional culture but did so with co-expression of BRAF V600E mutant, which co-occur at a high frequency in melanoma samples.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('MITF', 'Gene', '4286', (54, 58))	('MITF', 'Gene', (54, 58))	('V600E', 'Mutation', 'rs113488022', (239, 244))	('BRAF', 'Gene', '673', (234, 238))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('V600E', 'Var', (239, 244))	('BRAF', 'Gene', (234, 238))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
49635	24022702	For example, PREX2A, a gene found to possess widespread distribution of missense and truncating mutations discovered from WGS of 25 metastatic melanoma-normal pairs indicative of a tumor-suppressive function.	('missense and', 'Var', (72, 84))	('a tumor', 'Disease', 'MESH:D009369', (179, 186))	('truncating', 'MPA', (85, 95))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('PR', 'Gene', '5241', (13, 15))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('a tumor', 'Disease', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
49636	24022702	However, missense mutations were found to produce mild phenotypes in in vivo tumorigenic assays, whereas, truncating mutations were shown to possess oncogenic activity that could have only been elucidated through functional experiments.	('oncogenic activity', 'CPA', (149, 167))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('missense mutations', 'Var', (9, 27))	('tumor', 'Disease', (77, 82))
49643	24022702	More recently, WGS of mouse APL tumors was performed to identify cooperating somatic mutations in a mouse model expressing a PML-RARA fusion oncogene known to initiate APL in mice.	('mice', 'Species', '10090', (175, 179))	('mouse', 'Species', '10090', (100, 105))	('APL tumors', 'Disease', (28, 38))	('mutations', 'Var', (85, 94))	('APL tumors', 'Disease', 'MESH:D015473', (28, 38))	('APL', 'Phenotype', 'HP:0004836', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mouse', 'Species', '10090', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('APL', 'Phenotype', 'HP:0004836', (28, 31))
49644	24022702	The authors identified a deletion in a demethylase gene, Kdm6a, and a recurrent mutation in Jak1 V657F.	('Jak1', 'Gene', '3716', (92, 96))	('V657F', 'Var', (97, 102))	('V657F', 'Mutation', 'rs1057519753', (97, 102))	('deletion', 'Var', (25, 33))	('Jak1', 'Gene', (92, 96))	('Kdm6a', 'Gene', (57, 62))	('Kdm6a', 'Gene', '7403', (57, 62))
49645	24022702	The human JAK1 V658F mutation has been previously reported in APL, demonstrating analysis of WGS from GEM model tumors can be used as an unbiased approach for discovering functionally relevant mutations.	('human', 'Species', '9606', (4, 9))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('JAK1', 'Gene', '3716', (10, 14))	('JAK1', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('V658F', 'Var', (15, 20))	('APL', 'Phenotype', 'HP:0004836', (62, 65))	('V658F', 'Mutation', 'rs1057519753', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
49650	24022702	For example, WGS analysis from 17 NSCLC tumor-normal pairs validated the presence of EGFR and KRAS mutations in founder clones supporting their roles in cancer initiation.	('EGFR', 'Gene', (85, 89))	('cancer initiation', 'Disease', 'MESH:D009369', (153, 170))	('KRAS', 'Gene', (94, 98))	('cancer initiation', 'Disease', (153, 170))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('NSCLC tumor', 'Disease', 'MESH:D009369', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('EGFR', 'Gene', '1956', (85, 89))	('NSCLC tumor', 'Disease', (34, 45))
49652	24022702	Recently, geographical sampling and multi-region sequencing of primary renal carcinomas and associated distant metastatic sites demonstrated that 63-69% of all somatic mutations were not detected across every tumor region, and gene expression signatures indicative of both good and poor prognosis were detected in different regions of the same tumor.	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('primary renal carcinomas', 'Disease', (63, 87))	('tumor', 'Disease', (344, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('primary renal carcinomas', 'Disease', 'MESH:C538614', (63, 87))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('renal carcinomas', 'Phenotype', 'HP:0005584', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('mutations', 'Var', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (344, 349))
49656	24022702	Such studies are enabling classifications of cancers based on genetic alterations rather than tissues of origin.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Disease', (45, 52))	('genetic alterations', 'Var', (62, 81))
49659	23450706	Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies.	('GBM', 'Gene', (74, 77))	('neurotoxicity', 'Disease', 'MESH:D020258', (95, 108))	('neurotoxicity', 'Disease', (95, 108))	('pediatric', 'Var', (64, 73))
49671	23450706	The subtypes are not as well defined in pediatric GBM where genetic profiling revealed PDGFRalpha as the predominant focal amplification target and gene expression analyses indicated deregulation of PDGFRalpha signaling plays an important role in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('PDGFRalpha', 'Gene', (199, 209))	('tumor', 'Disease', (247, 252))	('deregulation', 'Var', (183, 195))	('PDGFRalpha', 'Gene', '5156', (87, 97))	('PDGFRalpha', 'Gene', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('PDGFRalpha', 'Gene', '5156', (199, 209))
49677	23450706	GSCs, which share markers of normal neural stem cells, have been isolated from both pediatric low-grade gliomas (LGG) and HGGs suggesting that pediatric GSCs may emerge from normal neural stem cells that become mutated resulting in the loss of regulated cell division.	('gliomas', 'Disease', (104, 111))	('mutated', 'Var', (211, 218))	('loss', 'NegReg', (236, 240))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('regulated cell division', 'CPA', (244, 267))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
49685	23450706	In a pediatric GBM model, found CD133+ cells expressed a higher percentage of the intermediate filament nestin, musashi-1, and CD15 (stage-specific embryonic antigen 1 or SSEA-1) and had increased proliferation compared to CD133- cells.	('musashi-1', 'Gene', '4440', (112, 121))	('nestin', 'Gene', (104, 110))	('higher', 'PosReg', (57, 63))	('musashi-1', 'Gene', (112, 121))	('CD15', 'Gene', '2526', (127, 131))	('CD15', 'Gene', (127, 131))	('stage-specific embryonic antigen 1', 'Gene', (133, 167))	('stage-specific embryonic antigen 1', 'Gene', '2526', (133, 167))	('increased', 'PosReg', (187, 196))	('nestin', 'Gene', '10763', (104, 110))	('proliferation', 'CPA', (197, 210))	('CD133+', 'Var', (32, 38))
49712	23450706	Inhibiting Hedgehog signaling prevented tumorigenicity and GSC proliferation in HGGs and decreased the self-renewal ability of DIPG neurospheres.	('Hedgehog', 'Protein', (11, 19))	('Inhibiting', 'Var', (0, 10))	('prevented', 'NegReg', (30, 39))	('GSC proliferation', 'CPA', (59, 76))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('self-renewal ability of DIPG neurospheres', 'CPA', (103, 144))	('DIPG', 'Chemical', '-', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('decreased', 'NegReg', (89, 98))
49720	23450706	While EGFR is more commonly amplified and overexpressed in adult gliomas, recent evidence suggests that EGFR amplification and EGFRvIII mutations may occur more often in pediatric HGGs than previously recognized.	('adult gliomas', 'Disease', (59, 72))	('HGGs', 'Disease', (180, 184))	('EGFR', 'Gene', (104, 108))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('amplification', 'Var', (109, 122))	('adult gliomas', 'Disease', 'MESH:D005910', (59, 72))	('mutations', 'Var', (136, 145))	('EGFRvIII', 'Gene', (127, 135))	('gliomas', 'Phenotype', 'HP:0009733', (65, 72))
49735	23450706	In a pediatric GBM cell line which was resistant to temozolomide in the absence of MGMT, discovered a PI3-K-mediated HOX/stem cell resistance gene signature.	('temozolomide', 'Chemical', 'MESH:D000077204', (52, 64))	('MGMT', 'Gene', '4255', (83, 87))	('PI3-K-mediated', 'Var', (102, 116))	('MGMT', 'Gene', (83, 87))
49740	23450706	showed that the CD133+ fraction in D456MG, a pediatric GBM, was enriched after radiation, and the CD133+ GSCs survived radiation by more effectively repairing radiation-induced DNA damage compared to CD133- cells.	('CD133+', 'Var', (98, 104))	('more effectively', 'PosReg', (132, 148))	('D456MG', 'Chemical', '-', (35, 41))	('D456MG', 'Var', (35, 41))	('repairing radiation-induced DNA damage', 'MPA', (149, 187))
49755	23450706	Candidate viruses either normally do not cause human disease but replicate in GSCs with altered signaling pathways or deficient interferon responses, or they contain mutations that prevent the virus from infecting or replicating in normal cells but permit infection and replication in GSCs.	('mutations', 'Var', (166, 175))	('replicating', 'CPA', (217, 228))	('prevent', 'NegReg', (181, 188))	('altered', 'Reg', (88, 95))	('infecting', 'CPA', (204, 213))	('human', 'Species', '9606', (47, 52))
49762	23450706	Importantly, deletion of certain HSV genes (e.g., the gamma134.5 neurovirulence gene) facilitates selective replication in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('HSV genes', 'Gene', (33, 42))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('facilitates', 'PosReg', (86, 97))	('deletion', 'Var', (13, 21))	('selective', 'CPA', (98, 107))	('glioma', 'Disease', (123, 129))
49763	23450706	In the unlikely event that a mutant virus produces toxicity in normal brain tissue, effective antiviral agents are clinically available.	('mutant', 'Var', (29, 35))	('toxicity', 'Disease', (51, 59))	('toxicity', 'Disease', 'MESH:D064420', (51, 59))
49766	23450706	It contains deletions in both copies of the gamma134.5 gene and a LacZ gene insertion (which encodes beta-galactosidase) into the UL39 locus thereby disabling expression of ICP6, the heavy chain for viral ribonucleotide reductase (RR).	('deletions', 'Var', (12, 21))	('beta-galactosidase', 'Gene', '2720', (101, 119))	('beta-galactosidase', 'Gene', (101, 119))	('LacZ gene', 'Gene', (66, 75))	('disabling', 'NegReg', (149, 158))	('viral ribonucleotide reductase', 'Disease', 'MESH:D001102', (199, 229))	('viral ribonucleotide reductase', 'Disease', (199, 229))	('expression', 'MPA', (159, 169))	('ICP6', 'Gene', (173, 177))
49771	23450706	Oncolytic HSVs deleted for the gamma134.5 gene are unable to evade PKR-mediated translational arrest thus limiting viral replication in normal cells containing a functional PKR response.	('viral replication', 'MPA', (115, 132))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('PKR', 'Gene', '5610', (67, 70))	('PKR', 'Gene', '5610', (173, 176))	('gamma134.5', 'Gene', (31, 41))	('arrest', 'Disease', (94, 100))	('limiting', 'NegReg', (106, 114))	('deleted', 'Var', (15, 22))	('PKR', 'Gene', (67, 70))	('PKR', 'Gene', (173, 176))
49773	23450706	Mutant viruses with gamma134.5-deletions may replicate in tumor cells which have defective signaling pathways (e.g., defective PTEN and activated MAPK, both of which can be present in HGG), or activating ras mutations that results in defective PKR.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('MAPK', 'Pathway', (146, 150))	('signaling pathways', 'Pathway', (91, 109))	('gamma134.5-deletions', 'Var', (20, 40))	('activated', 'PosReg', (136, 145))	('defective', 'NegReg', (81, 90))	('mutations', 'Var', (208, 217))	('PKR', 'Gene', '5610', (244, 247))	('ras', 'Gene', (204, 207))	('PTEN', 'Protein', (127, 131))	('PKR', 'Gene', (244, 247))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('defective', 'NegReg', (117, 126))	('activating', 'PosReg', (193, 203))
49775	23450706	The lacZ insertion adds additional protection for normal cells because RR is vital for nucleotide synthesis necessary for viral replication and mutants are hypersensitive to acyclovir.	('mutants', 'Var', (144, 151))	('acyclovir', 'Chemical', 'MESH:D000212', (174, 183))	('lacZ', 'Gene', (4, 8))	('hypersensitive', 'Disease', 'MESH:D004342', (156, 170))	('hypersensitive', 'Disease', (156, 170))
49777	23450706	Similar to G207, HSV1716 contains deletions in both copies of the gamma134.5 gene (also identified as RL1); however HSV1716 was derived from wild-type strain 17 which is a temperature insensitive isolate unlike the parental HSV-1(F) strain for G207.	('strain 17', 'Species', '2743', (151, 160))	('HSV-1', 'Species', '10298', (224, 229))	('deletions', 'Var', (34, 43))	('gamma134.5', 'Gene', (66, 76))
49778	23450706	HSV1716 virulence is greater than that of G207 based on murine studies and the maximum safe dose [105 PFU (plaque-forming unit) for 1716 vs. 3 x 109 PFU for G207] used in clinical trials.	('virulence', 'MPA', (8, 17))	('murine', 'Species', '10090', (56, 62))	('greater', 'PosReg', (21, 28))	('HSV1716', 'Var', (0, 7))
49785	23450706	The only abnormality seen was histological and MRI evidence of unilateral ventriculomegaly ipsilateral to the injection site in some of the G207-treated mice and in one saline-injected mouse that was attributed most likely to free-hand injection resulting in intraventricular delivery of the virus.	('mouse', 'Species', '10090', (185, 190))	('unilateral ventriculomegaly ipsilateral', 'Disease', (63, 102))	('ventriculomegaly', 'Phenotype', 'HP:0002119', (74, 90))	('G207-treated', 'Var', (140, 152))	('unilateral ventriculomegaly ipsilateral', 'Disease', 'MESH:D006849', (63, 102))	('mice', 'Species', '10090', (153, 157))	('saline', 'Chemical', 'MESH:D012965', (169, 175))
49795	23450706	While neither virus has been used in children with HGGs, HSV1716 is currently being used in a phase I trial in children older than 6 with recurrent solid tumors outside the central nervous system (ClinicalTrials.gov identifier: NCT00931931).	('tumors outside the central nervous system', 'Phenotype', 'HP:0100006', (154, 195))	('solid tumors', 'Disease', 'MESH:D009369', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('children', 'Species', '9606', (111, 119))	('children', 'Species', '9606', (37, 45))	('HSV1716', 'Var', (57, 64))	('solid tumors', 'Disease', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
49811	23450706	This was confirmed with cytotoxicity testing in vitro; the lethal dose required to kill 50% (LD50) of CD133+ or CD133- D456MG cells was not significantly different, and D456MG, including the GSCs, were more sensitive to killing by G207 and M002 than six adult GBM xenografts tested.	('D456MG', 'Chemical', '-', (119, 125))	('sensitive', 'MPA', (207, 216))	('cytotoxicity', 'Disease', (24, 36))	('D456MG', 'Chemical', '-', (169, 175))	('D456MG', 'Var', (169, 175))	('G207', 'Var', (231, 235))	('cytotoxicity', 'Disease', 'MESH:D064420', (24, 36))
49812	23450706	Athymic nude mice with D456MG implanted intracranially lived significantly longer after a single injection of the oHSV C134, a chimeric gamma134.5-deleted virus with the human cytomegalovirus (HCMV) IRS1 gene under control of the HCMV immediate early promoter; this insertion improves viral replication without restoring neurovirulence.	('improves', 'PosReg', (276, 284))	('viral replication', 'MPA', (285, 302))	('longer', 'PosReg', (75, 81))	('HCMV', 'Species', '10359', (230, 234))	('oHSV', 'Chemical', '-', (114, 118))	('IRS1', 'Gene', (199, 203))	('nude mice', 'Species', '10090', (8, 17))	('HCMV', 'Species', '10359', (193, 197))	('human cytomegalovirus', 'Species', '10359', (170, 191))	('IRS1', 'Gene', '3077574', (199, 203))	('D456MG', 'Chemical', '-', (23, 29))	('D456MG', 'Var', (23, 29))
49814	23450706	Interestingly, when GBM xenograft cells including D456MG were grown in 1% hypoxia to simulate the more severe physiologic hypoxic environment that glioma cells experience in vivo, nectin-1 expression increased significantly (12% increase in D456MG cells).	('hypoxic', 'Disease', (122, 129))	('hypoxic', 'Disease', 'MESH:D000860', (122, 129))	('nectin-1', 'Gene', (180, 188))	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('D456MG', 'Var', (241, 247))	('D456MG', 'Chemical', '-', (241, 247))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('hypoxia', 'Disease', (74, 81))	('increase', 'PosReg', (229, 237))	('increased', 'PosReg', (200, 209))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('expression', 'MPA', (189, 199))	('D456MG', 'Chemical', '-', (50, 56))	('nectin-1', 'Gene', '5818', (180, 188))	('glioma', 'Disease', (147, 153))
49816	23450706	Despite the increase in nectin-1, gamma134.5-deleted virus infectivity, replication, and cytotoxicity were significantly diminished in the pediatric GBM xenograft model under hypoxia.	('infectivity', 'CPA', (59, 70))	('nectin-1', 'Gene', '5818', (24, 32))	('cytotoxicity', 'Disease', (89, 101))	('increase', 'PosReg', (12, 20))	('hypoxia', 'Disease', 'MESH:D000860', (175, 182))	('replication', 'CPA', (72, 83))	('diminished', 'NegReg', (121, 131))	('hypoxia', 'Disease', (175, 182))	('gamma134.5-deleted', 'Var', (34, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))	('nectin-1', 'Gene', (24, 32))
49818	23450706	The decreased efficacy of a gamma134.5-deleted virus in physiologic hypoxic conditions is not inconsequential.	('hypoxic conditions', 'Disease', 'MESH:D009135', (68, 86))	('hypoxic conditions', 'Disease', (68, 86))	('gamma134.5-deleted', 'Var', (28, 46))
49820	23450706	While hypoxia significantly increased the CD133+ fraction in D456MG by nearly fourfold and decreased the percentage of CD133+ GSC infected, there was not a significant difference in the percentage of CD133+ cells infected compared to all tumor cells in normoxia or hypoxia suggesting that the CD133+ cells were not inherently more resistant (Figure 2).	('increased', 'PosReg', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('decreased', 'NegReg', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('hypoxia', 'Disease', 'MESH:D000860', (6, 13))	('tumor', 'Disease', (238, 243))	('hypoxia', 'Disease', (6, 13))	('hypoxia', 'Disease', (265, 272))	('hypoxia', 'Disease', 'MESH:D000860', (265, 272))	('CD133+', 'MPA', (42, 48))	('D456MG', 'Chemical', '-', (61, 67))	('D456MG', 'Var', (61, 67))
49832	23450706	While gamma134.5-deleted viruses can replicate in HGGs, replication is attenuated compared to wild-type HSV-1.	('HSV-1', 'Species', '10298', (104, 109))	('replication', 'MPA', (56, 67))	('attenuated', 'NegReg', (71, 81))	('gamma134.5-deleted', 'Var', (6, 24))
49836	23450706	Compared to its parent gamma134.5-deleted virus, C134 was superior at improving survival in animals with gliomas.	('improving', 'PosReg', (70, 79))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('C134', 'Var', (49, 53))	('survival', 'CPA', (80, 88))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))
49839	23450706	Recent research suggests ICP34.5 confers neurovirulence by inhibiting autophagy through beclin-1.	('beclin-1', 'Gene', '8678', (88, 96))	('autophagy', 'CPA', (70, 79))	('neurovirulence', 'MPA', (41, 55))	('ICP34.5', 'Var', (25, 32))	('inhibiting', 'NegReg', (59, 69))	('beclin-1', 'Gene', (88, 96))
49840	23450706	developed Delta68H-6, an ICP6 mutant with the gamma134.5 gene intact except for the Beclin-1 binding domain.	('Beclin-1', 'Gene', '8678', (84, 92))	('Delta68H-6', 'Var', (10, 20))	('Beclin-1', 'Gene', (84, 92))
49841	23450706	The mutant virus was minimally neuropathogenic but replicated well in GSCs in vitro and prolonged survival in mice bearing orthotopic gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('survival', 'CPA', (98, 106))	('mutant', 'Var', (4, 10))	('gliomas', 'Disease', (134, 141))	('mice', 'Species', '10090', (110, 114))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('prolonged', 'PosReg', (88, 97))
49842	23450706	In addition to the attenuated replication of gamma134.5-deleted mutants, the tumoral environment of highly necrotic and infiltrative HGGs may limit the virus' ability to infect all GSCs.	('necrotic', 'Disease', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('limit', 'NegReg', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('necrotic', 'Disease', 'MESH:D009336', (107, 115))	('mutants', 'Var', (64, 71))	('tumor', 'Disease', (77, 82))	('ability', 'MPA', (159, 166))
49851	23450706	Compared to its parent virus without Chase-ABC, OV-Chase significantly enhanced spread in glioma spheroids and prolonged survival in animals with intracranial glioma xenografts.	('glioma spheroids', 'Disease', 'MESH:D005910', (90, 106))	('enhanced', 'PosReg', (71, 79))	('glioma spheroids', 'Disease', (90, 106))	('intracranial glioma', 'Disease', (146, 165))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('prolonged', 'PosReg', (111, 120))	('survival', 'CPA', (121, 129))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('OV-Chase', 'Var', (48, 56))	('intracranial glioma', 'Disease', 'MESH:D005910', (146, 165))
49854	23450706	A similar virus that expresses VStat120, 34.5ENVE, was created within the backbone of rQNestin34.5 and likewise prolonged survival in glioma-bearing mice and showed evidence of antiangiogenesis with reduced microvessel density and increased tumoral necrosis compared to a control virus.	('prolonged', 'PosReg', (112, 121))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('Nestin', 'Gene', '10763', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('survival', 'CPA', (122, 130))	('increased', 'PosReg', (231, 240))	('reduced', 'NegReg', (199, 206))	('VStat120', 'Chemical', '-', (31, 39))	('Nestin', 'Gene', (88, 94))	('microvessel density', 'CPA', (207, 226))	('mice', 'Species', '10090', (149, 153))	('tumoral necrosis', 'Phenotype', 'HP:0010885', (241, 257))	('glioma', 'Disease', (134, 140))	('tumoral necrosis', 'Disease', (241, 257))	('tumoral necrosis', 'Disease', 'MESH:D009336', (241, 257))	('VStat120', 'Var', (31, 39))	('antiangiogenesis', 'CPA', (177, 193))
49858	23450706	Similarly, G47Delta-mAngio expresses angiostatin, and in combination with the VEGF inhibitor bevacizumab, the virus increased glioma tumor lysis and angiostatin-mediated inhibition of VEGF leading to a decreased invasive tumor phenotype.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('invasive tumor', 'Disease', (212, 226))	('decreased', 'NegReg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('G47Delta-mAngio', 'Var', (11, 26))	('increased', 'PosReg', (116, 125))	('glioma tumor', 'Disease', 'MESH:D005910', (126, 138))	('bevacizumab', 'Chemical', 'MESH:D000068258', (93, 104))	('invasive tumor', 'Disease', 'MESH:D009369', (212, 226))	('angiostatin', 'Gene', '18815', (149, 160))	('glioma tumor', 'Disease', (126, 138))	('VEGF', 'Gene', '7422', (184, 188))	('angiostatin', 'Gene', (149, 160))	('VEGF', 'Gene', (184, 188))	('angiostatin', 'Gene', '18815', (37, 48))	('VEGF', 'Gene', '7422', (78, 82))	('VEGF', 'Gene', (78, 82))	('angiostatin', 'Gene', (37, 48))
49865	23450706	MG18L, an oHSV with ICP6 disabled and deletion in Us3, which encodes a serine-threonine kinase with multiple functions including inhibition of virus-induced apoptosis and activation of Akt, acted synergistically with PI3-K/Akt inhibitors to target GSCs effectively.	('MG18L', 'Var', (0, 5))	('Akt', 'Gene', (223, 226))	('Us3', 'Gene', (50, 53))	('activation', 'PosReg', (171, 181))	('Akt', 'Gene', '207', (185, 188))	('deletion', 'Var', (38, 46))	('oHSV', 'Chemical', '-', (10, 14))	('Akt', 'Gene', '207', (223, 226))	('MG18L', 'Chemical', '-', (0, 5))	('Akt', 'Gene', (185, 188))
49918	33788825	However, the outcomes are better in those who receive long-term TMZ and those who do not have residual tumor following surgical resection.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('TMZ', 'Var', (64, 67))	('TMZ', 'Chemical', 'MESH:D000077204', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
49923	33788825	It is possible that individual components (eg, TMZ, NK, or DC) with or without CMV-pp65 could have been the cause of the CR.	('NK', 'Chemical', '-', (52, 54))	('TMZ', 'Disease', (47, 50))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('cause', 'Reg', (108, 113))	('CMV-pp65', 'Var', (79, 87))
49924	33788825	A patient with recurrent GBM achieved durable CR with a novel treatment strategy with allogeneic NK cells and DC pulsed with CMV-pp65 despite having residual tumor following surgical resection.	('tumor', 'Disease', (158, 163))	('CMV-pp65', 'Var', (125, 133))	('GBM', 'Phenotype', 'HP:0012174', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('NK', 'Chemical', '-', (97, 99))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (2, 9))
49926	31291646	Regulatory networks between Polycomb complexes and non-coding RNAs in the central nervous system High-throughput sequencing has facilitated the identification of many types of non-coding RNAs (ncRNAs) involved in diverse cellular processes.	('Polycomb', 'Gene', '12416', (28, 36))	('non-coding', 'Var', (176, 186))	('ncRNA', 'Gene', (193, 198))	('ncRNA', 'Gene', '220202', (193, 198))	('Polycomb', 'Gene', (28, 36))
49929	31291646	More importantly, dysregulation of ncRNAs, PcG proteins, and interplay among them is closely associated with the pathogenesis of central nervous system (CNS) disorders.	('ncRNA', 'Gene', '220202', (35, 40))	('PcG proteins', 'Protein', (43, 55))	('interplay', 'Interaction', (61, 70))	('central nervous system (CNS) disorders', 'Disease', 'MESH:D002493', (129, 167))	('associated', 'Reg', (93, 103))	('dysregulation', 'Var', (18, 31))	('ncRNA', 'Gene', (35, 40))
49935	31291646	Moreover, dysregulation of ncRNAs, PcG proteins, and ncRNA-PcG interactions is implicated in the pathogenesis of CNS disorders.	('ncRNA', 'Gene', (53, 58))	('CNS disorders', 'Disease', 'MESH:D002493', (113, 126))	('CNS disorders', 'Disease', (113, 126))	('interactions', 'Interaction', (63, 75))	('dysregulation', 'Var', (10, 23))	('ncRNA', 'Gene', '220202', (53, 58))	('PcG proteins', 'Protein', (35, 47))	('implicated', 'Reg', (79, 89))	('ncRNA', 'Gene', (27, 32))	('ncRNA', 'Gene', '220202', (27, 32))
49941	31291646	Short ncRNAs are a class of <200 nucleotides (nt) transcripts, including microRNAs (miRNAs), small interfering RNAs (siRNAs), and PIWI-associated RNAs (piRNAs).	('PIWI', 'Gene', (130, 134))	('ncRNA', 'Gene', (6, 11))	('PIWI', 'Gene', '9271', (130, 134))	('small interfering', 'Var', (93, 110))	('ncRNA', 'Gene', '220202', (6, 11))
49960	31291646	In addition, lncRNA plasmacytoma variant translocation 1 (PVT1) could facilitate autophagy by acting as a sponge of miR-365, which downregulated ATG3 protein level by targeting 3'-UTR of ATG3 mRNA.	('plasmacytoma variant translocation 1', 'Gene', '5820', (20, 56))	('targeting', 'Reg', (167, 176))	('ATG3', 'Gene', '64422', (145, 149))	('plasmacytoma variant translocation 1', 'Gene', (20, 56))	('plasmacytoma', 'Phenotype', 'HP:0011857', (20, 32))	('facilitate', 'PosReg', (70, 80))	('miR-365', 'Var', (116, 123))	("3'-UTR", 'MPA', (177, 183))	('ATG3', 'Gene', (145, 149))	('PVT1', 'Gene', (58, 62))	('ncRNA', 'Gene', (14, 19))	('ATG3', 'Gene', (187, 191))	('downregulated', 'NegReg', (131, 144))	('autophagy', 'CPA', (81, 90))	('ATG3', 'Gene', '64422', (187, 191))	('PVT1', 'Gene', '5820', (58, 62))	('ncRNA', 'Gene', '220202', (14, 19))
49967	31291646	Mounting evidence reveals that PcG-dependent epigenetic dysregulation is closely associated with many diseases, including epilepsy and glioma tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('epilepsy', 'Phenotype', 'HP:0001250', (122, 130))	('glioma', 'Disease', (135, 141))	('tumor', 'Disease', (142, 147))	('epilepsy', 'Disease', (122, 130))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('epigenetic dysregulation', 'Var', (45, 69))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('epilepsy', 'Disease', 'MESH:D004827', (122, 130))	('associated', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
49981	31291646	Several studies have suggested that PRC2 is responsible for PRC1 recruitment, then PRC1 carries out stable repression via H2AK119ub1 or forming compact chromatin structures.	('H2AK119ub1', 'Var', (122, 132))	('PRC1', 'Gene', (83, 87))	('H2AK119ub1', 'Chemical', '-', (122, 132))
49982	31291646	However, one recent study supported the opposite view that PRC1 is sufficient to recruit PRC2 via H2AK119ub1.	('H2AK119ub1', 'Chemical', '-', (98, 108))	('H2AK119ub1', 'Var', (98, 108))	('PRC2', 'Gene', (89, 93))
49986	31291646	Genetic disruption of EED and Tsix, an antisense transcript of Xist, causes the loss of Xist repression, in spite of the existence of other Xist regulators, such as RNF12, NANOG, and OCT4.	('EED', 'Gene', (22, 25))	('Xist', 'Gene', (63, 67))	('Xist', 'Gene', '7503', (88, 92))	('OCT4', 'Gene', (183, 187))	('loss', 'NegReg', (80, 84))	('Genetic disruption', 'Var', (0, 18))	('NANOG', 'Gene', '79923', (172, 177))	('RNF12', 'Gene', (165, 170))	('Xist', 'Gene', '7503', (140, 144))	('NANOG', 'Gene', (172, 177))	('Xist', 'Gene', '7503', (63, 67))	('Xist', 'Gene', (88, 92))	('Tsix', 'Gene', '9383', (30, 34))	('RNF12', 'Gene', '51132', (165, 170))	('EED', 'Gene', '8726', (22, 25))	('Tsix', 'Gene', (30, 34))	('OCT4', 'Gene', '5460', (183, 187))	('Xist', 'Gene', (140, 144))
49996	31291646	In cultured primary neurons, PRC2 interacts with the lncRNA survival motor neuron-antisense 1 (SMN-AS1), transcribed within the SMN2 promoter, thereby repressing SMN2 expression by PRC2-associated epigenetic changes.	('epigenetic changes', 'Var', (197, 215))	('AS1', 'Gene', '11881', (99, 102))	('ncRNA', 'Gene', (54, 59))	('PRC2-associated', 'Gene', (181, 196))	('AS1', 'Gene', (99, 102))	('PRC2', 'Gene', (29, 33))	('ncRNA', 'Gene', '220202', (54, 59))	('expression', 'MPA', (167, 177))	('SMN2', 'Gene', (162, 166))	('repressing', 'PosReg', (151, 161))
50000	31291646	Upregulation of lncOL1 can induce oligodendrocyte differentiation in the developing brain, whereas inactivation of lncOL1 leads to defects in the CNS myelination and remyelination following injury (; Figure 2).	('Upregulation', 'PosReg', (0, 12))	('lncOL1', 'Gene', (115, 121))	('defects', 'NegReg', (131, 138))	('oligodendrocyte differentiation', 'CPA', (34, 65))	('induce', 'Reg', (27, 33))	('lncOL1', 'Gene', (16, 22))	('CNS myelination', 'CPA', (146, 161))	('remyelination following injury', 'Disease', (166, 196))	('remyelination following injury', 'Disease', 'MESH:C537491', (166, 196))	('inactivation', 'Var', (99, 111))
50008	31291646	Epigenetic dysregulation has a significant role in neurological disorders, including CNS tumor and monogenic disease, etc.	('Epigenetic dysregulation', 'Var', (0, 24))	('CNS tumor', 'Phenotype', 'HP:0100006', (85, 94))	('neurological disorders', 'Disease', (51, 73))	('CNS tumor', 'Disease', (85, 94))	('monogenic disease', 'Disease', (99, 116))	('role', 'Reg', (43, 47))	('neurological disorders', 'Disease', 'MESH:D009422', (51, 73))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('CNS tumor', 'Disease', 'MESH:D016543', (85, 94))
50009	31291646	Thus, epigenetic mechanism will lead to a potential new therapeutic strategy or biomarker discovery for several neurological disorders.	('lead to', 'Reg', (32, 39))	('epigenetic mechanism', 'Var', (6, 26))	('neurological disorders', 'Disease', (112, 134))	('neurological disorders', 'Disease', 'MESH:D009422', (112, 134))
50024	31291646	Several miRNAs including miR-130a, miR-155, miR-328, and miR-210 are downregulated in GBM, while some are upregulated, such as miR-323, miR-326, miR-21, and miR-329.	('miR-329', 'Var', (157, 164))	('miR-323', 'Gene', '442897', (127, 134))	('miR-130a', 'Gene', '406919', (25, 33))	('miR-21', 'Gene', '406991', (145, 151))	('miR-130a', 'Gene', (25, 33))	('miR-21', 'Gene', '406991', (57, 63))	('miR-328', 'Gene', (44, 51))	('upregulated', 'PosReg', (106, 117))	('miR-155', 'Gene', (35, 42))	('downregulated', 'NegReg', (69, 82))	('miR-21', 'Gene', (145, 151))	('miR-21', 'Gene', (57, 63))	('miR-210', 'Gene', '406992', (57, 64))	('miR-328', 'Gene', '442901', (44, 51))	('miR-155', 'Gene', '406947', (35, 42))	('miR-326', 'Gene', (136, 143))	('miR-210', 'Gene', (57, 64))	('miR-323', 'Gene', (127, 134))	('miR-326', 'Gene', '442900', (136, 143))
50032	31291646	Furthermore, miR-128 in NSCs and glioma-initiating cells dramatically decreased the volume of neurospheres following the loss of BMI1.	('glioma', 'Disease', (33, 39))	('loss', 'NegReg', (121, 125))	('BMI1', 'Gene', (129, 133))	('miR-128', 'Chemical', '-', (13, 20))	('decreased', 'NegReg', (70, 79))	('volume of neurospheres', 'CPA', (84, 106))	('miR-128', 'Var', (13, 20))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))
50034	31291646	The expression of miR-194 is significantly reduced in glioma specimens and cell lines, and the dysregulation of miR-194 has a key role in cell migration and invasion of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('glioma', 'Disease', (169, 175))	('dysregulation', 'Var', (95, 108))	('invasion', 'CPA', (157, 165))	('expression', 'MPA', (4, 14))	('cell migration', 'CPA', (138, 152))	('glioma', 'Disease', (54, 60))	('miR-194', 'Gene', (18, 25))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('reduced', 'NegReg', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('miR-194', 'Gene', (112, 119))
50035	31291646	Moreover, bioinformatics analysis reveals that BMI1 is a functional target of miR-194 in glioma cells, and the recovery of BMI1 expression significantly abrogates the inhibitory effect of miR-194 on the epithelial-mesenchymal transition (EMT) of glioma cells.	('recovery', 'Var', (111, 119))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('abrogates', 'NegReg', (153, 162))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('BMI1', 'Gene', (123, 127))	('glioma', 'Disease', (246, 252))	('inhibitory effect', 'MPA', (167, 184))	('glioma', 'Disease', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
50043	31291646	miR-128a exerts a growth suppressive activity in MB, which is partially mediated by targeting BMI1.	('BMI1', 'Gene', (94, 98))	('growth suppressive activity', 'CPA', (18, 45))	('miR-128a', 'Chemical', '-', (0, 8))	('miR-128a', 'Var', (0, 8))
50044	31291646	Additionally, EZH2 is highly expressed in MB and important for the transformation of NSCs, meanwhile the inhibition of EZH2 suppresses MB cell growth and tumor sphere formation partially by inducing apoptosis.	('suppresses', 'NegReg', (124, 134))	('EZH2', 'Gene', (119, 123))	('inhibition', 'Var', (105, 115))	('MB cell growth', 'CPA', (135, 149))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('apoptosis', 'CPA', (199, 208))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('inducing', 'Reg', (190, 198))	('NSCs', 'Disease', (85, 89))	('tumor', 'Disease', (154, 159))
50046	31291646	Spinal muscular atrophy (SMA) is a debilitating and fatal neuromuscular disorder with loss of spinal cord motor neurons and substantial muscle atrophy, owing to the homozygous mutation or deletion of SMN1 gene at position 5q13 on chromosome 5.	('muscle atrophy', 'Disease', (136, 150))	('Spinal muscular atrophy', 'Disease', (0, 23))	('loss of spinal cord motor neurons', 'Disease', (86, 119))	('Spinal muscular atrophy', 'Disease', 'MESH:D009134', (0, 23))	('muscle atrophy', 'Disease', 'MESH:D009133', (136, 150))	('fatal neuromuscular disorder', 'Disease', 'MESH:D009468', (52, 80))	('fatal neuromuscular disorder', 'Disease', (52, 80))	('deletion', 'Var', (188, 196))	('SMN1', 'Gene', '6606', (200, 204))	('Spinal muscular atrophy', 'Phenotype', 'HP:0007269', (0, 23))	('muscular atrophy', 'Phenotype', 'HP:0003202', (7, 23))	('loss of spinal cord motor neurons', 'Disease', 'MESH:D016472', (86, 119))	('SMN1', 'Gene', (200, 204))	('muscle atrophy', 'Phenotype', 'HP:0003202', (136, 150))
50052	31291646	In addition, accumulating evidence has shown that dysregulation of ncRNAs, PcG proteins, and ncRNA-PcG interactions is often related to aggressive clinic pathological features and poor prognosis in various kinds of cancer.	('ncRNA', 'Gene', '220202', (93, 98))	('related', 'Reg', (125, 132))	('cancer', 'Disease', (215, 221))	('PcG proteins', 'Protein', (75, 87))	('ncRNA', 'Gene', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('interactions', 'Interaction', (103, 115))	('ncRNA', 'Gene', '220202', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ncRNA', 'Gene', (93, 98))	('dysregulation', 'Var', (50, 63))
50058	31291646	miR-139-5p directly bind to the 3'-UTR of BMI1 mRNA to suppress BMI1 translation, suggesting that they are potential therapeutic targets for bladder cancer treatment.	('bladder cancer', 'Disease', (141, 155))	('BMI1 translation', 'MPA', (64, 80))	('miR-139-5p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('BMI1', 'Gene', (42, 46))	('miR-139-5p', 'Chemical', '-', (0, 10))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('suppress', 'NegReg', (55, 63))
50071	31291646	The dynamic and reversible nature of epigenetic regulation by ncRNAs is emblematic of its ubiquitous importance in modifying gene expression.	('ncRNA', 'Gene', '220202', (62, 67))	('epigenetic regulation', 'Var', (37, 58))	('ncRNA', 'Gene', (62, 67))
50075	31291646	Thus, it is obvious that PcG complexes and ncRNAs play vital roles in the CNS development and function, and their dysregulation is implicated in neurodegenerative, neurodevelopmental, neuroimmunological, and neurological diseases.	('implicated', 'Reg', (131, 141))	('neurological diseases', 'Disease', 'MESH:D020271', (208, 229))	('ncRNA', 'Gene', (43, 48))	('ncRNA', 'Gene', '220202', (43, 48))	('CNS development', 'CPA', (74, 89))	('dysregulation', 'Var', (114, 127))	('neurological diseases', 'Disease', (208, 229))
50103	32098401	Among the particles with increased expression, the authors most often mentioned: miR10b, miR17-92, miR21, miR26a, miR92 miR221/222, miR335, miR451, and miR486 while the low levels were often presented by: miR7, miR34a, miR106a, miR124, miR128, miR129, miR137, miR139, miR-181a, miR181b, miR218, miR323 and miR328, and miR342-3p.	('miR342', 'Gene', (318, 324))	('miR-181a', 'Var', (268, 276))	('miR21', 'Gene', (99, 104))	('miR92', 'Gene', '407047', (114, 119))	('miR181b', 'Var', (278, 285))	('miR34a', 'Gene', '407040', (211, 217))	('miR92', 'Gene', (114, 119))	('miR128', 'Chemical', '-', (236, 242))	('miR21', 'Gene', '406991', (99, 104))	('miR26a', 'Gene', (106, 112))	('miR21', 'Gene', (287, 292))	('miR139', 'Gene', (260, 266))	('miR7', 'Gene', '10859', (205, 209))	('miR124', 'Var', (228, 234))	('miR328', 'Gene', '442901', (306, 312))	('miR129', 'Var', (244, 250))	('miR106a', 'Gene', (219, 226))	('miR21', 'Gene', '406991', (287, 292))	('miR323', 'Gene', '442897', (295, 301))	('miR137', 'Gene', (252, 258))	('miR7', 'Gene', (205, 209))	('miR17-92', 'Gene', (89, 97))	('miR328', 'Gene', (306, 312))	('miR128', 'Var', (236, 242))	('miR10b', 'Gene', '406903', (81, 87))	('miR17-92', 'Gene', '407975', (89, 97))	('miR221', 'Gene', '407006', (120, 126))	('miR139', 'Gene', '406931', (260, 266))	('miR26a', 'Gene', '407015', (106, 112))	('miR323', 'Gene', (295, 301))	('miR221', 'Gene', (120, 126))	('miR342', 'Gene', '442909', (318, 324))	('miR451', 'Gene', (140, 146))	('miR10b', 'Gene', (81, 87))	('miR486', 'Gene', (152, 158))	('miR106a', 'Gene', '406899', (219, 226))	('miR486', 'Gene', '619554', (152, 158))	('miR34a', 'Gene', (211, 217))	('miR335', 'Gene', (132, 138))	('miR137', 'Gene', '406928', (252, 258))	('miR335', 'Gene', '442904', (132, 138))	('miR451', 'Gene', '574411', (140, 146))
50115	32098401	The immunological variability of GBM harmonizes with IDH 1/2 mutations.	('IDH 1/2', 'Gene', (53, 60))	('mutations', 'Var', (61, 70))	('IDH 1/2', 'Gene', '3417;3418', (53, 60))	('GBM', 'Disease', (33, 36))	('GBM', 'Disease', 'MESH:D005909', (33, 36))
50119	32098401	Particular molecules interplay with precise IC: miR-28 (PD-1), miR-34a (PD-L1), mir-124 (PD-1), mir-138 (PD-1 and CTLA-4), miR-138-5p (PD-L1), mir-155 (CTLA4), miR-200 (PD-L1) miR-424 (PD-L1), and miR-513, (PD-L1).	('miR-138', 'Chemical', '-', (123, 130))	('miR-200', 'Var', (160, 167))	('miR-28', 'Gene', '407020', (48, 54))	('mir-138', 'Var', (96, 103))	('CTLA-4', 'Gene', '1493', (114, 120))	('mir-155', 'Gene', (143, 150))	('CTLA-4', 'Gene', (114, 120))	('mir-155', 'Gene', '406947', (143, 150))	('mir-124', 'Var', (80, 87))	('miR-424', 'Gene', (176, 183))	('miR-28', 'Gene', (48, 54))	('CTLA4', 'Gene', '1493', (152, 157))	('miR-424', 'Gene', '494336', (176, 183))	('miR-138-5p', 'Var', (123, 133))	('miR-34a', 'Gene', (63, 70))	('CTLA4', 'Gene', (152, 157))	('miR-513', 'Var', (197, 204))	('miR-200', 'Chemical', '-', (160, 167))	('miR-34a', 'Gene', '407040', (63, 70))
50134	32098401	miR-424 and miR 513 inhibit PD-1L formation in glioma.	('miR-424', 'Gene', (0, 7))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('miR-424', 'Gene', '494336', (0, 7))	('glioma', 'Disease', (47, 53))	('miR 513', 'Var', (12, 19))	('PD-1L formation', 'MPA', (28, 43))	('inhibit', 'NegReg', (20, 27))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
50136	32098401	PD-1L in GBM is blocked by miR-513, miR 424, miR-200, miR-138-5p, miR-124, and miR 34a.	('miR-138', 'Chemical', '-', (54, 61))	('miR-200', 'Var', (45, 52))	('miR-200', 'Chemical', '-', (45, 52))	('PD-1L', 'Gene', (0, 5))	('miR-124', 'Var', (66, 73))	('GBM', 'Disease', (9, 12))	('miR 34a', 'Gene', '407040', (79, 86))	('miR-513', 'Var', (27, 34))	('miR-138-5p', 'Var', (54, 64))	('miR 34a', 'Gene', (79, 86))	('miR 424', 'Gene', '494336', (36, 43))	('GBM', 'Disease', 'MESH:D005909', (9, 12))	('miR 424', 'Gene', (36, 43))
50147	32098401	The group consisted of: miR7, miR15b, miR21, miR124a, miR129, miR139, and miR218.	('miR124a', 'Gene', (45, 52))	('miR139', 'Gene', '406931', (62, 68))	('miR15b', 'Gene', (30, 36))	('miR124a', 'Gene', '406907', (45, 52))	('miR21', 'Gene', (38, 43))	('miR139', 'Gene', (62, 68))	('miR21', 'Gene', '406991', (74, 79))	('miR7', 'Gene', (24, 28))	('miR129', 'Var', (54, 60))	('miR7', 'Gene', '10859', (24, 28))	('miR15b', 'Gene', '406949', (30, 36))	('miR21', 'Gene', (74, 79))	('miR21', 'Gene', '406991', (38, 43))
50160	32098401	Many researchers also pointed out other miRNAs in which presence may be associated with better prognosis and longer survival of patients with glioma and glioblastoma.	('presence', 'Var', (56, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('glioma', 'Disease', (142, 148))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('patients', 'Species', '9606', (128, 136))	('glioblastoma', 'Disease', (153, 165))
50161	32098401	This group includes, among others (Table 1): miR29c, miR101, miR107, miR144-3p, mir181d, miR203, miR205, and miR328.	('miR29c', 'Gene', '407026', (45, 51))	('miR205', 'Gene', '406988', (97, 103))	('mir181d', 'Gene', '574457', (80, 87))	('miR101', 'Var', (53, 59))	('mir181d', 'Gene', (80, 87))	('miR144', 'Gene', '406936', (69, 75))	('miR205', 'Gene', (97, 103))	('miR203', 'Gene', (89, 95))	('miR144', 'Gene', (69, 75))	('miR107', 'Gene', '406901', (61, 67))	('miR328', 'Gene', (109, 115))	('miR29c', 'Gene', (45, 51))	('miR203', 'Gene', '406986', (89, 95))	('miR328', 'Gene', '442901', (109, 115))	('miR107', 'Gene', (61, 67))
50162	32098401	on 480 GMB samples, it was noted that patients with longer survival rates showed high levels of miR130a and miR326, as well as low levels of miR155, miR210, miR323, and miR329.	('miR323', 'Gene', (157, 163))	('miR326', 'Gene', '442900', (108, 114))	('miR155', 'Gene', (141, 147))	('miR130a', 'Gene', '406919', (96, 103))	('miR210', 'Gene', '406992', (149, 155))	('patients', 'Species', '9606', (38, 46))	('miR155', 'Gene', '406947', (141, 147))	('miR329', 'Var', (169, 175))	('miR326', 'Gene', (108, 114))	('GMB', 'Chemical', 'MESH:C032138', (7, 10))	('miR130a', 'Gene', (96, 103))	('miR210', 'Gene', (149, 155))	('miR323', 'Gene', '442897', (157, 163))
50167	32098401	In the work carried out by Regazzo et al., it has been shown that testing the level of expression of some miRNAs (miR125b, miR497) can provide information on whether the examined tumor belongs to high-grade glioma or low grade.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('miR497', 'Gene', '574456', (123, 129))	('glioma', 'Disease', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('miR497', 'Gene', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('miR125b', 'Var', (114, 121))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('tumor', 'Disease', (179, 184))
50169	32098401	The existence of similar correlations has been demonstrated by many other researchers, including: miR19, miR137, miR144-3p, and miR182.	('miR137', 'Gene', '406928', (105, 111))	('miR182', 'Gene', (128, 134))	('miR182', 'Gene', '406958', (128, 134))	('miR137', 'Gene', (105, 111))	('miR19', 'Var', (98, 103))	('miR144', 'Gene', '406936', (113, 119))	('miR144', 'Gene', (113, 119))
50170	32098401	It was also found that the relationship between the stage of tumor histology is positive for miR19 and miR182, and negative for le7e, miR145 and miR181a.	('miR145', 'Gene', '406937', (134, 140))	('miR19', 'Var', (93, 98))	('miR181a', 'Var', (145, 152))	('miR182', 'Gene', (103, 109))	('miR182', 'Gene', '406958', (103, 109))	('le7e', 'Var', (128, 132))	('positive', 'Reg', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR145', 'Gene', (134, 140))	('negative', 'NegReg', (115, 123))	('tumor', 'Disease', (61, 66))
50174	32098401	They included: miR9, miR15a, miR16, miR17, miR19a, miR20a, miR21, miR25, miR28, miR130b, and miR140; miR210 (elevated level); and miR184 and miR328 (reduced level).	('miR140', 'Gene', (93, 99))	('miR16', 'Gene', (29, 34))	('miR328', 'Gene', '442901', (141, 147))	('miR17', 'Gene', (36, 41))	('miR140', 'Gene', '406932', (93, 99))	('miR130b', 'Gene', (80, 87))	('miR20a', 'Gene', '406982', (51, 57))	('miR210', 'Gene', (101, 107))	('miR184', 'Gene', '406960', (130, 136))	('miR328', 'Gene', (141, 147))	('miR19a', 'Gene', '406979', (43, 49))	('miR17', 'Gene', '406952', (36, 41))	('miR21', 'Gene', '406991', (59, 64))	('miR15a', 'Gene', (21, 27))	('miR28', 'Gene', (73, 78))	('miR9', 'Var', (15, 19))	('miR15a', 'Gene', '406948', (21, 27))	('miR21', 'Gene', (101, 106))	('miR16', 'Gene', '51573', (29, 34))	('miR25', 'Gene', '407014', (66, 71))	('miR21', 'Gene', (59, 64))	('miR28', 'Gene', '407020', (73, 78))	('miR21', 'Gene', '406991', (101, 106))	('miR210', 'Gene', '406992', (101, 107))	('miR25', 'Gene', (66, 71))	('miR184', 'Gene', (130, 136))	('miR130b', 'Gene', '406920', (80, 87))	('miR19a', 'Gene', (43, 49))	('miR20a', 'Gene', (51, 57))
50175	32098401	also found that the levels of miR21, miR128 and miR342-3p change under the influence of anti-cancer treatment (returns to levels characteristic of healthy tissue).	('miR128', 'Var', (37, 43))	('cancer', 'Disease', (93, 99))	('miR21', 'Gene', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('change', 'Reg', (58, 64))	('miR128', 'Chemical', '-', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miR342', 'Gene', '442909', (48, 54))	('miR342', 'Gene', (48, 54))	('miR21', 'Gene', '406991', (30, 35))
50186	32098401	Inactivation of O6-methylguanine-DNA methyl-transferase would allow blocking repair processes, thereby increasing the effectiveness of temozolomide.	('O6-methylguanine-DNA methyl-transferase', 'Gene', '4255', (16, 55))	('effectiveness', 'MPA', (118, 131))	('O6-methylguanine-DNA methyl-transferase', 'Gene', (16, 55))	('increasing', 'PosReg', (103, 113))	('temozolomide', 'Chemical', 'MESH:D000077204', (135, 147))	('blocking', 'NegReg', (68, 76))	('repair processes', 'CPA', (77, 93))	('Inactivation', 'Var', (0, 12))
50187	32098401	The first studies regarding silencing of MGMT in gliomas date back to 2005.	('gliomas', 'Phenotype', 'HP:0009733', (49, 56))	('gliomas', 'Disease', (49, 56))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('silencing', 'Var', (28, 37))	('MGMT', 'Gene', '4255', (41, 45))	('MGMT', 'Gene', (41, 45))	('gliomas', 'Disease', 'MESH:D005910', (49, 56))
50189	32098401	The results indicated that the methylation of the O6-methylguanine-DNA methyl-transferase promoter predicted a positive response to treatment regardless of other factors.	('O6-methylguanine-DNA methyl-transferase', 'Gene', '4255', (50, 89))	('methylation', 'Var', (31, 42))	('O6-methylguanine-DNA methyl-transferase', 'Gene', (50, 89))	('positive', 'PosReg', (111, 119))
50206	32098401	conducted on 22 patients with primary glioblastoma suggested that there was no correlation between the survival rate of chemoradiotherapy-treated patients and MGMT methylation status.	('MGMT', 'Gene', '4255', (159, 163))	('methylation', 'Var', (164, 175))	('patients', 'Species', '9606', (16, 24))	('glioblastoma', 'Disease', (38, 50))	('MGMT', 'Gene', (159, 163))	('glioblastoma', 'Disease', 'MESH:D005909', (38, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('patients', 'Species', '9606', (146, 154))
50207	32098401	However, the authors found that miR181b and miR181c levels may serve as a marker of a positive response of glioblastoma patients to chemoradiotherapy with TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (155, 158))	('miR181c', 'Gene', (44, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('glioblastoma', 'Disease', (107, 119))	('miR181b', 'Var', (32, 39))	('patients', 'Species', '9606', (120, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('miR181c', 'Gene', '406957', (44, 51))
50219	32098401	Overexpression of this micro RNA was associated with inhibition of the sensitivity of GBM cells to TMZ.	('inhibition', 'NegReg', (53, 63))	('GBM', 'Disease', (86, 89))	('GBM', 'Disease', 'MESH:D005909', (86, 89))	('TMZ', 'Chemical', 'MESH:D000077204', (99, 102))	('Overexpression', 'Var', (0, 14))	('sensitivity', 'MPA', (71, 82))
50226	32098401	They included miR10a, miR195 and miR455-3p.	('miR10a', 'Gene', '406902', (14, 20))	('miR10a', 'Gene', (14, 20))	('miR195', 'Gene', (22, 28))	('miR195', 'Gene', '406971', (22, 28))	('miR455-3p', 'Var', (33, 42))
50228	32098401	Other researchers also mentioned in this group: miR17-5p, miR101, miR155, miR193a-5p, miR203, miR204, miR221, miR222, and miR328.	('miR155', 'Gene', (66, 72))	('miR221', 'Gene', (102, 108))	('miR204', 'Gene', '406987', (94, 100))	('miR203', 'Gene', '406986', (86, 92))	('miR101', 'Var', (58, 64))	('miR328', 'Gene', (122, 128))	('miR17-5p', 'Gene', (48, 56))	('miR155', 'Gene', '406947', (66, 72))	('miR222', 'Gene', '407007', (110, 116))	('miR193a', 'Gene', '406968', (74, 81))	('miR221', 'Gene', '407006', (102, 108))	('miR222', 'Gene', (110, 116))	('miR203', 'Gene', (86, 92))	('miR328', 'Gene', '442901', (122, 128))	('miR17-5p', 'Gene', '406952', (48, 56))	('miR193a', 'Gene', (74, 81))	('miR204', 'Gene', (94, 100))
50237	30871102	When divided into malignancy groups, the regions identified as significantly deleted in high grades were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while amplified were: 3q28; 12q13.3 and 21q22.3.	('malignancy', 'Disease', (18, 28))	('9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11', 'Var', (106, 148))	('malignancy', 'Disease', 'MESH:D009369', (18, 28))
50238	30871102	Low grades comprised significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 indicating their involvement in early stages of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('involvement', 'Reg', (119, 130))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('p15', 'Gene', (56, 59))	('p15', 'Gene', '1030', (56, 59))	('tumor', 'Disease', (150, 155))	('deletions', 'Var', (33, 42))
50244	30871102	Based on new discoveries on patterns of somatic mutations and DNA copy number variations involved in glioblastoma etiology, four molecular signatures were proposed that classify glioblastoma into proneural, neural, classical and mesenchymal.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('glioblastoma', 'Disease', (178, 190))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('glioblastoma', 'Disease', (101, 113))	('mutations', 'Var', (48, 57))
50251	30871102	It has been shown by several investigations that genomic copy number changes play important roles in glioblastoma.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('roles', 'Reg', (92, 97))	('genomic copy number changes', 'Var', (49, 76))	('glioblastoma', 'Disease', (101, 113))
50261	30871102	There are several major advantages to aCGH including the ability to detect copy number changes at very high resolution, ease of implementation and the ability to analyze archival specimen.	('copy number changes', 'Var', (75, 94))	('CGH', 'Gene', (39, 42))	('CGH', 'Gene', '3342', (39, 42))
50265	30871102	aCGH is a reliable and sensitive technique for detecting gene CNA across the entire genome.	('CGH', 'Gene', (1, 4))	('CGH', 'Gene', '3342', (1, 4))	('gene CNA', 'Var', (57, 65))
50266	30871102	Oligonucleotide microarrays provide high resolution and diagnostic yield of detection of copy number changes comprised in the tumor genome.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('copy number changes', 'Var', (89, 108))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
50268	30871102	Hence, we investigated the genomes of 14 intracranial astrocytic brain tumors of different WHO grades for changes in DNA copy number using high-resolution CGH arrays that contained 180,000 probes with the possibility to screen the genome with an average resolution of 10-50 kb.	('intracranial astrocytic brain tumors', 'Disease', 'MESH:D001254', (41, 77))	('changes', 'Var', (106, 113))	('brain tumors', 'Phenotype', 'HP:0030692', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('intracranial astrocytic brain tumors', 'Disease', (41, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('CGH', 'Gene', (155, 158))	('CGH', 'Gene', '3342', (155, 158))
50277	30871102	The multitude of changes that we observed in astrocytoma cells is indicative of the accumulation of deletions and amplifications characteristic of tumor cells.	('astrocytoma', 'Disease', 'MESH:D001254', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('astrocytoma', 'Disease', (45, 56))	('astrocytoma', 'Phenotype', 'HP:0009592', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('amplifications', 'Var', (114, 128))	('deletions', 'Var', (100, 109))
50279	30871102	Altogether, our aCGH results showed 1438 CNA found across astrocytomas of different malignancy grades, including 21 amplifications, 397 gains, 929 losses and 91 deletions.	('amplifications', 'Var', (116, 130))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('deletions', 'Var', (161, 170))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('astrocytomas', 'Disease', 'MESH:D001254', (58, 70))	('CGH', 'Gene', (17, 20))	('CGH', 'Gene', '3342', (17, 20))	('gains', 'PosReg', (136, 141))	('malignancy', 'Disease', (84, 94))	('astrocytomas', 'Disease', (58, 70))	('losses', 'NegReg', (147, 153))
50280	30871102	When grouping tumors grades I, II and III as one category and glioblastomas (grade IV) as another, we noticed that the first group predominantly harbored losses and deletions, while glioblastomas were characterized with more gains and amplifications.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('glioblastomas', 'Phenotype', 'HP:0012174', (182, 195))	('deletions', 'Var', (165, 174))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('glioblastomas', 'Disease', 'MESH:D005909', (182, 195))	('glioblastomas', 'Phenotype', 'HP:0012174', (62, 75))	('losses', 'Var', (154, 160))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('glioblastomas', 'Disease', 'MESH:D005909', (62, 75))	('glioblastomas', 'Disease', (182, 195))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('glioblastomas', 'Disease', (62, 75))
50281	30871102	The average number of deletions and losses per I, II and III grouped tumors was 145 and per glioblastomas 32.8.	('glioblastomas', 'Phenotype', 'HP:0012174', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('deletions', 'Var', (22, 31))	('glioblastomas', 'Disease', 'MESH:D005909', (92, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('losses', 'NegReg', (36, 42))	('glioblastomas', 'Disease', (92, 105))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
50297	30871102	CNA that were concurrent for pilocytic (grade I), anaplastic (grade III) and glioblastoma (grade IV) cases were: losses on 3q26.2; 4q28.2; 5q23.2; 6q13; 7p15.2 (gain and loss both); 10q11.21-q11.22; 10q21.3-q22.1; 11p15.4; 12p13.2 (deletion in high grades loss in pilocytic); 14q11.2; 14q13.1-q13.2; 15q11.1-q11.2; 18p11.22.	('glioblastoma', 'Disease', (77, 89))	('p15', 'Gene', '1030', (154, 157))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('p15', 'Gene', (216, 219))	('p15', 'Gene', '1030', (216, 219))	('loss', 'NegReg', (256, 260))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('p11.2', 'Gene', '5707', (317, 322))	('losses', 'Var', (113, 119))	('p11.2', 'Gene', (317, 322))	('p15', 'Gene', (154, 157))
50298	30871102	Gains that were shared among I, III and IV grades were 7p15.2 and 15q11.1-q11.2.	('p15', 'Gene', '1030', (56, 59))	('15q11.1-q11.2', 'Var', (66, 79))	('p15', 'Gene', (56, 59))
50310	30871102	Seven glioblastoma patients harbored amplification of chromosome 7 (trisomy of the whole chromosome 7) (Table 4).	('patients', 'Species', '9606', (19, 27))	('glioblastoma', 'Disease', (6, 18))	('amplification', 'Var', (37, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (6, 18))	('glioblastoma', 'Disease', 'MESH:D005909', (6, 18))
50315	30871102	Autologous blood DNA from pilocytic astrocytoma sample showed altogether 23 copy number changes of which there were three amplifications, eight gains, nine losses and three deletions.	('copy number changes', 'Var', (76, 95))	('pilocytic astrocytoma', 'Disease', (26, 47))	('losses', 'NegReg', (156, 162))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (26, 47))	('astrocytoma', 'Phenotype', 'HP:0009592', (36, 47))	('gains', 'PosReg', (144, 149))
50319	30871102	Furthermore, GISTIC v2.0.23 was also used to identify significant amplification and deletion events assigned to malignancy grades.	('malignancy', 'Disease', (112, 122))	('amplification', 'MPA', (66, 79))	('deletion', 'Var', (84, 92))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))
50328	30871102	Of note is that deletions 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 were all found in low grade samples at a threshold level of q-0.45 and also on our total sample at q-0.25, but were not repeatedly found in high grades.	('p15', 'Gene', '1030', (36, 39))	('p15', 'Gene', (36, 39))	('deletions 3p14.3', 'Var', (16, 32))
50342	30871102	We found losses in pilocytic astrocytomas of which: 3q; 10q; 11p; 12p; 14q; 15q and 18p have not previously been reported, while there were fewer gains found in our study, only on 7p15.2 and 15q11.1-q11.2.	('losses', 'NegReg', (9, 15))	('p15', 'Gene', (181, 184))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (19, 41))	('pilocytic astrocytomas', 'Disease', (19, 41))	('p15', 'Gene', '1030', (181, 184))	('3q; 10q; 11p', 'Var', (52, 64))	('astrocytoma', 'Phenotype', 'HP:0009592', (29, 40))
50343	30871102	Grade II astrocytomas harbored very few recurrent aberrations, only losses on 1p36.33-p11.2 and 1q21.1 and gains on 1q21.1-q25.1.	('gains', 'PosReg', (107, 112))	('1q21.1', 'Gene', (96, 102))	('II astrocytomas', 'Disease', 'MESH:D001254', (6, 21))	('1q21.1-q25.1', 'Var', (116, 128))	('II astrocytomas', 'Disease', (6, 21))	('losses', 'NegReg', (68, 74))	('p11.2', 'Gene', '5707', (86, 91))	('p11.2', 'Gene', (86, 91))	('astrocytoma', 'Phenotype', 'HP:0009592', (9, 20))
50349	30871102	The high number of copy number changes found to be increasing with the grade can also be indicative of the acquisition of genomic instability in glioblastoma, especially since deleted regions may harbor genes involved in mismatch DNA repair.	('genomic', 'MPA', (122, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('copy number changes', 'Var', (19, 38))	('glioblastoma', 'Disease', (145, 157))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
50352	30871102	This finding, which is in accordance with literature and included loss of heterozygosity on chromosomal arm 10p, is commonly reported for high-grade gliomas, usually concentrated in the region 10p14-p15.	('gliomas', 'Disease', (149, 156))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('loss', 'Var', (66, 70))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('p15', 'Gene', (199, 202))	('p15', 'Gene', '1030', (199, 202))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))
50356	30871102	We found EGFR amplification to be targeted in 89% of glioblastomas and one astrocytoma grade II, with a total of 90% of cases with amplified EGFR genes.	('glioblastomas', 'Phenotype', 'HP:0012174', (53, 66))	('EGFR', 'Gene', '1956', (141, 145))	('glioblastomas', 'Disease', 'MESH:D005909', (53, 66))	('glioblastomas', 'Disease', (53, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('EGFR', 'Gene', (141, 145))	('EGFR', 'Gene', '1956', (9, 13))	('astrocytoma', 'Disease', 'MESH:D001254', (75, 86))	('EGFR', 'Gene', (9, 13))	('astrocytoma', 'Disease', (75, 86))	('astrocytoma', 'Phenotype', 'HP:0009592', (75, 86))	('amplification', 'Var', (14, 27))
50362	30871102	Common genetic changes and tumor associated mutations found in higher grade gliomas, p53, PDGF, p16 (CDKN2A), IDH1 and IDH2 are rarely reported in pilocytic astrocytomas, which is consistent with our results that also indicate a lack of focal abnormalities in loci where those genes reside.	('CDKN2A', 'Gene', (101, 107))	('PDGF', 'Gene', (90, 94))	('focal abnormalities', 'Disease', 'MESH:D005490', (237, 256))	('IDH1', 'Gene', (110, 114))	('gliomas', 'Disease', (76, 83))	('tumor', 'Disease', (27, 32))	('p16', 'Gene', (96, 99))	('CDKN2A', 'Gene', '1029', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('p53', 'Gene', '7157', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('p16', 'Gene', '1029', (96, 99))	('IDH1', 'Gene', '3417', (110, 114))	('pilocytic astrocytomas', 'Disease', (147, 169))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('focal abnormalities', 'Disease', (237, 256))	('p53', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (147, 169))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('IDH2', 'Gene', (119, 123))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('mutations', 'Var', (44, 53))	('IDH2', 'Gene', '3418', (119, 123))
50366	30871102	Thus, the significantly deleted regions in high grade astrocytoma groups were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while significantly amplified were 3q28; 12q13.3 and 21q22.3.	('9p21.3', 'Var', (79, 85))	('astrocytoma', 'Disease', 'MESH:D001254', (54, 65))	('astrocytoma', 'Disease', (54, 65))	('1p36.11', 'Var', (114, 121))	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))
50369	30871102	Of note is that deletions 3p14.3, 11p15.4, 15q15.1, 16q22.1, 20q11.22 and 22q12.3 were all found in low grade samples at a threshold level of q-0.45 and also on our total sample at q-0.25, but were not repeatedly found in high grades.	('p15', 'Gene', '1030', (36, 39))	('p15', 'Gene', (36, 39))	('deletions 3p14.3', 'Var', (16, 32))
50371	30871102	We could not establish any differences between IDH1 mutant and WT tumors in regard to the presence of listed CNAs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('WT tumors', 'Disease', 'MESH:C536751', (63, 72))	('mutant', 'Var', (52, 58))	('IDH1', 'Gene', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('WT tumors', 'Disease', (63, 72))	('IDH1', 'Gene', '3417', (47, 51))
50373	30871102	At first, cancer-related aCGH studies have showed a high level of discordance in the reported genomic aberrations, leading to conclusions that random mutations and CNA are prevalent.	('CNA', 'Disease', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('random mutations', 'Var', (143, 159))	('CGH', 'Gene', (26, 29))	('CGH', 'Gene', '3342', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
50375	30871102	The accordance rate among different studies improved and a concordant picture of biologically significant CNAs in the glioma genome emerged.	('accordance', 'MPA', (4, 14))	('glioma', 'Disease', (118, 124))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('CNAs', 'Var', (106, 110))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('improved', 'PosReg', (44, 52))
50380	30871102	Nevertheless, EGFR amplification and mutations have been shown to be responsible for many other cancer types.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('amplification', 'Var', (19, 32))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('responsible', 'Reg', (69, 80))
50385	30871102	The region 10q23.31 where tumor suppressor PTEN resides is also known to be frequently lost in glioblastoma, but also mutated or lost in a large number of other human tumors (prostate cancer, glioblastoma, endometrial, lung and breast cancer).	('human', 'Species', '9606', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutated', 'Var', (118, 125))	('lost', 'NegReg', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('glioblastoma', 'Disease', 'MESH:D005909', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('PTEN', 'Gene', (43, 47))	('tumor', 'Disease', (26, 31))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('tumor', 'Disease', (167, 172))	('endometrial', 'Disease', (206, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('glioblastoma', 'Disease', (192, 204))	('lung and breast cancer', 'Disease', 'MESH:D001943', (219, 241))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('prostate cancer', 'Disease', (175, 190))	('glioblastoma', 'Phenotype', 'HP:0012174', (192, 204))	('PTEN', 'Gene', '5728', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('lost', 'NegReg', (129, 133))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (167, 173))
50391	30871102	Of note is our result on the deletions of loci at 9p21.3, where genes CDKN2A/CDKN2B reside, that have been identified with GISTIC as significantly deleted regions both on our total sample as well as on malignant cases only.	('CDKN2B', 'Gene', (77, 83))	('CDKN2B', 'Gene', '1030', (77, 83))	('CDKN2A', 'Gene', (70, 76))	('deletions', 'Var', (29, 38))	('CDKN2A', 'Gene', '1029', (70, 76))
50392	30871102	It has been shown that the region is significant for glioblastomas and highly recurrent homozygous deletions of CDKN2A/B genes were established.	('glioblastomas', 'Phenotype', 'HP:0012174', (53, 66))	('deletions', 'Var', (99, 108))	('glioblastomas', 'Disease', 'MESH:D005909', (53, 66))	('glioblastomas', 'Disease', (53, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('CDKN2A/B', 'Gene', '1029;1030', (112, 120))	('CDKN2A/B', 'Gene', (112, 120))
50396	30871102	report on amplifications of 4q12 and 7p11.2 (18-26% of samples) and deletions of 1p36.31 and 9p21.3 (35-49%).	('deletions', 'Var', (68, 77))	('p11.2', 'Gene', (38, 43))	('p11.2', 'Gene', '5707', (38, 43))	('9p21.3', 'Gene', (93, 99))	('1p36.31', 'Gene', (81, 88))
50403	30871102	Furthermore, in the majority of malignant samples, systematic amplification of segments in chromosome 7 and respective deletion in chromosome 10 were evident, a pattern previously reported for glioblastoma patients.	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('deletion', 'Var', (119, 127))	('patients', 'Species', '9606', (206, 214))	('glioblastoma', 'Disease', (193, 205))
50404	30871102	Next, we restricted our analysis to KEGG database and evidenced that only genes associated with deleted segments were significantly enriched in 18 out of 325 total Homo sapiens associated KEGG pathways.	('deleted segments', 'Var', (96, 112))	('Homo sapiens', 'Species', '9606', (164, 176))	('KEGG pathways', 'Pathway', (188, 201))
50419	30871102	The cBioPortal for Cancer Genomics website (, accessed on 23 February 2019) data mining validated this finding since all of the genes within 9p21.3 region were also reported to be substantially deleted in high grade gliomas.	('February 2019', 'Disease', (61, 74))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', (19, 25))	('February 2019', 'Disease', 'MESH:C000657245', (61, 74))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('gliomas', 'Disease', 'MESH:D005910', (216, 223))	('gliomas', 'Phenotype', 'HP:0009733', (216, 223))	('gliomas', 'Disease', (216, 223))	('deleted', 'Var', (194, 201))
50425	30871102	Furthermore, oligodeoxynucleotides that act on Toll signaling by binding to intracellular Toll-like receptor 9 (TLR9) and thus activate innate and adaptive immunity at first showed no improvement of overall survival of glioblastoma patients, but are being further investigated.	('overall survival', 'CPA', (199, 215))	('activate', 'PosReg', (127, 135))	('binding', 'Interaction', (65, 72))	('improvement', 'PosReg', (184, 195))	('patients', 'Species', '9606', (232, 240))	('Toll-like receptor 9', 'Gene', '54106', (90, 110))	('Toll-like receptor 9', 'Gene', (90, 110))	('TLR9', 'Gene', (112, 116))	('glioblastoma', 'Disease', (219, 231))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('oligodeoxynucleotides', 'Var', (13, 34))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (13, 34))	('TLR9', 'Gene', '54106', (112, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))
50428	30871102	EGFRvIII is a glioblastoma-specific EGFR mutation consisting of a deletion that causes constitutive activity of tyrosine kinase contributing to glioblastoma aggressiveness.	('glioblastoma aggressiveness', 'Disease', 'MESH:D005909', (144, 171))	('EGFR', 'Gene', (0, 4))	('constitutive activity', 'MPA', (87, 108))	('glioblastoma', 'Disease', (144, 156))	('EGFR', 'Gene', '1956', (36, 40))	('mutation', 'Var', (41, 49))	('glioblastoma', 'Disease', (14, 26))	('glioblastoma aggressiveness', 'Disease', (144, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (14, 26))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('aggressiveness', 'Phenotype', 'HP:0000718', (157, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('EGFR', 'Gene', (36, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('EGFR', 'Gene', '1956', (0, 4))
50429	30871102	It is important to mention that STAT signaling emerged as another potential therapeutic target in glioblastoma, since siRNAs or pharmacological inhibitors of STAT 3 and its activator, IL-6, showed promising results for several other malignancies including multiple myeloma, head and neck cancer and prostate cancer.	('malignancies', 'Disease', 'MESH:D009369', (233, 245))	('STAT 3', 'Gene', '6774', (158, 164))	('inhibitors', 'Var', (144, 154))	('malignancies', 'Disease', (233, 245))	('head and neck cancer', 'Phenotype', 'HP:0012288', (274, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('multiple myeloma', 'Phenotype', 'HP:0006775', (256, 272))	('glioblastoma', 'Disease', (98, 110))	('head and neck cancer', 'Disease', 'MESH:D006258', (274, 294))	('IL-6', 'Gene', '3569', (184, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('multiple myeloma', 'Disease', 'MESH:D009101', (256, 272))	('STAT 3', 'Gene', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('IL-6', 'Gene', (184, 188))	('prostate cancer', 'Disease', 'MESH:D011471', (299, 314))	('prostate cancer', 'Phenotype', 'HP:0012125', (299, 314))	('prostate cancer', 'Disease', (299, 314))	('multiple myeloma', 'Disease', (256, 272))
50449	30871102	Fragmented DNAs were labeled with Cy3 (reference DNA) and Cy5 (test samples) fluorescent dUTP, respectively, using the SureTag Complete Labeling Kit (Agilent Technologies).	('Cy3', 'Var', (34, 37))	('Cy5', 'Var', (58, 61))	('Cy5', 'Chemical', 'MESH:C085321', (58, 61))	('Cy3', 'Chemical', '-', (34, 37))	('dUTP', 'Chemical', 'MESH:C027078', (89, 93))
50451	30871102	Hybridizations of labeled DNAs to SurePrint G3 Human CGH Arrays (4 x 180 K) (Agilent Technologies) were performed in a hybridization oven at 65  C at 20 rpm for 24 h. The slide was scanned at 3 mum resolution on Agilent Microarray Scanner System (G2565BA, Agilent Technologies).	('G2565BA', 'Var', (247, 254))	('CGH', 'Gene', (53, 56))	('CGH', 'Gene', '3342', (53, 56))	('Human', 'Species', '9606', (47, 52))
50459	30871102	Identifying narrow regions with altered DNA copy number is an important finding in tumor genetics, as genes mapped in these regions may represent potential candidate tumor suppressor genes and oncogenes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (166, 171))	('altered', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('DNA', 'Gene', (40, 43))
50461	30871102	The regions identified as significantly deleted and amplified in high grades, 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11, 13q12.11, 3q28; 12q13.3 and 21q22.3 might be associated with progression events, while significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 were comprised of low grades to early stages of tumorigenesis.	('3q28', 'Var', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', (338, 343))	('p15', 'Gene', (244, 247))	('progression', 'Disease', (183, 194))	('p15', 'Gene', '1030', (244, 247))	('associated', 'Reg', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (338, 343))
50465	30871102	Our data contributes to better understanding of human astrocytoma genetic profiles and suggests that copy number alterations play important roles in its etiology and progression.	('human', 'Species', '9606', (48, 53))	('copy number alterations', 'Var', (101, 124))	('astrocytoma', 'Disease', 'MESH:D001254', (54, 65))	('astrocytoma', 'Disease', (54, 65))	('astrocytoma', 'Phenotype', 'HP:0009592', (54, 65))
50486	30423822	Like all cytotoxic therapies, PDT stimulates the expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) which increases secretion of vascular endothelial growth factor (VEGF), a key player in the formation of blood vessels and subsequent tumor regrowth.	('PDT', 'Var', (30, 33))	('HIF-1alpha', 'Gene', '3091', (97, 107))	('VEGF', 'Gene', '7422', (174, 178))	('hypoxia-inducible factor-1 alpha', 'Gene', '3091', (63, 95))	('stimulates', 'PosReg', (34, 44))	('increases', 'PosReg', (115, 124))	('expression', 'MPA', (49, 59))	('vascular endothelial growth factor', 'Gene', (138, 172))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('HIF-1alpha', 'Gene', (97, 107))	('secretion', 'MPA', (125, 134))	('hypoxia-inducible factor-1 alpha', 'Gene', (63, 95))	('VEGF', 'Gene', (174, 178))	('vascular endothelial growth factor', 'Gene', '7422', (138, 172))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
50494	30423822	A major advantage of using BPD as a PS is its longer wavelength activation which allows for better tumor penetration and reactive oxygen species generation while causing less peripheral tissue damage.	('tumor', 'Disease', (99, 104))	('reactive oxygen species generation', 'MPA', (121, 155))	('BPD', 'Chemical', 'MESH:C017228', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('BPD', 'Var', (27, 30))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (121, 144))	('better', 'PosReg', (92, 98))
50574	30423822	There was approximately 21% increased cell death caused by 100 nM NP BPD, compared to 50 nM BPD with light toxicity, shown by cell viability averages of 65.4% and 44.4%, respectively.	('BPD', 'Chemical', 'MESH:C017228', (92, 95))	('cell death', 'CPA', (38, 48))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('toxicity', 'Disease', (107, 115))	('BPD', 'Chemical', 'MESH:C017228', (69, 72))	('100 nM NP BPD', 'Var', (59, 72))
50589	30423822	Surface modification of nanoparticles with PEG also improves the colloidal stability of nanoparticles allowing them to be stored in solution prior to use.	('PEG', 'Var', (43, 46))	('improves', 'PosReg', (52, 60))	('colloidal', 'MPA', (65, 74))	('PEG', 'Chemical', 'MESH:D011092', (43, 46))
50593	30423822	In addition, the hydrophobic nature of the encapsulated drugs, CED and BPD, may cause swelling of the nanoparticles by interacting with the hydrophobic methyl groups of lactide in PLGA chains, electrostatic interactions and van der Waal's forces within the amorphous nanoparticle core.	('hydrophobic', 'Var', (17, 28))	('swelling', 'MPA', (86, 94))	('BPD', 'Chemical', 'MESH:C017228', (71, 74))	('electrostatic interactions', 'CPA', (193, 219))	('lactide', 'Chemical', 'MESH:C091880', (169, 176))	('van der Waal', 'Disease', 'MESH:C536528', (224, 236))	('CED', 'Disease', 'MESH:D003966', (63, 66))	('interacting', 'Interaction', (119, 130))	('CED', 'Disease', (63, 66))	('van der Waal', 'Disease', (224, 236))	('lactide', 'Protein', (169, 176))	('cause', 'Reg', (80, 85))
50620	30423822	The following are available online at , Figure S1: Absorbance spectra data using ultraviolet-visible (UV-Vis) spectroscopy for CED (@328 nm) and BPD (@424 nm and 686 nm) in acetone.	('@328 nm', 'Var', (132, 139))	('CED', 'Disease', 'MESH:D003966', (127, 130))	('@424 nm', 'Var', (150, 157))	('CED', 'Disease', (127, 130))	('BPD', 'Chemical', 'MESH:C017228', (145, 148))	('acetone', 'Chemical', 'MESH:D000096', (173, 180))
50637	30573757	While detection of IDH1 mutation and/or methylation of the MGMT promoter are now correlated to increased overall survival, the prognostic value of other common genetic mutations, including amplification of the EGFR locus, remains unclear.	('methylation', 'Var', (40, 51))	('increased', 'PosReg', (95, 104))	('EGFR', 'Gene', (210, 214))	('IDH1', 'Gene', (19, 23))	('IDH1', 'Gene', '3417', (19, 23))	('mutation', 'Var', (24, 32))	('overall', 'MPA', (105, 112))	('MGMT', 'Gene', (59, 63))	('MGMT', 'Gene', '4255', (59, 63))	('EGFR', 'Gene', '1956', (210, 214))
50640	30573757	Amplification at this locus, which is detected in 40-50% of GBM tissues, is typically mosaic and believed to enhance pro-invasive signaling through EGFR.	('Amplification', 'Var', (0, 13))	('pro-invasive signaling', 'MPA', (117, 139))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('enhance', 'PosReg', (109, 116))
50642	30573757	Supporting these data, our ex vivo slice cultures demonstrated increased tumor cell migration in EGFR-amplified tumors, and blockade of EGFR signaling with the small molecule inhibitor, gefitinib, induced a statistically significant reduction in migratory behavior within the same sample set.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('rat', 'Species', '10116', (57, 60))	('migratory behavior', 'CPA', (246, 264))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('rat', 'Species', '10116', (87, 90))	('EGFR', 'Gene', (97, 101))	('tumor', 'Disease', (112, 117))	('reduction', 'NegReg', (233, 242))	('EGFR', 'Gene', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('gefitinib', 'Chemical', 'MESH:D000077156', (186, 195))	('tumor', 'Disease', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('increased', 'PosReg', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('EGFR', 'Gene', '1956', (97, 101))	('rat', 'Species', '10116', (249, 252))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('blockade', 'Var', (124, 132))	('EGFR', 'Gene', '1956', (136, 140))	('tumors', 'Disease', (112, 118))
50648	30573757	To date, the extent to which genetically or epigenetically distinct subsets of cells, present within individual human GBM tumors, contribute to overall variation in cell behavior and drug response in vivo remains unclear.	('epigenetically', 'Var', (44, 58))	('contribute', 'Reg', (130, 140))	('variation', 'Reg', (152, 161))	('GBM tumors', 'Disease', (118, 128))	('GBM tumors', 'Disease', 'MESH:D005910', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('human', 'Species', '9606', (112, 117))
50683	30573757	Genomic amplification of the WT EGFR receptor is common in GBM and displays intratumoral cell-to-cell heterogeneity.	('Genomic amplification', 'Var', (0, 21))	('GBM', 'Disease', (59, 62))	('common', 'Reg', (49, 55))	('EGFR', 'Gene', '1956', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('EGFR', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('rat', 'Species', '10116', (79, 82))	('tumor', 'Disease', (81, 86))
50685	30573757	Therefore, we sought to determine whether EGFR amplification correlated with heterogeneity in individual tumor cell migration patterns.	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('rat', 'Species', '10116', (119, 122))	('amplification', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
50688	30573757	Across all tumors, these data support an association between EGFR amplification and fast migratory behavior of cells, which contributes to overall tumor invasiveness.	('tumor invasiveness', 'Disease', (147, 165))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('amplification', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('fast migratory behavior of cells', 'CPA', (84, 116))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('rat', 'Species', '10116', (92, 95))	('tumor invasiveness', 'Disease', 'MESH:D009369', (147, 165))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
50693	30573757	In amplified tumors, we identified a significant decrease in the standard deviation of instantaneous speed and in the distance traveled by each tumor cell, per peak, with no significant effects observed in non-amplified tumors (Fig.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (220, 225))	('standard deviation', 'MPA', (65, 83))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('amplified', 'Var', (3, 12))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('distance', 'CPA', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', (220, 226))	('decrease', 'NegReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('instantaneous speed', 'MPA', (87, 106))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
50698	30573757	Inhibition of EGFR reduced fast bursting behavior in a subset of cells, thus, we hypothesized that overall population heterogeneity based on these migration parameters would decrease accordingly with gefitinib treatment.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('decrease', 'NegReg', (174, 182))	('gefitinib', 'Chemical', 'MESH:D000077156', (200, 209))	('rat', 'Species', '10116', (150, 153))	('reduced', 'NegReg', (19, 26))	('Inhibition', 'Var', (0, 10))	('fast bursting behavior', 'MPA', (27, 49))
50707	30573757	Although, experiments to confirm that the subpopulation of cells harboring amplification of the EGFR locus corresponds specifically to the affected subpopulation of highly invasive cells are underway, our data highlight the potential relevance of personalized therapeutics based upon patient-specific genetic alterations.	('EGFR', 'Gene', '1956', (96, 100))	('EGFR', 'Gene', (96, 100))	('amplification', 'Var', (75, 88))	('patient', 'Species', '9606', (284, 291))	('rat', 'Species', '10116', (313, 316))
50710	30573757	Efforts to trace the evolution of GBM reveal that many mutations present in the initial tumor are not present in secondary tumors and satellite lesions.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
50717	30573757	While amplification and mutation of the EGFR locus is the most common genetic alteration in GBM, recent phylogenetic analysis of primary tissue suggests this may be a late-occurring change, enriched within cells near the infiltrative tumor edge or within satellite lesions.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', (234, 239))	('EGFR', 'Gene', '1956', (40, 44))	('rat', 'Species', '10116', (82, 85))	('EGFR', 'Gene', (40, 44))	('mutation', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('amplification', 'Var', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
50729	30573757	This study suggests that targeting EGFR in human GBM slices selectively inhibits migration of receptor-amplified GBM cells, resulting in homogenization of the migratory behavior of the population.	('rat', 'Species', '10116', (162, 165))	('rat', 'Species', '10116', (84, 87))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('inhibits', 'NegReg', (72, 80))	('targeting', 'Var', (25, 34))	('migration', 'CPA', (81, 90))	('homogenization', 'CPA', (137, 151))	('human', 'Species', '9606', (43, 48))
50741	30573757	Though in vivo experiments are necessary, this proof of principle study, demonstrates inhibition of a key node in the molecular migration pathway, homogenizes migratory behavior, representing an important step toward improved treatment for GBM patients.	('rat', 'Species', '10116', (131, 134))	('rat', 'Species', '10116', (162, 165))	('rat', 'Species', '10116', (80, 83))	('molecular migration pathway', 'Pathway', (118, 145))	('migratory behavior', 'CPA', (159, 177))	('inhibition', 'Var', (86, 96))	('patients', 'Species', '9606', (244, 252))
50769	29302995	In vitro cytotoxic tests demonstrated that Cur SD induced higher cytotoxicity against glioblastoma U-87 MG cells than free Cur.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('U-87 MG', 'CellLine', 'CVCL:0022', (99, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('rat', 'Species', '10116', (32, 35))	('SD', 'Chemical', '-', (47, 49))	('cytotoxicity', 'Disease', (65, 77))	('higher', 'PosReg', (58, 64))	('glioblastoma', 'Disease', (86, 98))	('Cur SD', 'Var', (43, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
50893	29302995	As shown in Figure 2(g), in the presence of Na2GA in aqueous-methanol solution, there was a substantial shortening of T 2 relaxation time of O-CH3 protons due to lowering of diffusion mobility of molecules.	('Na2GA', 'Var', (44, 49))	('Na2GA', 'Chemical', '-', (44, 49))	('diffusion mobility of molecules', 'MPA', (174, 205))	('O-CH3 protons', 'MPA', (141, 154))	('methanol', 'Chemical', 'MESH:D000432', (61, 69))	('shortening', 'NegReg', (104, 114))	('T 2 relaxation time', 'MPA', (118, 137))	('lowering', 'NegReg', (162, 170))
50930	29302995	Na2GA enhanced the solubility of Cur by forming micelles and aided the formation of a homogenous solution.	('formation of a homogenous solution', 'MPA', (71, 105))	('solubility of Cur', 'MPA', (19, 36))	('Na2GA', 'Var', (0, 5))	('aided', 'PosReg', (61, 66))	('enhanced', 'PosReg', (6, 14))	('micelles', 'MPA', (48, 56))	('Na2GA', 'Chemical', '-', (0, 5))
50940	29302995	The significant increase in bioavailability was also corresponding to the increase in bio-efficacy and membrane permeability, with Cur SD demonstrating greater cytotoxic activity than free Cur.	('cytotoxic activity', 'CPA', (160, 178))	('membrane permeability', 'MPA', (103, 124))	('increase', 'PosReg', (74, 82))	('increase', 'PosReg', (16, 24))	('Cur SD', 'Var', (131, 137))	('bio-efficacy', 'MPA', (86, 98))	('bioavailability', 'MPA', (28, 43))	('rat', 'Species', '10116', (145, 148))	('SD', 'Chemical', '-', (135, 137))
50943	27453950	PD-1 blockade enhances the vaccination-induced immune response in glioma DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies.	('glioma', 'Disease', (66, 72))	('blockade', 'Var', (5, 13))	('PD-1', 'Gene', '18566', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (173, 185))	('PD-1', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('clinical', 'Species', '191496', (211, 219))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('clinical', 'Species', '191496', (198, 206))	('enhances', 'PosReg', (14, 22))	('GBM', 'Phenotype', 'HP:0012174', (187, 190))	('glioblastoma', 'Disease', (173, 185))	('vaccination-induced', 'CPA', (27, 46))
50949	27453950	Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors.	('tumors', 'Disease', (178, 184))	('PD-1 mAb', 'Gene', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('blockade', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
50962	27453950	PD-1/PD-L1 (programmed death 1/programmed death ligand 1) has been shown to induce functional anergy and limit activation of cytotoxic T cells during long-term exposure to antigen, a phenomenon associated with neoplastic disease.	('limit', 'NegReg', (105, 110))	('activation', 'CPA', (111, 121))	('neoplastic disease', 'Disease', 'MESH:D009386', (210, 228))	('PD-1/PD-L1', 'Var', (0, 10))	('neoplastic disease', 'Disease', (210, 228))	('neoplastic disease', 'Phenotype', 'HP:0002664', (210, 228))	('functional anergy', 'MPA', (83, 100))
50963	27453950	The upregulation of inhibitory PD-L1 in tumor cells appears to be associated with increased tumor-infiltrating lymphocytes (TILs), a phenomenon readily noted in immunogenic cancers with an endogenous immune infiltrate.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('immunogenic cancers', 'Disease', 'MESH:D009369', (161, 180))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inhibitory', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('PD-L1', 'Gene', (31, 36))	('increased', 'PosReg', (82, 91))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('upregulation', 'PosReg', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('immunogenic cancers', 'Disease', (161, 180))
50965	27453950	It was first shown that inhibition of PD-1/PD-L1 promotes the antitumoral activity of TILs present in B16 melanoma models.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('tumor', 'Disease', (66, 71))	('promotes', 'PosReg', (49, 57))	('inhibition', 'Var', (24, 34))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('melanoma', 'Disease', (106, 114))	('PD-1/PD-L1', 'Gene', (38, 48))
50980	27453950	DC vaccine-treated tumors showed a robust CD3+ infiltrating population (Figure 1, C-F) similar to what was seen in patients' tumors, suggesting that DC vaccine treatment elicited a significant intratumoral immune response compared with nontreated controls, despite being ineffective at promoting long-term survival in mice with established tumors.	('tumors', 'Disease', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('tumors', 'Disease', (125, 131))	('patients', 'Species', '9606', (115, 123))	('tumors', 'Disease', (340, 346))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('elicited', 'Reg', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mice', 'Species', '10090', (318, 322))	('tumor', 'Disease', (340, 345))	('DC vaccine', 'Var', (149, 159))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (340, 345))
51006	27453950	Only in mice treated with both DC vaccination and PD-1 mAb blockade was there a significant increase in both the proportion and number of activated CD8+CD25+ T cells (Figure 3D).	('CD8', 'Gene', '925', (148, 151))	('PD-1 mAb', 'Gene', (50, 58))	('increase', 'PosReg', (92, 100))	('blockade', 'Var', (59, 67))	('CD8', 'Gene', (148, 151))	('CD25', 'Gene', (152, 156))	('mice', 'Species', '10090', (8, 12))	('CD25', 'Gene', '16184', (152, 156))
51010	27453950	These findings suggested that suppression of the PD-1/PD-L1 signaling mechanism via PD-1 mAb blockade activates CD8+ TILs.	('CD8', 'Gene', (112, 115))	('PD-1 mAb', 'Gene', (84, 92))	('CD8', 'Gene', '925', (112, 115))	('activates', 'PosReg', (102, 111))	('suppression', 'NegReg', (30, 41))	('blockade', 'Var', (93, 101))
51014	27453950	However, a significant increase in the percentage of tumor-infiltrating memory T cells was observed with adjuvant PD-1 blockade, such that there was an approximate 2-fold increase across treatment groups (Figure 4, B and C).	('increase', 'PosReg', (171, 179))	('blockade', 'Var', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('increase', 'PosReg', (23, 31))	('tumor', 'Disease', (53, 58))	('PD-1', 'Gene', (114, 118))
51058	27453950	Depletion of CD4+ T cells did not provide any added benefit compared with DC vaccine alone.	('CD4', 'Gene', '12504', (13, 16))	('CD4', 'Gene', (13, 16))	('Depletion', 'Var', (0, 9))
51128	26685681	One concern relates to the fact that osmotic BBBD results in transient cerebral edema, with a 1.5% increase in brain water.	('osmotic BBBD', 'Var', (37, 49))	('cerebral edema', 'Phenotype', 'HP:0002181', (71, 85))	('edema', 'Phenotype', 'HP:0000969', (80, 85))	('BBBD', 'Chemical', '-', (45, 49))	('cerebral edema', 'Disease', 'MESH:D001929', (71, 85))	('water', 'Chemical', 'MESH:D014867', (117, 122))	('cerebral edema', 'Disease', (71, 85))	('brain water', 'MPA', (111, 122))	('increase', 'PosReg', (99, 107))
51140	26685681	When applied to the delivery of chemotherapeutic agents, RMP-7 improved the transport of carboplatin across the BBB by two-fold, resulting in improved survival of rats with RG2 gliomas.	('RG2', 'Var', (173, 176))	('carboplatin', 'Chemical', 'MESH:D016190', (89, 100))	('improved', 'PosReg', (63, 71))	('gliomas', 'Disease', (177, 184))	('survival', 'CPA', (151, 159))	('gliomas', 'Disease', 'MESH:D005910', (177, 184))	('improved', 'PosReg', (142, 150))	('RMP-7', 'Gene', (57, 62))	('gliomas', 'Phenotype', 'HP:0009733', (177, 184))	('rats', 'Species', '10116', (163, 167))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('RMP', 'Chemical', '-', (57, 60))	('transport of carboplatin across the BBB', 'MPA', (76, 115))
51144	26685681	An early, single-arm Phase II trial also found a beneficial effect of BBBD via RMP-7 for patients with recurrent malignant glioma undergoing carboplatin treatment.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('beneficial', 'PosReg', (49, 59))	('BBBD', 'Var', (70, 74))	('malignant glioma', 'Disease', (113, 129))	('RMP', 'Chemical', '-', (79, 82))	('carboplatin', 'Chemical', 'MESH:D016190', (141, 152))	('malignant glioma', 'Disease', 'MESH:D005910', (113, 129))	('patients', 'Species', '9606', (89, 97))	('BBBD', 'Chemical', '-', (70, 74))	('RMP-7', 'Gene', (79, 84))
51151	26685681	Several studies have used an antibody for the transferrin receptor to achieve RMT-based delivery across the BBB.	('RMT-based delivery across the BBB', 'MPA', (78, 111))	('antibody', 'Var', (29, 37))	('transferrin', 'Gene', (46, 57))	('transferrin', 'Gene', '7018', (46, 57))	('RMT', 'Chemical', '-', (78, 81))
51157	26685681	There was no evidence of CNS toxicity, and the chimeric peptide appeared to deliver paclitaxel successfully across the BBB, thereby paving the way for future Phase II studies.	('toxicity', 'Disease', 'MESH:D064420', (29, 37))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('chimeric', 'Var', (47, 55))	('deliver paclitaxel', 'MPA', (76, 94))	('toxicity', 'Disease', (29, 37))
51183	26685681	Gene silencing was achieved without significant cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('Gene', 'Var', (0, 4))	('cytotoxicity', 'Disease', (48, 60))
51237	26685681	A Phase I clinical trial was recently completed for the treatment of Essential Tremor (NCT01304758), and the use of MRgFUS for Parkinson's disease is being studied as well (NCT01772693, NCT02246374, and NCT02263885).	('NCT01772693', 'Var', (173, 184))	('Essential Tremor', 'Phenotype', 'HP:0030186', (69, 85))	('NCT02263885', 'Var', (203, 214))	("Parkinson's disease", 'Disease', (127, 146))	('Tremor', 'Disease', 'MESH:D014202', (79, 85))	('Tremor', 'Phenotype', 'HP:0001337', (79, 85))	("Parkinson's disease", 'Disease', 'MESH:D010300', (127, 146))	('Tremor', 'Disease', (79, 85))	('NCT01304758', 'Var', (87, 98))	('NCT02246374', 'Var', (186, 197))	('FUS', 'Chemical', '-', (119, 122))
51246	26685681	Electron microscopy revealed the reduction of several tight junction proteins following sonication, including claudin 5, occludin, and ZO-1, with intercellular leakage of intravenously administered horseradish peroxidase.	('occludin', 'Protein', (121, 129))	('reduction', 'NegReg', (33, 42))	('sonication', 'Var', (88, 98))	('intercellular leakage', 'MPA', (146, 167))	('horseradish', 'Species', '3704', (198, 209))	('tight junction proteins', 'Protein', (54, 77))	('claudin 5', 'Protein', (110, 119))
51251	26685681	Additionally, multiphoton imaging has revealed that sonication produces temporary vasoconstriction prior to the leakage of a tracer, suggesting that transient ischemia may further contribute to BBBD.	('BBBD', 'Chemical', '-', (194, 198))	('vasoconstriction', 'MPA', (82, 98))	('BBBD', 'Disease', (194, 198))	('sonication', 'Var', (52, 62))	('leakage of a tracer', 'MPA', (112, 131))	('ischemia', 'Disease', 'MESH:D007511', (159, 167))	('ischemia', 'Disease', (159, 167))	('transient ischemia', 'Phenotype', 'HP:0002326', (149, 167))	('contribute', 'Reg', (180, 190))
51269	26685681	Sonication resulted in glial activation, enhanced the delivery of endogenous IgG and IgM antibodies, and facilitated the delivery of exogenous anti-amyloid beta antibodies, resulting in reduced plaque number and size.	('Sonication', 'Var', (0, 10))	('delivery', 'MPA', (54, 62))	('glial activation', 'CPA', (23, 39))	('endogenous', 'MPA', (66, 76))	('enhanced', 'PosReg', (41, 49))	('facilitated', 'PosReg', (105, 116))	('reduced', 'NegReg', (186, 193))	('plaque number', 'CPA', (194, 207))	('delivery of exogenous anti-amyloid beta antibodies', 'MPA', (121, 171))	('IgG', 'Gene', '668542', (77, 80))	('IgG', 'Gene', (77, 80))	('IgM antibodies', 'Protein', (85, 99))
51275	26685681	Indeed, gene therapy has the potential to treat congenital disorders (e.g.	('congenital disorders', 'Disease', 'MESH:D000013', (48, 68))	('gene therapy', 'Var', (8, 20))	('congenital disorders', 'Disease', (48, 68))
51281	26685681	These effects were further enhanced by conjugating the vascular endothelial growth factor-A (VEGF-A) ligand to the microbubbles, thereby targeting the chemotherapeutic effects to regions of tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('enhanced', 'PosReg', (27, 35))	('vascular endothelial growth factor-A', 'Gene', '7422', (55, 91))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('VEGF-A', 'Gene', '7422', (93, 99))	('vascular endothelial growth factor-A', 'Gene', (55, 91))	('VEGF-A', 'Gene', (93, 99))	('conjugating', 'Var', (39, 50))
51378	25926743	What is more, EGFR overexpression is related to more aggressive disease, resistant to both radiation and chemotherapy, and a poorer prognosis.	('aggressive disease', 'Disease', 'MESH:D001523', (53, 71))	('EGFR', 'Gene', (14, 18))	('aggressive disease', 'Disease', (53, 71))	('more', 'PosReg', (48, 52))	('overexpression', 'Var', (19, 33))
51379	25926743	With regard to the subtype analysis, EGFR amplification has been reported only in 3% of anaplastic (grade III) astrocytomas, and it is infrequent in secondary GBMs (only 8%), whereas 60% of primary GBMs show EGFR overexpression, and 40% of them contain EGFR amplifications.	('overexpression', 'PosReg', (213, 227))	('astrocytomas', 'Disease', 'MESH:D001254', (111, 123))	('amplification', 'Var', (42, 55))	('EGFR', 'Gene', (37, 41))	('astrocytomas', 'Disease', (111, 123))
51380	25926743	Furthermore, EGFR amplification is rare in GBM patients younger than 35 years.	('patients', 'Species', '9606', (47, 55))	('amplification', 'Var', (18, 31))	('EGFR', 'Gene', (13, 17))
51381	25926743	Studies of the mouse glioma models have indicated that the EGFRvIII variant is more tumorigenic than the wild-type receptor in primary GBMs, EGFR aberrations are accompanied by mutations in tumor suppressors p16Ink4a, p19Arf, and PTEN, constitutively activating several oncogenes like STATs, Akt, Erk1/2, and so on, while secondary GBMs are mostly associated with mutation/deletions in p53, deregulating the cell cycle and also aberrant activation of isocitrate dehydrogenase (IDH) and PDGFR (platelet-derived growth factor receptor) pathway.	('cell cycle', 'CPA', (408, 418))	('platelet-derived growth factor receptor', 'Gene', (493, 532))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('IDH', 'Gene', (477, 480))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('p16Ink4a', 'Gene', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Erk1/2', 'Gene', '26417;26413', (297, 303))	('mutations', 'Var', (177, 186))	('p19Arf', 'Gene', '12578', (218, 224))	('PDGFR', 'Gene', (486, 491))	('mouse', 'Species', '10090', (15, 20))	('p16Ink4a', 'Gene', '12578', (208, 216))	('platelet-derived growth factor receptor', 'Gene', '18596', (493, 532))	('isocitrate dehydrogenase', 'Gene', (451, 475))	('PDGFR', 'Gene', '18596', (486, 491))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('IDH', 'Gene', '15926', (477, 480))	('p53', 'Gene', '22060', (386, 389))	('activation', 'PosReg', (437, 447))	('activating', 'PosReg', (251, 261))	('p19Arf', 'Gene', (218, 224))	('deregulating', 'PosReg', (391, 403))	('tumor', 'Disease', (190, 195))	('Erk1/2', 'Gene', (297, 303))	('mutation/deletions', 'Var', (364, 382))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('p53', 'Gene', (386, 389))	('tumor', 'Disease', (84, 89))	('isocitrate dehydrogenase', 'Gene', '15926', (451, 475))	('glioma', 'Disease', (21, 27))
51402	25926743	The expression of the constitutively active mutant EGFRvIII could sensitize tumors to EGFR inhibitors, whereas PTEN loss would impair the response to such inhibitors.	('sensitize', 'Reg', (66, 75))	('impair', 'NegReg', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('loss', 'NegReg', (116, 120))	('EGFRvIII', 'Gene', (51, 59))	('mutant', 'Var', (44, 50))	('response to such inhibitors', 'MPA', (138, 165))
51425	25926743	Forty-one malignant glioma patients were entered in either the treatment group nimotuzumab plus radiochemotherapy or the control group with the placebo and radiochemotherapy.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('nimotuzumab', 'Var', (79, 90))	('patients', 'Species', '9606', (27, 35))	('malignant glioma', 'Disease', 'MESH:D005910', (10, 26))	('nimotuzumab', 'Chemical', 'MESH:C501466', (79, 90))	('malignant glioma', 'Disease', (10, 26))
51503	25926743	The EGFR-histochemistry, the rate of MGMT-promoter-methylation, of EGFR mutant VIII, and of incomplete surgical resection, were similar in both arms.	('mutant', 'Var', (72, 78))	('VIII', 'Gene', '1351', (79, 83))	('VIII', 'Gene', (79, 83))	('MGMT', 'Gene', '4255', (37, 41))	('MGMT', 'Gene', (37, 41))	('EGFR', 'Gene', (67, 71))
51506	25926743	Therefore, future studies on the efficacy of nimotuzumab should focus on patients with nonmethylated MGMT and EGFR-positive glioblastoma that present with residual tumor after surgery.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('EGFR-positive', 'Gene', (110, 123))	('MGMT', 'Gene', (101, 105))	('MGMT', 'Gene', '4255', (101, 105))	('glioblastoma', 'Disease', (124, 136))	('nimotuzumab', 'Chemical', 'MESH:C501466', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('nonmethylated', 'Var', (87, 100))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('patients', 'Species', '9606', (73, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
51515	24856037	Here we review the recently identified central regulatory role for mTORC2, a downstream effector of many cancer-causing mutations, in metabolic reprogramming and cancer drug resistance.	('mTORC2', 'Gene', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('mTORC2', 'Gene', '74343', (67, 73))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
51535	24856037	Understanding how cancer-causing mutations cause coordinated engagement of cellular signaling pathways, biochemical repertoires and global transcription ensembles may yield critical insights into the pathogenesis of cancer and shed new light on how tumor cells resist targeted therapies to which they should be vulnerable.	('engagement', 'PosReg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', (249, 254))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
51536	24856037	In this light, it is not surprising that mutations in key regulators of PI3K-AKT/PKB-mTOR signaling and/or upstream receptor tyrosine kinases (RTKs) are found in the vast majority of cancers.	('mutations', 'Var', (41, 50))	('cancers', 'Disease', (183, 190))	('found', 'Reg', (153, 158))	('tyrosine', 'Chemical', 'MESH:D014443', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mTOR', 'Gene', '2475', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('mTOR', 'Gene', (85, 89))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
51538	24856037	Further, it is not surprising that c-Myc, a critical regulator of glutaminolysis, is also amplified or mutated in some types of cancer, although co-occurrence of PI3K-activating mutations and c-Myc amplification appears to be the exception.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('c-Myc', 'Gene', '4609', (35, 40))	('mutated', 'Var', (103, 110))	('c-Myc', 'Gene', (192, 197))	('c-Myc', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('c-Myc', 'Gene', '4609', (192, 197))	('cancer', 'Disease', (128, 134))
51539	24856037	Understanding how tumors with PI3K-AKT-mTOR activating mutations engage c-Myc signaling may provide important clues as to how tumor cells coordinate metabolic reprogramming to optimize growth.	('c-Myc', 'Gene', '4609', (72, 77))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', (18, 23))	('c-Myc', 'Gene', (72, 77))	('mTOR', 'Gene', (39, 43))	('tumors', 'Disease', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mTOR', 'Gene', '2475', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('engage', 'Reg', (65, 71))	('tumor', 'Disease', (126, 131))
51540	24856037	Mutations in metabolic enzymes such as isocitrate dehydrogenase 1/2 (IDH1/2) are highly informative because they provide a direct link between altered cellular metabolism and epigenetics.	('citrate', 'Chemical', 'MESH:D019343', (42, 49))	('Mutations', 'Var', (0, 9))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('IDH1/2', 'Gene', (69, 75))
51541	24856037	How does metabolic reprogramming caused by more common cancer-causing mutations alter the epigenetic landscape of the cell?	('epigenetic landscape of the cell', 'MPA', (90, 122))	('mutations', 'Var', (70, 79))	('metabolic reprogramming', 'CPA', (9, 32))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('alter', 'Reg', (80, 85))	('cancer', 'Disease', (55, 61))
51545	24856037	In particular, EGFRvIII (Box 1), a constitutively active gain-of-function mutation resulting from an extracellular in-frame genomic deletion, has recently been shown to reprogram tumor cell metabolism, driving the Warburg effect, glutaminolysis and lipogenesis.	('lipogenesis', 'MPA', (249, 260))	('deletion', 'Var', (132, 140))	('mutation', 'Var', (74, 82))	('EGFRvIII', 'Gene', (15, 23))	('Warburg effect', 'CPA', (214, 228))	('gain-of-function', 'PosReg', (57, 73))	('driving', 'PosReg', (202, 209))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('glutaminolysis', 'MPA', (230, 244))	('tumor', 'Disease', (179, 184))
51547	24856037	In many cancers, RTK amplification and mutations, PIK3CA mutations and PTEN loss conspire to constitutively activate PI3K-AKT-mTOR signaling and thereby to reprogram cellular metabolism.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('PIK3CA', 'Gene', '5290', (50, 56))	('loss', 'NegReg', (76, 80))	('reprogram', 'Reg', (156, 165))	('mutations', 'Var', (39, 48))	('PTEN', 'Gene', (71, 75))	('activate', 'PosReg', (108, 116))	('mutations', 'Var', (57, 66))	('cellular metabolism', 'MPA', (166, 185))	('RTK', 'Gene', (17, 20))	('mTOR', 'Gene', '2475', (126, 130))	('PTEN', 'Gene', '5728', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mTOR', 'Gene', (126, 130))	('amplification', 'Var', (21, 34))	('PIK3CA', 'Gene', (50, 56))
51548	24856037	EGFRvIII mutation and PTEN loss, a common cooccurrence in GBM, play a central role both in tumorigenesis and in metabolic reprogramming through PI3K-AKT-mTOR activation.	('mutation', 'Var', (9, 17))	('metabolic reprogramming', 'CPA', (112, 135))	('mTOR', 'Gene', (153, 157))	('mTOR', 'Gene', '2475', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('activation', 'PosReg', (158, 168))	('PTEN', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PTEN', 'Gene', '5728', (22, 26))	('EGFRvIII', 'Gene', (0, 8))	('tumor', 'Disease', (91, 96))	('loss', 'NegReg', (27, 31))
51557	24856037	AKT is recruited to the plasma membrane enabling phosphorylation at Thr308 in the catalytic domain by phosphoinositide-dependent kinase 1, and Rictor-mTOR complex phosphorylates AKT at Ser473 for its maximal activation.	('AKT', 'Gene', (0, 3))	('AKT', 'Gene', (178, 181))	('Thr308', 'Chemical', '-', (68, 74))	('phosphorylation', 'MPA', (49, 64))	('Thr308', 'Var', (68, 74))	('mTOR', 'Gene', '2475', (150, 154))	('mTOR', 'Gene', (150, 154))	('Ser473', 'Chemical', '-', (185, 191))
51569	24856037	C-Myc is amplified in a relatively small subset of cancers, but its coordination with activating mutations in growth factor receptor-PI3K signaling appears to be important for cancer metabolic reprogramming, including through regulation of glucose transport, glycolysis, glutaminolysis, lipogenesis and nucleotide synthesis.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('glycolysis', 'MPA', (259, 269))	('lipogenesis', 'MPA', (287, 298))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('glutaminolysis', 'MPA', (271, 285))	('glucose transport', 'MPA', (240, 257))	('nucleotide synthesis', 'MPA', (303, 323))	('cancer', 'Disease', (51, 57))	('glucose', 'Chemical', 'MESH:D005947', (240, 247))	('C-Myc', 'Gene', (0, 5))	('regulation', 'Reg', (226, 236))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Disease', (176, 182))	('cancers', 'Disease', (51, 58))	('C-Myc', 'Gene', '4609', (0, 5))
51570	24856037	Thus, c-Myc may be a critical node of convergence through which growth factor receptor signaling mutations reprogram cellular metabolism.	('c-Myc', 'Gene', (6, 11))	('mutations', 'Var', (97, 106))	('c-Myc', 'Gene', '4609', (6, 11))	('reprogram', 'Reg', (107, 116))
51574	24856037	Inactivation of FoxOs releases c-Myc from a suppressive miR-34c-dependent network which targets the 3'UTR of c-Myc mRNA and inhibits its translation.	('c-Myc', 'Gene', (109, 114))	('miR-34c', 'Gene', (56, 63))	('FoxOs', 'Gene', (16, 21))	("3'UTR", 'MPA', (100, 105))	('inhibits', 'NegReg', (124, 132))	('c-Myc', 'Gene', (31, 36))	('translation', 'MPA', (137, 148))	('c-Myc', 'Gene', '4609', (109, 114))	('miR-34c', 'Gene', '407042', (56, 63))	('Inactivation', 'Var', (0, 12))	('c-Myc', 'Gene', '4609', (31, 36))
51579	24856037	In the livers of Rictor knockout mice, loss of AKT Ser473 phosphorylation and glucokinase leads to constitutive gluconeogenesis and impaired glycolysis which alters whole-body glucose homeostasis.	('impaired', 'NegReg', (132, 140))	('glucose', 'Chemical', 'MESH:D005947', (176, 183))	('constitutive gluconeogenesis', 'MPA', (99, 127))	('AKT', 'Enzyme', (47, 50))	('Ser473', 'Chemical', '-', (51, 57))	('glucokinase', 'Gene', '103988', (78, 89))	('constitutive gluconeogenesis', 'Phenotype', 'HP:0005959', (99, 127))	('glucokinase', 'Gene', (78, 89))	('alters', 'Reg', (158, 164))	('loss', 'NegReg', (39, 43))	('mice', 'Species', '10090', (33, 37))	('Ser473', 'Var', (51, 57))	('whole-body glucose homeostasis', 'MPA', (165, 195))	('glycolysis', 'MPA', (141, 151))
51603	24856037	In GBM, activating cleavage of SREBP1 is downstream of mutant EGFR signaling through AKT, potently driving tumor growth in vivo.	('cleavage', 'MPA', (19, 27))	('driving', 'PosReg', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SREBP1', 'Gene', (31, 37))	('tumor', 'Disease', (107, 112))	('AKT', 'Pathway', (85, 88))	('EGFR', 'Gene', (62, 66))	('mutant', 'Var', (55, 61))	('activating', 'PosReg', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('SREBP1', 'Gene', '6720', (31, 37))
51609	24856037	Growth factor receptor signaling through PI3K-AKT, or low levels of cholesterol in the cell, activate SREBPs to promote expression of genes involved in cholesterol and fatty acid synthesis, including LDLR.	('expression', 'MPA', (120, 130))	('promote', 'PosReg', (112, 119))	('low levels of cholesterol', 'Phenotype', 'HP:0003146', (54, 79))	('cholesterol', 'Chemical', 'MESH:D002784', (68, 79))	('LDLR', 'Gene', (200, 204))	('fatty acid', 'Chemical', 'MESH:D005227', (168, 178))	('PI3K-AKT', 'Var', (41, 49))	('LDLR', 'Gene', '3949', (200, 204))	('cholesterol', 'Chemical', 'MESH:D002784', (152, 163))
51620	24856037	The FoxO-Myc axis is regulated via complementary posttranslational mechanisms and microRNA networks - PI3K/AKT-dependent inactivating phosphorylation of FoxO which relieves miR-145-mediated suppression of c-Myc and mTORC2-dependent acetylation of FoxO releasing c-Myc from miR-34c suppression (Figure 5).	('miR-145', 'Gene', '406937', (173, 180))	('FoxO', 'Gene', (153, 157))	('miR-145', 'Gene', (173, 180))	('relieves', 'NegReg', (164, 172))	('inactivating', 'Var', (121, 133))	('mTORC2', 'Gene', (215, 221))	('Myc', 'Gene', '4609', (264, 267))	('c-Myc', 'Gene', (262, 267))	('Myc', 'Gene', '4609', (9, 12))	('Myc', 'Gene', '4609', (207, 210))	('suppression', 'MPA', (190, 201))	('c-Myc', 'Gene', '4609', (262, 267))	('mTORC2', 'Gene', '74343', (215, 221))	('miR-34c', 'Gene', '407042', (273, 280))	('miR-34c', 'Gene', (273, 280))	('c-Myc', 'Gene', (205, 210))	('acetylation', 'MPA', (232, 243))	('c-Myc', 'Gene', '4609', (205, 210))	('Myc', 'Gene', (264, 267))	('Myc', 'Gene', (9, 12))	('Myc', 'Gene', (207, 210))
51622	24856037	mTORC2 inhibition may also be required to abrogate c-Myc expression and metabolic reprogramming in order to achieve clinical remission (Figure 5).	('c-Myc', 'Gene', '4609', (51, 56))	('c-Myc', 'Gene', (51, 56))	('inhibition', 'Var', (7, 17))	('mTORC2', 'Gene', (0, 6))	('clinical', 'Species', '191496', (116, 124))	('mTORC2', 'Gene', '74343', (0, 6))	('metabolic reprogramming', 'CPA', (72, 95))	('abrogate', 'NegReg', (42, 50))
51625	24856037	Further, new types of PET radiotracers may be a prospective candidate for identifying molecular subtypes and therapeutic effects in metabolically-active tumors stimulated by mTORC2/c-Myc signaling, including 89Zr-transferrin which binds to Myc-regulated transferrin receptor 1, L-[5-11C]-glutamine for glutaminolytic tumors and 11C-acetate for non 18F-FDG-avid neoplasms as well as 18F-FDG for Myc-activated tumors.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumors', 'Disease', 'MESH:D009369', (408, 414))	('L-[', 'Var', (278, 281))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('neoplasms', 'Phenotype', 'HP:0002664', (361, 370))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('transferrin', 'Gene', (213, 224))	('Myc', 'Gene', (394, 397))	('transferrin', 'Gene', (254, 265))	('mTORC2', 'Gene', (174, 180))	('binds', 'Interaction', (231, 236))	('Myc', 'Gene', '4609', (240, 243))	('Myc', 'Gene', '4609', (183, 186))	('tumors', 'Disease', (317, 323))	('11C-acetate', 'Chemical', 'MESH:C438206', (328, 339))	('glutamine', 'Chemical', 'MESH:D005973', (288, 297))	('transferrin', 'Gene', '7018', (213, 224))	('c-Myc', 'Gene', (181, 186))	('transferrin', 'Gene', '7018', (254, 265))	('tumors', 'Phenotype', 'HP:0002664', (408, 414))	('18F-FDG', 'Var', (382, 389))	('neoplasms', 'Disease', 'MESH:D009369', (361, 370))	('FDG', 'Chemical', 'MESH:D019788', (386, 389))	('mTORC2', 'Gene', '74343', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('c-Myc', 'Gene', '4609', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (408, 413))	('Myc', 'Gene', '4609', (394, 397))	('tumors', 'Disease', (408, 414))	('FDG', 'Chemical', 'MESH:D019788', (352, 355))	('neoplasms', 'Disease', (361, 370))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Myc', 'Gene', (240, 243))	('Myc', 'Gene', (183, 186))	('tumors', 'Disease', (153, 159))
51627	24856037	Mutations in IDH1/2 play an important role in gliomas through their effects on global transcription.	('IDH1/2', 'Gene', '3417;3418', (13, 19))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('gliomas', 'Disease', (46, 53))	('IDH1/2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('effects', 'Reg', (68, 75))	('global transcription', 'MPA', (79, 99))
51628	24856037	R132H IDH1 mutations cause the enzyme to acquire a neomorphic activity that converts alpha-ketoglutarate to 2-hydroxyglutarate, which inhibits the TET2 and the Jumonji-domain-containing protein 2A (JMJD2A/KDM4A) DNA demethylases, thus maintaining DNA in a hypermethylated state.	('inhibits', 'NegReg', (134, 142))	('KDM4A', 'Gene', (205, 210))	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (6, 10))	('JMJD2A', 'Gene', '9682', (198, 204))	('JMJD2A', 'Gene', (198, 204))	('R132H', 'Mutation', 'rs121913500', (0, 5))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (108, 126))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (85, 104))	('Jumonji-domain-containing protein 2A', 'Gene', '9682', (160, 196))	('Jumonji-domain-containing protein 2A', 'Gene', (160, 196))	('TET2', 'Gene', '54790', (147, 151))	('KDM4A', 'Gene', '9682', (205, 210))	('IDH1', 'Gene', (6, 10))	('R132H', 'Var', (0, 5))	('TET2', 'Gene', (147, 151))
51629	24856037	One current model posits that in the presence of IDH mutations, differentiation-related genes become "locked" in an inactive state, contributing to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('differentiation-related genes', 'Gene', (64, 93))	('IDH', 'Gene', (49, 52))	('tumor', 'Disease', (148, 153))	('IDH', 'Gene', '3417', (49, 52))	('mutations', 'Var', (53, 62))	('contributing to', 'Reg', (132, 147))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
51630	24856037	IDH1 mutations occur largely in lower grade gliomas and in only a small fraction of adult de novo GBMs.	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', 'MESH:D005910', (44, 51))	('gliomas', 'Disease', (44, 51))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('occur', 'Reg', (15, 20))	('IDH1', 'Gene', '3417', (0, 4))
51631	24856037	Also, the histone 3.3 mutations and the chromatin modifier mutations detected in pediatric gliomas are not common in adult de novo GBMs.	('gliomas', 'Disease', (91, 98))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('mutations', 'Var', (22, 31))	('histone 3.3', 'Protein', (10, 21))
51632	24856037	Taken together, these findings suggest that most adult GBMs, which are driven by RTK mutations and PI3K-AKT-mTOR pathway activation, utilize an alternative mechanism to hijack the epigenetic machinery.	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (108, 112))	('adult GBMs', 'CPA', (49, 59))	('RTK', 'Gene', (81, 84))	('mutations', 'Var', (85, 94))	('activation', 'PosReg', (121, 131))	('driven by', 'Reg', (71, 80))
51633	24856037	First, EGFR activation causes the glycolytic enzyme PKM2 to translocate to the nucleus where it phosphorylates histone 3 at Thr11, causing dissociation of HDAC3 to regulate transcription.	('EGFR', 'Gene', (7, 11))	('Thr11', 'Chemical', '-', (124, 129))	('HDAC3', 'Gene', '8841', (155, 160))	('PKM2', 'Gene', (52, 56))	('HDAC3', 'Gene', (155, 160))	('dissociation', 'MPA', (139, 151))	('causing', 'Reg', (131, 138))	('PKM2', 'Gene', '5315', (52, 56))	('activation', 'Var', (12, 22))	('regulate', 'Reg', (164, 172))	('transcription', 'MPA', (173, 186))
51634	24856037	Acetylation on the N-terminal lysine tail of histones leads to an open chromatin configuration facilitating transcription.	('open chromatin configuration', 'MPA', (66, 94))	('Acetylation', 'Var', (0, 11))	('lysine', 'Chemical', 'MESH:D008239', (30, 36))	('transcription', 'MPA', (108, 121))	('leads to', 'Reg', (54, 62))
51640	24856037	Therefore, it is possible that EGFR mutant GBMs may control epigenetic regulation by elevating the level of acetyl-CoA, while coordinately shifting the balance of HATs and HDACs towards one that supports tumor growth.	('epigenetic regulation', 'MPA', (60, 81))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('EGFR', 'Gene', (31, 35))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (108, 118))	('tumor', 'Disease', (204, 209))	('mutant', 'Var', (36, 42))	('shifting', 'Reg', (139, 147))	('elevating', 'PosReg', (85, 94))	('control', 'Reg', (52, 59))	('level of acetyl-CoA', 'MPA', (99, 118))
51647	24856037	However, that promise is unlikely to be realized until the consequences of cancer-causing mutations on metabolic reprogramming and epigenetic regulation are understood, including the flexible ways in which tumor cells adapt to changing conditions (such as drug treatment) to coordinately maintain the activity of downstream effectors necessary for tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('tumor', 'Disease', (206, 211))	('cancer', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('tumor', 'Disease', (348, 353))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('activity', 'MPA', (301, 309))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
51650	24856037	Understanding how cancer-causing mutations engage signaling pathways to coordinate repertoires of biochemical reactions linked to global transcription ensembles may yield critical insights into the pathogenesis of cancer, shed new light on how tumor cells resist targeted therapies to which they should be vulnerable, and possibly point the way towards more effective targeted cancer treatments.	('signaling pathways', 'Pathway', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancer', 'Disease', (214, 220))	('tumor', 'Disease', (244, 249))	('yield', 'Reg', (165, 170))	('engage', 'Reg', (43, 49))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
51655	24856037	Among the several reported tumorigenic mutations of EGFR, the most common, EGFRvIII (also known as de2-7 EGFR and DeltaEGFR) which is characterized by an in-frame deletion of exons 2-7 and results in a constitutively active oncogenic form, occurs in the ECD.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EGFRvIII', 'Disease', (75, 83))	('tumor', 'Disease', (27, 32))	('EGFR', 'Gene', (52, 56))	('constitutively active oncogenic form', 'MPA', (202, 238))	('ECD', 'Disease', 'MESH:C574275', (254, 257))	('mutations', 'Var', (39, 48))	('ECD', 'Disease', (254, 257))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('results in', 'Reg', (189, 199))
51661	24856037	Expression of the constitutively active mutant EGFRvIII sensitizes tumors to EGFR inhibitors, but only if the PTEN tumor suppressor protein is intact because PI3K signal flux is sustained by PTEN deficiency.	('PTEN', 'Gene', '5728', (110, 114))	('sensitizes', 'Reg', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('PTEN', 'Gene', (191, 195))	('tumor', 'Disease', (115, 120))	('PTEN', 'Gene', '5728', (191, 195))	('PTEN deficiency', 'Disease', (191, 206))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EGFRvIII', 'Gene', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('mutant', 'Var', (40, 46))	('PTEN deficiency', 'Disease', 'MESH:D006223', (191, 206))	('tumors', 'Disease', (67, 73))	('PTEN', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
51662	24856037	Recent single-cell analyses using GBM patient-derived models and clinical samples revealed that resistance to EGFR TKI occurs by a surprisingly dynamic elimination and re-emergence of mutant EGFR (EGFRvIII) from extrachromosomal DNA (episomes), indicating a highly adaptive route by which cancers can circumvent therapies which target oncogenes.	('cancers', 'Disease', 'MESH:D009369', (289, 296))	('clinical samples', 'Species', '191496', (65, 81))	('mutant', 'Var', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('patient', 'Species', '9606', (38, 45))	('EGFR', 'Gene', (191, 195))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('elimination', 'NegReg', (152, 163))	('EGFR TKI', 'Gene', (110, 118))	('cancers', 'Disease', (289, 296))
51673	23308224	Disruption of the Neurofibromatosis type 2 (NF2) gene, on human chromosome 22, leads to the development of the autosomal dominant disorder Neurofibromatosis type 2, characterized by the development of schwannomas, meningiomas, and ependymomas.	('meningiomas', 'Phenotype', 'HP:0002858', (214, 225))	('human', 'Species', '9606', (58, 63))	('Neurofibromatosis type 2', 'Gene', (139, 163))	('meningiomas', 'Disease', (214, 225))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (18, 35))	('Neurofibromatosis type 2', 'Gene', (18, 42))	('ependymomas', 'Disease', 'MESH:D004806', (231, 242))	('Disruption', 'Var', (0, 10))	('schwannomas', 'Phenotype', 'HP:0100008', (201, 212))	('schwannoma', 'Phenotype', 'HP:0100008', (201, 211))	('leads to', 'Reg', (79, 87))	('ependymomas', 'Disease', (231, 242))	('autosomal dominant disorder Neurofibromatosis type 2', 'Disease', 'MESH:C537392', (111, 163))	('Neurofibromatosis type 2', 'Gene', '4771', (139, 163))	('meningioma', 'Phenotype', 'HP:0002858', (214, 224))	('NF2', 'Gene', (44, 47))	('schwannomas', 'Disease', 'MESH:D009442', (201, 212))	('Neurofibromatosis type 2', 'Gene', '4771', (18, 42))	('schwannomas', 'Disease', (201, 212))	('meningiomas', 'Disease', 'MESH:D008577', (214, 225))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (139, 156))
51675	23308224	Loss of NF2 in glial cultures can lead to hyperproliferation, and formation of tumors in animal models.	('NF2', 'Gene', (8, 11))	('lead to', 'Reg', (34, 41))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Loss', 'Var', (0, 4))	('hyperproliferation', 'MPA', (42, 60))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
51676	23308224	Expression of NF2 has been shown to be absent in certain human glioblastomas and reintroduction can greatly suppress their growth.	('human', 'Species', '9606', (57, 62))	('NF2', 'Gene', (14, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (63, 76))	('growth', 'MPA', (123, 129))	('reintroduction', 'Var', (81, 95))	('absent', 'NegReg', (39, 45))	('glioblastomas', 'Disease', 'MESH:D005909', (63, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('glioblastomas', 'Disease', (63, 76))	('suppress', 'NegReg', (108, 116))
51682	23308224	In addition to its role in PML pathogenesis, JCV has exhibited oncogenic potential in cell culture and experimental animal models where T-antigen expression leads to a broad range of CNS malignancies, most notably the formation of neuronal and glial origin tumors including medulloblastomas, astrocytomas, and primitive neuroectodermal tumors.	('medulloblastomas', 'Disease', (274, 290))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Disease', (336, 342))	('primitive neuroectodermal tumor', 'Phenotype', 'HP:0030065', (310, 341))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('astrocytomas', 'Disease', (292, 304))	('medulloblastomas', 'Disease', 'MESH:D008527', (274, 290))	('leads to', 'Reg', (157, 165))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('primitive neuroectodermal tumors', 'Phenotype', 'HP:0030065', (310, 342))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (320, 342))	('malignancies', 'Disease', (187, 199))	('T-antigen expression', 'Var', (136, 156))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('neuroectodermal tumors', 'Disease', 'MESH:D017599', (320, 342))	('tumors', 'Disease', (257, 263))	('astrocytomas', 'Disease', 'MESH:D001254', (292, 304))	('neuroectodermal tumor', 'Phenotype', 'HP:0030061', (320, 341))	('JCV', 'Species', '10632', (45, 48))	('neuroectodermal tumors', 'Disease', (320, 342))
51684	23308224	Potential mechanisms of JCV T-antigen induced oncogenesis have focused on the ability of T-antigen to disrupt the activity of cell cycle regulatory proteins including p53 and Rb, T-antigen's enhancement of oncogenic signaling through the Wnt pathway by stabilizing key members, such as beta-catenin, LEF-1, and c-myc , and its interaction with DNA repair proteins, to name a few.	('LEF-1', 'CellLine', 'CVCL:B526', (300, 305))	('beta-catenin', 'Protein', (286, 298))	('oncogenic signaling', 'MPA', (206, 225))	('activity', 'MPA', (114, 122))	('stabilizing', 'PosReg', (253, 264))	('enhancement', 'PosReg', (191, 202))	('LEF-1', 'Gene', (300, 305))	('myc', 'Gene', (313, 316))	('interaction', 'Interaction', (327, 338))	('JCV', 'Species', '10632', (24, 27))	('myc', 'Gene', '4609', (313, 316))	('Wnt pathway', 'Pathway', (238, 249))	('T-antigen', 'Var', (179, 188))	('disrupt', 'NegReg', (102, 109))
51695	23308224	To this end, human U-87 MG glioblastoma cells were transiently transfected with plasmids encoding JCV T-antigen and increasing amounts of HA tagged NF2 (HA-NF2).	('U-87 MG', 'CellLine', 'CVCL:0022', (19, 26))	('JCV', 'Species', '10632', (98, 101))	('human', 'Species', '9606', (13, 18))	('JCV', 'Var', (98, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('MG glioblastoma', 'Disease', 'MESH:D005909', (24, 39))	('MG glioblastoma', 'Disease', (24, 39))
51700	23308224	The presence of increasing amounts of NF2 resulted in retention of basal promoter activity of the JCVE promoter (Figure 1C) and minor suppression of JCVL activity (Figure 1D).	('basal promoter activity', 'MPA', (67, 90))	('JCV', 'Species', '10632', (98, 101))	('JCV', 'Species', '10632', (149, 152))	('suppression', 'NegReg', (134, 145))	('NF2', 'Var', (38, 41))	('JCVL activity', 'MPA', (149, 162))
51715	23308224	Co-transfection of these NF2 mutants into U-87 MG cells along with T-antigen, revealed a dose-dependent decline in T-antigen levels with the HA-FERM mutant, similar to full length NF2 (Figure 3A, lanes 1-3), while T-antigen expression remained unaltered in the presence of the HA-DeltaFERM mutant (Figure 3A, lanes 4-6).	('NF2', 'Gene', (25, 28))	('decline', 'NegReg', (104, 111))	('T-antigen levels', 'MPA', (115, 131))	('mutant', 'Var', (149, 155))	('HA-FERM mutant', 'Var', (141, 155))	('mutants', 'Var', (29, 36))	('U-87 MG', 'CellLine', 'CVCL:0022', (42, 49))
51719	23308224	Increasing amounts of NF2 led to a decline in T-antigen protein in samples treated with vehicle alone (Figure 4A, left), while treatment with MG132 ameliorated these affects, such that T-antigen expression was unaltered in the presence of NF2 (Figure 4A, right).	('NF2', 'Var', (22, 25))	('T-antigen protein', 'MPA', (46, 63))	('MG132', 'Chemical', 'MESH:C072553', (142, 147))	('decline', 'NegReg', (35, 42))
51720	23308224	Increasing amounts of MG132 led to an accumulation of p21, another protein known to be regulated by this pathway (Figure 4B), indicating the stabilization of proteins subjected to proteasomal degradation.	('p21', 'MPA', (54, 57))	('accumulation', 'PosReg', (38, 50))	('B', 'Gene', '2035', (122, 123))	('MG132', 'Var', (22, 27))	('stabilization', 'MPA', (141, 154))	('MG132', 'Chemical', 'MESH:C072553', (22, 27))
51731	23308224	Interestingly, high levels of NF2 and p53 were detected in another glioblastoma sample (Gli906A) in the absence of T-antigen (Figure 5C).	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('NF2', 'Protein', (30, 33))	('p53', 'Var', (38, 41))
51737	23308224	Reintroduction of NF2 in these cells can significantly inhibit cell proliferation, cellular transformation, and tumorigenesis.	('NF2', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cell proliferation', 'CPA', (63, 81))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('inhibit', 'NegReg', (55, 62))	('Reintroduction', 'Var', (0, 14))	('cellular transformation', 'CPA', (83, 106))
51747	23308224	NF2 has not been shown to directly regulate the cell cycle; however its presence promotes cell cycle arrest in schwannoma, primary endothelial, mesothelioma, and patient-derived meningioma cells.	('meningioma', 'Disease', 'MESH:D008577', (178, 188))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('presence', 'Var', (72, 80))	('promotes', 'PosReg', (81, 89))	('mesothelioma', 'Disease', (144, 156))	('meningioma', 'Disease', (178, 188))	('meningioma', 'Phenotype', 'HP:0002858', (178, 188))	('schwannoma', 'Disease', 'MESH:D009442', (111, 121))	('schwannoma', 'Disease', (111, 121))	('cell cycle arrest', 'CPA', (90, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('patient', 'Species', '9606', (162, 169))	('schwannoma', 'Phenotype', 'HP:0100008', (111, 121))
51749	23308224	Furthermore, NF2 inhibits PAK2 from acting as a positive transcriptional regulator of the cell cycle enhancer, cyclin D1.	('inhibits', 'NegReg', (17, 25))	('cyclin D1', 'Gene', (111, 120))	('PAK2', 'Gene', (26, 30))	('NF2', 'Var', (13, 16))	('PAK2', 'Gene', '5062', (26, 30))	('cyclin D1', 'Gene', '595', (111, 120))
51755	23308224	The NF2 and p53 genes are linked in the mouse genome, and loss of both genes leads to the development of multiple highly metastatic tumors and in meningiomas, the loss of functional NF2 and p53 correlate with enhanced tumor grade.	('enhanced', 'PosReg', (209, 217))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (218, 223))	('mouse', 'Species', '10090', (40, 45))	('NF2', 'Gene', (182, 185))	('meningioma', 'Phenotype', 'HP:0002858', (146, 156))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('meningiomas', 'Disease', 'MESH:D008577', (146, 157))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('meningiomas', 'Phenotype', 'HP:0002858', (146, 157))	('meningiomas', 'Disease', (146, 157))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('loss', 'Var', (163, 167))	('p53', 'Gene', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Disease', (132, 138))	('leads to', 'Reg', (77, 85))	('loss', 'Var', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
51761	23308224	Previously, we have observed wild-type p53 in nervous system tumors from T-antigen transgenic mice and have demonstrated that T-antigen only interacts with wild type and not mutant p53.	('nervous system tumors', 'Phenotype', 'HP:0004375', (46, 67))	('nervous system tumors', 'Disease', (46, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('nervous system tumors', 'Disease', 'MESH:D009423', (46, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('transgenic mice', 'Species', '10090', (83, 98))	('mutant', 'Var', (174, 180))
51762	23308224	However, immunohistochemical detection in formalin-fixed tissue does not allow the distinction between wild-type and mutant forms of p53, therefore other means, i.e.	('p53', 'Gene', (133, 136))	('mutant', 'Var', (117, 123))	('formalin', 'Chemical', 'MESH:D005557', (42, 50))
51764	23308224	Alteration of p53 remains one of the key genetic changes in human glioblastoma and its mutation or loss has been reported in some percentage of all subtypes of glioblastomas thus far described.	('glioblastoma', 'Disease', (160, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('glioblastomas', 'Disease', (160, 173))	('p53', 'Gene', (14, 17))	('Alteration', 'Var', (0, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('glioblastoma', 'Disease', (66, 78))	('loss', 'NegReg', (99, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('glioblastomas', 'Phenotype', 'HP:0012174', (160, 173))	('mutation', 'Var', (87, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('human', 'Species', '9606', (60, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (160, 173))
51765	23308224	While NF2 inactivation has been linked to schwannomas and other tumors such as mesotheliomas, loss of NF2 expression appears to be infrequent in human glioblastoma, though it has been reported in up to one third of cases.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('schwannomas', 'Disease', (42, 53))	('human', 'Species', '9606', (145, 150))	('schwannoma', 'Phenotype', 'HP:0100008', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('mesotheliomas', 'Disease', (79, 92))	('loss', 'Var', (94, 98))	('linked', 'Reg', (32, 38))	('NF2', 'Gene', (102, 105))	('schwannomas', 'Phenotype', 'HP:0100008', (42, 53))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('mesotheliomas', 'Disease', 'MESH:D008654', (79, 92))	('NF2', 'Gene', (6, 9))	('inactivation', 'Var', (10, 22))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Disease', (151, 163))	('schwannomas', 'Disease', 'MESH:D009442', (42, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))
51801	23308224	The following primers (20 microM) and a FAM fluorophore labeled mRNA probe (10 microM) specific to JCV T-antigen were used in the PCR reaction: forward primer (4255-4274) 5' AGTCTTTAGGGTCTTCTACC 3', reverse primer (4408-4427) 5' GTGCCAACCTATGGAACAG 3', probe (4303-4327) 5' FAM-AGTGTTGGGATCCTGTGTTTTCATCATC-BHQ1 3'.	('4255-4274', 'Var', (160, 169))	('4408-4427', 'Var', (215, 224))	('JCV', 'Species', '10632', (99, 102))	('4303-4327', 'Var', (260, 269))	('B', 'Gene', '2035', (307, 308))
51810	23308224	Primary antibodies to NF2 (C-18), p53 (D-07) and T-antigen (SV40 T-antigen Ab2) were incubated on the slides overnight in a humidified chamber.	('C-18', 'Gene', '27241', (27, 31))	('p53', 'Var', (34, 37))	('C-18', 'Gene', (27, 31))	('NF2', 'Gene', (22, 25))
51824	33207694	However, non-canonical RNA transcripts are frequently made through a process called alternative splicing as a result of many factors including RNA secondary structure, strength of splice recognition sites and dynamic permutations of RNA and protein factors within the spliceosome.	('permutations', 'Var', (217, 229))	('nt', 'Chemical', 'MESH:D009711', (49, 51))	('alternative splicing', 'Disease', (84, 104))	('result', 'Reg', (110, 116))
51827	33207694	Perhaps unsurprisingly, misregulation of alternative splicing through mutations of RNA splicing factors and RNA splice sites can be devastating, with evidence of aberrant splicing found in cancer and in neurological diseases.	('mutations', 'Var', (70, 79))	('nt', 'Chemical', 'MESH:D009711', (168, 170))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('neurological diseases', 'Disease', (203, 224))	('neurological diseases', 'Disease', 'MESH:D020271', (203, 224))	('alternative splicing', 'MPA', (41, 61))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
51828	33207694	The most common alternative splicing events in humans are exon skipping/inclusion (>40% of variants), use of alternative splice sites, and intron retention.	('nt', 'Chemical', 'MESH:D009711', (150, 152))	('nt', 'Chemical', 'MESH:D009711', (140, 142))	('nt', 'Chemical', 'MESH:D009711', (96, 98))	('humans', 'Species', '9606', (47, 53))	('variants', 'Var', (91, 99))	('exon skipping/inclusion', 'Var', (58, 81))	('nt', 'Chemical', 'MESH:D009711', (40, 42))	('intron retention', 'Var', (139, 155))
51839	33207694	This REST/NSRF variant, called REST4, encodes an inactive protein lacking five critical zinc finger DNA binding domains.	('lacking', 'NegReg', (66, 73))	('nt', 'Chemical', 'MESH:D009711', (20, 22))	('variant', 'Var', (15, 22))
51846	33207694	It has emerged that alternative splicing is a critical factor in the initiation and progression of human pathologies, including cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('alternative splicing', 'Var', (20, 40))	('human', 'Species', '9606', (99, 104))	('cancer', 'Disease', (128, 134))
51847	33207694	Mutation, or mis-regulation, of splicing factors and snRNAs have been found in various cancers, including the most lethal brain cancer, glioblastoma (GBM).	('cancers', 'Disease', (87, 94))	('snRNAs', 'Gene', (53, 59))	('brain cancer', 'Disease', 'MESH:D001932', (122, 134))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('splicing factors', 'Protein', (32, 48))	('glioblastoma', 'Disease', (136, 148))	('mis-regulation', 'Var', (13, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('brain cancer', 'Phenotype', 'HP:0030692', (122, 134))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('brain cancer', 'Disease', (122, 134))	('found', 'Reg', (70, 75))
51851	33207694	Alternative splicing signatures have been proposed as a novel prognostic marker, but also targeting alternative splicing in GBM could represent a novel and desperately needed therapeutic strategy.	('Alternative splicing', 'Var', (0, 20))	('alternative splicing', 'Var', (100, 120))	('nt', 'Chemical', 'MESH:D009711', (141, 143))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))
51855	33207694	While upregulation of SRRM4 has been reported to promote neuroendocrine prostate cancer through alternative splicing, SRRM4 is seen to decrease in expression within the tumor proper compared with the leading edge and infiltrating tumor in GBM based on RNA sequencing data from the IVY Glioblastoma Atlas Project.	('Glioblastoma', 'Phenotype', 'HP:0012174', (285, 297))	('expression', 'MPA', (147, 157))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (57, 87))	('promote', 'PosReg', (49, 56))	('decrease', 'NegReg', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('IVY Glioblastoma Atlas', 'Disease', 'MESH:D005909', (281, 303))	('neuroendocrine prostate cancer', 'Disease', (57, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (72, 87))	('SRRM4', 'Var', (118, 123))	('SRRM4', 'Gene', (22, 27))	('tumor', 'Disease', (169, 174))	('upregulation', 'PosReg', (6, 18))	('IVY Glioblastoma Atlas', 'Disease', (281, 303))	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('GBM', 'Phenotype', 'HP:0012174', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('alternative splicing', 'MPA', (96, 116))
51890	33207694	Full-length SRRM3 (HsCD00813375) and SRRM4 (HsCD00295084) in pENTR223.1 were obtained from DNASU Plasmid Repository.	('HsCD00295084', 'Var', (44, 56))	('SRRM3', 'Gene', '222183', (12, 17))	('HsCD00813375', 'Var', (19, 31))	('SRRM3', 'Gene', (12, 17))
51956	33207694	The 218 bp PCR product corresponding to the ME-circRNA was detected in the tumors and at the same relative abundance of that ME from within each RNA-seq dataset (#158 had 307 ME counts, #190 had 114 and #217 had 130 ME counts), with Sanger sequencing confirming the ME comprises the backsplice junction (Figure 2f).	('nt', 'Chemical', 'MESH:D009711', (222, 224))	('#158', 'Var', (162, 166))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('ME', 'Chemical', '-', (216, 218))	('#190', 'Var', (186, 190))	('ME', 'Chemical', '-', (125, 127))	('#217', 'Var', (203, 207))	('nt', 'Chemical', 'MESH:D009711', (181, 183))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ME', 'Chemical', '-', (266, 268))	('ME', 'Chemical', '-', (44, 46))	('tumors', 'Disease', (75, 81))	('ME', 'Chemical', '-', (175, 177))
51968	33207694	Comparing expression by qRT-PCR, SRRM4 was the only family member to be significantly decreased (One-way ANOVA, Mann-Whitney test, p = 0.023) in expression in GBM compared with the normal brain tissue (Figure 3a).	('nt', 'Chemical', 'MESH:D009711', (81, 83))	('expression', 'MPA', (145, 155))	('decreased', 'NegReg', (86, 95))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('GBM', 'Var', (159, 162))
51987	33207694	While MEF2C mRNA containing a ME was present in EV and SRRM3 lines, it visibly increased in abundance with SRRM4 expression, suggesting SRRM4 can boost ME inclusion when there is a basal level of expression (Figure 3c).	('nt', 'Chemical', 'MESH:D009711', (19, 21))	('increased', 'PosReg', (79, 88))	('boost', 'PosReg', (146, 151))	('SRRM3', 'Gene', (55, 60))	('ME', 'Chemical', '-', (30, 32))	('nt', 'Chemical', 'MESH:D009711', (42, 44))	('ME', 'Chemical', '-', (6, 8))	('ME', 'Chemical', '-', (152, 154))	('ME inclusion', 'MPA', (152, 164))	('SRRM3', 'Gene', '222183', (55, 60))	('SRRM4', 'Var', (136, 141))	('MEF2C', 'Gene', '4208', (6, 11))	('MEF2C', 'Gene', (6, 11))
52002	33207694	Despite the focus of these reports being on the alternative splicing of the coding transcriptome, our study opens the possibility that ME-circRNAs, like other circRNAs, could play a pathogenic role in cancer.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('ME', 'Chemical', '-', (135, 137))	('play', 'Reg', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ME-circRNAs', 'Var', (135, 146))
52003	33207694	With respect to glioma, we identified a significant correlation (p < 0.0001) between low SRRM4 expression and poor survival in GBM and low-grade glioma across the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA) and Repository of Molecular Brain Neoplasia Data (Rembrandt) datasets (Figure S5b-d).	('nt', 'Chemical', 'MESH:D009711', (30, 32))	('Glioma', 'Phenotype', 'HP:0009733', (171, 177))	('Cancer', 'Disease', (203, 209))	('S5b', 'Gene', '5711', (308, 311))	('glioma', 'Disease', (145, 151))	('Glioma', 'Disease', (171, 177))	('Cancer', 'Disease', 'MESH:D009369', (203, 209))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('Neoplasia', 'Phenotype', 'HP:0002664', (264, 273))	('S5b', 'Gene', (308, 311))	('expression', 'MPA', (95, 105))	('Brain Neoplasia', 'Phenotype', 'HP:0030692', (258, 273))	('glioma', 'Disease', (16, 22))	('Brain Neoplasia', 'Disease', 'MESH:D009369', (258, 273))	('nt', 'Chemical', 'MESH:D009711', (49, 51))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('Brain Neoplasia', 'Disease', (258, 273))	('Glioma', 'Disease', 'MESH:D005910', (171, 177))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('low', 'Var', (85, 88))	('Cancer', 'Phenotype', 'HP:0002664', (203, 209))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('SRRM4', 'Gene', (89, 94))
52015	33207694	; resources (clinical information and patient sample curation), R.J.O., S.P., and G.K.; investigation, V.M.C., B.W.S., M.G., T.P., and S.J.C.	('patient', 'Species', '9606', (38, 45))	('B.W.S.', 'Var', (111, 117))	('M.G.', 'Var', (119, 123))
52023	32518380	In patients with high EGR1 expression, 83% had methylated MGMT-promoters, while all patients with low EGR1 expression had un-methylated MGMT-promoters.	('methylated', 'Var', (47, 57))	('MGMT', 'Gene', '4255', (58, 62))	('MGMT', 'Gene', (58, 62))	('patients', 'Species', '9606', (84, 92))	('high', 'Var', (17, 21))	('expression', 'MPA', (27, 37))	('patients', 'Species', '9606', (3, 11))	('MGMT', 'Gene', '4255', (136, 140))	('EGR1', 'Gene', (22, 26))	('MGMT', 'Gene', (136, 140))
52024	32518380	High EGR3 expression in MGMT-methylated patients was associated with poor survival (HR = 1.98; 95%CI 1.22-3.22; P = 0.006), while EGR1 high/EGR3 high, was associated with poor survival vs. EGR1 high/EGR3 low (HR = 2.11; 95%CI 1.25-3.56; P = 0.005).	('EGR3', 'Gene', (5, 9))	('MGMT', 'Gene', '4255', (24, 28))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (40, 48))	('poor', 'NegReg', (69, 73))	('MGMT', 'Gene', (24, 28))
52081	32518380	When stratifying GBMs based on mutational status of IDH1/2, no significant differences in EGR1 or EGR3 protein levels were found in IDH1/2 wildtype vs. IDH1/2 mutated tumours (Fig.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('IDH1/2', 'Gene', (132, 138))	('IDH1/2', 'Gene', (152, 158))	('mutated', 'Var', (159, 166))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('IDH1/2', 'Gene', '3417;3418', (52, 58))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('IDH1/2', 'Gene', '3417;3418', (132, 138))	('tumours', 'Disease', (167, 174))	('IDH1/2', 'Gene', '3417;3418', (152, 158))	('IDH1/2', 'Gene', (52, 58))
52091	32518380	Interestingly, 78/94 (83%) of patients with methylated MGMT-promoters were in the EGR1 high group with a mean EGR1-positive cell fraction of 38.4%, while 71/71 (100%) of patients with un-methylated MGMT-promoters were in the EGR1 low group with a mean EGR1 fraction of 15.72% (Fig.	('methylated', 'Var', (44, 54))	('patients', 'Species', '9606', (170, 178))	('MGMT', 'Gene', '4255', (55, 59))	('MGMT', 'Gene', (55, 59))	('MGMT', 'Gene', (198, 202))	('MGMT', 'Gene', '4255', (198, 202))	('patients', 'Species', '9606', (30, 38))	('EGR1', 'Gene', (82, 86))
52104	32518380	In this study, we found a significant association between high EGR1 expression and improved overall patient survival in univariate analysis; however, the results were non-significant when adjusting for confounders.	('EGR1', 'Gene', (63, 67))	('improved', 'PosReg', (83, 91))	('expression', 'MPA', (68, 78))	('patient', 'Species', '9606', (100, 107))	('high', 'Var', (58, 62))
52105	32518380	MGMT methylation status is known as a strong independent predictor of both progression-free survival and overall survival in GBM patients.	('MGMT', 'Gene', (0, 4))	('patients', 'Species', '9606', (129, 137))	('methylation', 'Var', (5, 16))	('MGMT', 'Gene', '4255', (0, 4))
52106	32518380	Nearly all patients with high EGR1 expression had a methylated MGMT promoter, while most patients with low EGR1 expression had an unmethylated MGMT promoter.	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('expression', 'MPA', (35, 45))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (89, 97))	('MGMT', 'Gene', (143, 147))	('methylated', 'MPA', (52, 62))	('patients', 'Species', '9606', (11, 19))	('MGMT', 'Gene', '4255', (143, 147))	('EGR1', 'Gene', (30, 34))
52119	32518380	High nuclear levels of EGR3 remained significantly associated with poor patient survival in MGMT-methylated patients after adjustment for confounders, as did the combination of EGR1 high/EGR3 high compared to EGR1 high/EGR3 low.	('EGR3', 'Gene', (23, 27))	('high', 'Var', (192, 196))	('High nuclear levels', 'MPA', (0, 19))	('poor', 'NegReg', (67, 71))	('MGMT', 'Gene', '4255', (92, 96))	('patient', 'Species', '9606', (72, 79))	('MGMT', 'Gene', (92, 96))	('patient survival', 'CPA', (72, 88))	('EGR1', 'Gene', (177, 181))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))	('high/EGR3 high', 'Var', (182, 196))
52125	32518380	Overall, our findings suggest that high EGR3 protein expression was associated with a poor prognosis in GBM patients with a methylated MGMT-promoter, while EGR1 expression was not associated with prognosis after adjustment for clinically relevant confounders.	('high', 'PosReg', (35, 39))	('EGR3', 'Gene', (40, 44))	('GBM', 'Disease', (104, 107))	('protein', 'Protein', (45, 52))	('MGMT', 'Gene', (135, 139))	('MGMT', 'Gene', '4255', (135, 139))	('methylated', 'Var', (124, 134))	('expression', 'MPA', (53, 63))	('patients', 'Species', '9606', (108, 116))
52133	30873355	Lee and colleagues demonstrated that cells in the SVZ contained driver mutations of IDH wild-type glioblastoma.	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('IDH', 'Gene', (84, 87))	('mutations', 'Var', (71, 80))	('IDH', 'Gene', '3417', (84, 87))
52135	30873355	The tumor-free SVZ in 9 of the 16 (56.3%) patients with IDH wild-type glioblastoma already had at least one somatic, low-level (as low as 1% of the mutational burden) driver mutation that was present at high levels in the tumor.	('tumor', 'Disease', (4, 9))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('mutation', 'Var', (174, 182))	('IDH', 'Gene', (56, 59))	('IDH', 'Gene', '3417', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('glioblastoma', 'Disease', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('patients', 'Species', '9606', (42, 50))
52136	30873355	All the 9 tumor-free SVZ samples had a mutation in the TERT coding or promoter region.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutation', 'Var', (39, 47))	('tumor', 'Disease', (10, 15))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
52137	30873355	Other mutations were also found in EGFR, PTEN and TP53.	('EGFR', 'Gene', '1956', (35, 39))	('TP53', 'Gene', '7157', (50, 54))	('EGFR', 'Gene', (35, 39))	('found', 'Reg', (26, 31))	('TP53', 'Gene', (50, 54))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('mutations', 'Var', (6, 15))
52138	30873355	Single-cell targeted sequencing of an IDH wild-type glioblastoma and its single-cell-derived clonal cell populations demonstrated that all clones had mutations shared with the respective tumor-free SVZ, in addition to the tumor-private mutations.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('IDH', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('IDH', 'Gene', '3417', (38, 41))	('tumor', 'Disease', (187, 192))	('glioblastoma', 'Disease', (52, 64))	('tumor', 'Disease', (222, 227))	('mutations', 'Var', (150, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))
52139	30873355	On the other hand, tumor-free SVZ (in another patient) had few clones with the shared mutations of the respective tumor but lacked the tumor-private mutations.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patient', 'Species', '9606', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
52140	30873355	Through laser microdissection of the SVZ microarchitecture in two patients and targeted deep sequencing, TERT promoter mutation was found to be enriched only in GFAP-positive, astrocyte-like stem cells of the astrocytic ribbon of the SVZ.	('TERT', 'Gene', (105, 109))	('TERT', 'Gene', '7015', (105, 109))	('mutation', 'Var', (119, 127))	('patients', 'Species', '9606', (66, 74))
52141	30873355	When some of the discovered driver mutations (p53, Pten, and Egfr) were engineered specifically in the neural stem cells of the SVZ in mice, the mutated neural stem cells developed tumors, two-thirds of which were distant from the SVZ, especially in the dorsolateral-caudal cortex.	('Pten', 'Gene', '19211', (51, 55))	('mutated', 'Var', (145, 152))	('tumors', 'Disease', (181, 187))	('p53', 'Gene', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('mice', 'Species', '10090', (135, 139))	('Egfr', 'Gene', (61, 65))	('p53', 'Gene', '22060', (46, 49))	('Pten', 'Gene', (51, 55))	('Egfr', 'Gene', '13649', (61, 65))	('developed', 'PosReg', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
52143	30873355	Thereby, Lee and colleagues provide a direct evidence that SVZ cells containing driver mutations migrate to distant regions and clonally evolve into glioblastoma.	('glioblastoma', 'Disease', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('evolve', 'Reg', (137, 143))	('mutations', 'Var', (87, 96))
52144	30873355	One was the systematic sequencing of triple-matched samples of the tumor, tumor-free SVZ, and blood (or cortex) which led to discovery of low-level driver mutations in the tumor-free SVZ.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutations', 'Var', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
52151	30873355	For example, what are the cellular origins of IDH mutant glioblastomas (3 studied) and 7 of the 16 IDH wild-type glioblastomas without a discovered mutation in their respective tumor-free SVZ samples?	('IDH', 'Gene', '3417', (99, 102))	('glioblastomas', 'Phenotype', 'HP:0012174', (113, 126))	('glioblastomas', 'Disease', 'MESH:D005909', (57, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('IDH', 'Gene', (46, 49))	('glioblastomas', 'Disease', (57, 70))	('glioblastomas', 'Disease', 'MESH:D005909', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('IDH', 'Gene', '3417', (46, 49))	('glioblastomas', 'Disease', (113, 126))	('mutant', 'Var', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('IDH', 'Gene', (99, 102))	('tumor', 'Disease', (177, 182))	('glioblastomas', 'Phenotype', 'HP:0012174', (57, 70))
52153	30873355	For example, what are the mechanisms or environmental events that cause the mutated neural stem cells to explode into tumors?	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutated', 'Var', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
52154	30873355	Specifically, how might mutations in the TERT coding or promoter region in the neural stem cells, found in all the tumor-free SVZ samples studied by Lee and colleagues that had a genetic aberration, result in gliomagenesis is intriguing.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('TERT', 'Gene', (41, 45))	('gliomagenesis', 'Disease', (209, 222))	('TERT', 'Gene', '7015', (41, 45))	('mutations', 'Var', (24, 33))	('result in', 'Reg', (199, 208))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
52155	30873355	Lastly, understanding the environmental factors that govern neural stem cells with cancer driver mutations to differentiate to mature neurons when migrating to the olfactory bulb may broaden our approaches of therapy development.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))
52179	28936153	For example methylation of methyl guanine methyl transferase (MGMT) predict better survival rate in patients with high-grade glioma, particularly in elderly patients.	('glioma', 'Disease', (125, 131))	('survival rate', 'CPA', (83, 96))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('patients', 'Species', '9606', (157, 165))	('better', 'PosReg', (76, 82))	('patients', 'Species', '9606', (100, 108))	('methylation', 'Var', (12, 23))
52181	28936153	Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) and IDH2 improves overall survival, independent of other established prognostic factors, especially in anaplastic gliomas.	('anaplastic glioma', 'Disease', (161, 178))	('IDH1', 'Gene', '3417', (52, 56))	('overall survival', 'MPA', (76, 92))	('anaplastic glioma', 'Disease', 'MESH:D005910', (161, 178))	('gliomas', 'Phenotype', 'HP:0009733', (172, 179))	('improves', 'PosReg', (67, 75))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('isocitrate dehydrogenase 1', 'Gene', '3417', (24, 50))	('Mutations', 'Var', (0, 9))	('isocitrate dehydrogenase 1', 'Gene', (24, 50))	('gliomas', 'Disease', (172, 179))	('IDH2', 'Gene', (62, 66))	('gliomas', 'Disease', 'MESH:D005910', (172, 179))	('IDH1', 'Gene', (52, 56))	('IDH2', 'Gene', '3418', (62, 66))
52249	28936153	In addition, the bevacizumab group experienced the worse quality of life, and a sharp decline in neurocognitive function compared with the placebo group.	('bevacizumab', 'Chemical', 'MESH:D000068258', (17, 28))	('decline', 'NegReg', (86, 93))	('neurocognitive function', 'MPA', (97, 120))	('bevacizumab', 'Var', (17, 28))
52259	28936153	Oligodendroglial tumors carry certain favorable molecular markers, such as 1p19q co-deletion and IDH mutations.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('1p19q co-deletion', 'Var', (75, 92))	('IDH', 'Gene', (97, 100))	('IDH', 'Gene', '3417', (97, 100))	('Oligodendroglial tumors', 'Disease', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Oligodendroglial tumors', 'Disease', 'MESH:D009369', (0, 23))
52260	28936153	Two randomized Phase III trials (EORTC 26951 trial and RTOG 9402 trial) have shown that a combination of both RT and PCV following surgical resection improves overall survival on long-term follow-up in the subset of patients with 1p19q co-deletion.	('patients', 'Species', '9606', (216, 224))	('1p19q co-deletion', 'Var', (230, 247))	('overall survival', 'MPA', (159, 175))	('improves', 'PosReg', (150, 158))
52305	28936153	In anaplastic oligodendroglioma, TMZ is the preferred regimen compared to PCV, based on its convenience of administration and better tolerability.	('TMZ', 'Var', (33, 36))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('TMZ', 'Chemical', 'MESH:D000077204', (33, 36))	('anaplastic oligodendroglioma', 'Disease', (3, 31))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (3, 31))
52353	28034905	Both probe sets (ACD 425971 - V-HHPV5-IE1 and ACD 425981 - V-HHPV5-PP65) showed strongly positive hybridization signals in the control HCMV infected cells but not in the mock infected cells (Figure 1).	('mock infected', 'Disease', (170, 183))	('mock infected', 'Disease', 'MESH:D007239', (170, 183))	('hybridization', 'Interaction', (98, 111))	('positive', 'PosReg', (89, 97))	('ACD 425981 - V-HHPV5-PP65', 'Var', (46, 71))
52360	28034905	All 27 human brain tumor tissues were negative for CMV IE1 and pp65 protein (Supplemental Table 2).	('pp65', 'Var', (63, 67))	('brain tumor', 'Disease', (13, 24))	('human', 'Species', '9606', (7, 12))	('brain tumor', 'Disease', 'MESH:D001932', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('brain tumor', 'Phenotype', 'HP:0030692', (13, 24))
52418	26231762	Providing the rationale for the current study, we recently demonstrated that elevated levels of KLK6 are associated with high-grade glioma and poor patient survival.	('patient', 'Species', '9606', (148, 155))	('glioma', 'Disease', (132, 138))	('levels', 'Var', (86, 92))	('poor', 'NegReg', (143, 147))	('elevated', 'PosReg', (77, 85))	('KLK6', 'Gene', '5653', (96, 100))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('associated', 'Reg', (105, 115))	('KLK6', 'Gene', (96, 100))
52485	26231762	Expression of KLK6 RNA is also linked to poor patient survival in a group of intracranial malignancies, including glioblastomas, meningiomas, oligodendrogliomas, ependymomas and other rare malignancies and brain metastases.	('glioblastomas', 'Disease', 'MESH:D005909', (114, 127))	('Expression', 'Var', (0, 10))	('KLK6', 'Gene', '5653', (14, 18))	('ependymomas', 'Disease', (162, 173))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('KLK6', 'Gene', (14, 18))	('malignancies', 'Disease', (90, 102))	('brain metastases', 'Disease', 'MESH:D009362', (206, 222))	('brain metastases', 'Disease', (206, 222))	('poor', 'NegReg', (41, 45))	('meningiomas', 'Disease', 'MESH:D008577', (129, 140))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (142, 160))	('glioblastomas', 'Phenotype', 'HP:0012174', (114, 127))	('intracranial malignancies', 'Disease', (77, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('patient', 'Species', '9606', (46, 53))	('intracranial malignancies', 'Disease', 'MESH:D009369', (77, 102))	('linked', 'Reg', (31, 37))	('meningiomas', 'Phenotype', 'HP:0002858', (129, 140))	('malignancies', 'Disease', 'MESH:D009369', (189, 201))	('meningiomas', 'Disease', (129, 140))	('malignancies', 'Disease', (189, 201))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('oligodendrogliomas', 'Disease', (142, 160))	('glioblastomas', 'Disease', (114, 127))	('ependymomas', 'Disease', 'MESH:D004806', (162, 173))
52491	26231762	Both studies support the idea that KLK7 expression leads to more aggressive brain tumors.	('more', 'PosReg', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('aggressive brain tumors', 'Disease', (65, 88))	('expression', 'Var', (40, 50))	('leads to', 'Reg', (51, 59))	('KLK7', 'Gene', (35, 39))	('KLK7', 'Gene', '5650', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('aggressive brain tumors', 'Disease', 'MESH:D001927', (65, 88))	('aggressive brain', 'Phenotype', 'HP:0000718', (65, 81))	('brain tumors', 'Phenotype', 'HP:0030692', (76, 88))
52493	26231762	By contrast, the current study and prior efforts suggest that changes in KLK8 expression in GBM or other intracranial malignancies have little association with prognosis.	('KLK8', 'Gene', (73, 77))	('intracranial malignancies', 'Disease', (105, 130))	('changes', 'Var', (62, 69))	('intracranial malignancies', 'Disease', 'MESH:D009369', (105, 130))	('GBM', 'Disease', (92, 95))	('KLK8', 'Gene', '11202', (73, 77))
52524	26110872	In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects.	('enhances', 'PosReg', (141, 149))	('tumor', 'Disease', (158, 163))	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('reduces', 'NegReg', (183, 190))	('PROG', 'Var', (136, 140))	('temozolomide', 'Chemical', 'MESH:D000077204', (51, 63))	('PROG', 'Chemical', 'MESH:D011374', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('TMZ', 'Chemical', 'MESH:D000077204', (175, 178))	('PROG', 'Chemical', 'MESH:D011374', (41, 45))	('side effects', 'MPA', (195, 207))	('progesterone', 'Chemical', 'MESH:D011374', (27, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (65, 68))
52525	26110872	Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days.	('TMZ', 'Chemical', 'MESH:D000077204', (138, 141))	('human', 'Species', '9606', (17, 22))	('U87MG', 'CellLine', 'CVCL:0022', (40, 45))	('PROG', 'Chemical', 'MESH:D011374', (129, 133))	('human', 'Species', '9606', (70, 75))	('U87MG', 'Var', (40, 45))	('U118MG', 'CellLine', 'CVCL:0633', (50, 56))	('U118MG', 'Var', (50, 56))
52542	26110872	It has been reported that GBM patients with a methylated MGMT promoter have increased overall survival and better response to combined TMZ and radiation therapy compared with radiation alone.	('response', 'MPA', (114, 122))	('overall', 'MPA', (86, 93))	('increased', 'PosReg', (76, 85))	('TMZ', 'Chemical', 'MESH:D000077204', (135, 138))	('patients', 'Species', '9606', (30, 38))	('MGMT', 'Gene', '4255', (57, 61))	('MGMT', 'Gene', (57, 61))	('methylated', 'Var', (46, 56))
52554	26110872	For our proof-of-concept research, we used an in vitro model of cytotoxicity to evaluate the anti-tumor effects of TMZ and PROG, alone or in combination, in two WHO grade IV human GBM cell lines, U87MG and U118MG.	('human', 'Species', '9606', (174, 179))	('cytotoxicity', 'Disease', (64, 76))	('U118MG', 'Var', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('TMZ', 'Chemical', 'MESH:D000077204', (115, 118))	('U118MG', 'CellLine', 'CVCL:0633', (206, 212))	('PROG', 'Chemical', 'MESH:D011374', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (64, 76))	('U87MG', 'CellLine', 'CVCL:0022', (196, 201))	('tumor', 'Disease', (98, 103))
52563	26110872	WHO grade IV human GBM cell lines (U87MG and U118MG) were purchased from ATCC (Manassas, VA).	('U87MG', 'Var', (35, 40))	('human', 'Species', '9606', (13, 18))	('U118MG', 'Var', (45, 51))	('U118MG', 'CellLine', 'CVCL:0633', (45, 51))	('U87MG', 'CellLine', 'CVCL:0022', (35, 40))
52565	26110872	U87MG, U118MG and HDF cells were seeded in a 24-well plate at a density of 0.5 x 105/well.	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('U87MG', 'Var', (0, 5))	('U118MG', 'CellLine', 'CVCL:0633', (7, 13))	('U118MG', 'Var', (7, 13))
52579	26110872	Cells were repeatedly exposed to different concentrations of PROG and/or TMZ (P5, P80, T100, P5+T100, P80+T100 muM) for 3 days.	('TMZ', 'Chemical', 'MESH:D000077204', (73, 76))	('P80', 'Gene', '8161', (82, 85))	('P80', 'Gene', (82, 85))	('P80', 'Gene', (102, 105))	('P5', 'Var', (78, 80))	('P80', 'Gene', '8161', (102, 105))	('PROG', 'Chemical', 'MESH:D011374', (61, 65))	('muM', 'Gene', '56925', (111, 114))	('muM', 'Gene', (111, 114))	('T100', 'Var', (87, 91))	('P5+T100', 'Var', (93, 100))
52584	26110872	The membranes were probed with the following primary antibodies overnight at 4 C: Akt (#9272); Phospho-AKT (#9271S); MGMT (#2739, Cell Signaling Technology, Danvers, MA); PCNA (#SC-56); EGFR (Santa Cruz #SC-03); mTOR (#32028, Abcam, Cambridge, MA); and beta-Actin (AC74)lll (Sigma).	('#9271S', 'Var', (108, 114))	('AKT', 'Gene', '207', (103, 106))	('#2739', 'Var', (123, 128))	('MGMT', 'Gene', (117, 121))	('Akt', 'Gene', '207', (82, 85))	('MGMT', 'Gene', '4255', (117, 121))	('PCNA', 'Gene', (171, 175))	('AKT', 'Gene', (103, 106))	('EGFR', 'Gene', '1956', (186, 190))	('Akt', 'Gene', (82, 85))	('EGFR', 'Gene', (186, 190))	('beta-Actin', 'Gene', (253, 263))	('#32028', 'Var', (218, 224))	('PCNA', 'Gene', '5111', (171, 175))	('mTOR', 'Gene', (212, 216))	('mTOR', 'Gene', '2475', (212, 216))	('beta-Actin', 'Gene', '728378', (253, 263))
52596	26110872	PROG alone produced significant cell death following 3 and 6 days exposure in both U87MG (F(7, 40) = 6.0 and F(7, 40) = 235.3, respectively; P<0.001) and U118MG (F(7, 40) = 32.01 and F(7, 40) = 557.95, respectively; P<0.001) cell lines in a concentration-dependent manner (Fig 1).	('cell death', 'CPA', (32, 42))	('U118MG', 'CellLine', 'CVCL:0633', (154, 160))	('PROG', 'Chemical', 'MESH:D011374', (0, 4))	('U87MG', 'CellLine', 'CVCL:0022', (83, 88))	('U87MG', 'Var', (83, 88))
52597	26110872	Maximum cell death was observed at the 80 muM concentration following 6 days of exposure in U87MG (~74%) and U118MG (~87%) cell lines.	('U118MG', 'CellLine', 'CVCL:0633', (109, 115))	('muM', 'Gene', '56925', (42, 45))	('U87MG', 'CellLine', 'CVCL:0022', (92, 97))	('U87MG', 'Var', (92, 97))	('muM', 'Gene', (42, 45))	('U118MG', 'Var', (109, 115))	('cell death', 'CPA', (8, 18))
52600	26110872	When the GBM cells were treated with different combinations of PROG and TMZ, a significant group effect was observed following both 3 and 6 days' exposure in both U87MG (F(5, 42) = 14.6 and F(5, 42) = 137.51, respectively; P<0.001) and U118MG cells (F(5, 30) = 15.43 and F(5, 30) = 63.27, respectively; P<0.001) (Fig 2).	('U118MG', 'CellLine', 'CVCL:0633', (236, 242))	('U87MG', 'CellLine', 'CVCL:0022', (163, 168))	('TMZ', 'Chemical', 'MESH:D000077204', (72, 75))	('U87MG', 'Var', (163, 168))	('PROG', 'Chemical', 'MESH:D011374', (63, 67))	('U118MG', 'Var', (236, 242))
52602	26110872	This combination effect was more pronounced (P<0.05) after 6 days of exposure in P5 + TMZ100 and P80+ TMZ100 groups (30% and 49% respectively) compared to TMZ100 alone (Fig 2).	('P80', 'Gene', (97, 100))	('TMZ100', 'Chemical', '-', (102, 108))	('P5 + TMZ100', 'Var', (81, 92))	('TMZ100', 'Chemical', '-', (155, 161))	('TMZ100', 'Chemical', '-', (86, 92))	('P80', 'Gene', '8161', (97, 100))
52603	26110872	In U118MG cells, P5+TMZ100 led to 19% and 24% more cell death (P<0.05) compared to TMZ100 alone after 3 and 6 days of treatment respectively.	('U118MG', 'Var', (3, 9))	('P5+TMZ100', 'Var', (17, 26))	('U118MG', 'CellLine', 'CVCL:0633', (3, 9))	('TMZ100', 'Chemical', '-', (20, 26))	('cell death', 'CPA', (51, 61))	('TMZ100', 'Chemical', '-', (83, 89))
52620	26110872	Western blot data revealed a significant effect on the expression of EGFR in U87MG (F(5, 30) = 146.31; P<0.001) and U118MG (F(5, 30) = 27.38; P<0.001) cell lines (Fig 6A and 6B).	('EGFR', 'Gene', '1956', (69, 73))	('U118MG', 'CellLine', 'CVCL:0633', (116, 122))	('EGFR', 'Gene', (69, 73))	('U87MG', 'CellLine', 'CVCL:0022', (77, 82))	('expression', 'MPA', (55, 65))	('U87MG', 'Var', (77, 82))	('U118MG', 'Var', (116, 122))
52622	26110872	We observed a significant effect on the expression profile of both Akt and phosphorylated Akt (pAkt) in both U87MG (F(5, 30) = 263.73; P<0.001 and F(5, 30) = 84.91 respectively; P<0.001) and U118MG (F(5, 30) = 27.82; P<0.001 and F(5, 30) = 54.0 respectively; P<0.001) cell lines (Fig 6A and 6B).	('expression', 'MPA', (40, 50))	('Akt', 'Gene', (90, 93))	('Akt', 'Gene', (67, 70))	('Akt', 'Gene', '207', (67, 70))	('U87MG', 'CellLine', 'CVCL:0022', (109, 114))	('U87MG', 'Var', (109, 114))	('Akt', 'Gene', '207', (96, 99))	('Akt', 'Gene', '207', (90, 93))	('Akt', 'Gene', (96, 99))	('U118MG', 'CellLine', 'CVCL:0633', (191, 197))
52624	26110872	Analysis of the mTOR expression profile revealed a significant group effect in U87MG (F(5, 30) = 57.82; P<0.001) and U118MG (F(5, 30) = 20.04; P<0.001) cell lines (Fig 6A and 6B).	('U118MG', 'CellLine', 'CVCL:0633', (117, 123))	('mTOR', 'Gene', '2475', (16, 20))	('mTOR', 'Gene', (16, 20))	('U87MG', 'CellLine', 'CVCL:0022', (79, 84))	('U87MG', 'Var', (79, 84))
52626	26110872	Individual and combined treatment with P5 and TMZ100 did not show any significant effect on the expression of EGFR, Akt, pAkt and mTOR expression in either U87MG or U118MG cell lines compared to controls.	('TMZ100', 'Chemical', '-', (46, 52))	('TMZ100', 'Var', (46, 52))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('U87MG', 'CellLine', 'CVCL:0022', (156, 161))	('U118MG', 'CellLine', 'CVCL:0633', (165, 171))	('U87MG', 'Var', (156, 161))	('Akt', 'Gene', '207', (116, 119))	('Akt', 'Gene', '207', (122, 125))	('mTOR', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (130, 134))	('Akt', 'Gene', (116, 119))	('Akt', 'Gene', (122, 125))
52628	26110872	A significant group effect on PCNA expression was observed in both U87MG (F(5, 30) = 38.53; P<0.001) and U118MG (F(5, 30) = 82.35; P<0.001) cell lines.	('U118MG', 'CellLine', 'CVCL:0633', (105, 111))	('PCNA', 'Gene', (30, 34))	('U87MG', 'CellLine', 'CVCL:0022', (67, 72))	('U87MG', 'Var', (67, 72))	('expression', 'MPA', (35, 45))	('PCNA', 'Gene', '5111', (30, 34))	('U118MG', 'Var', (105, 111))
52631	26110872	First we determined the baseline expression of MGMT in U87MG and U118MG cells and found that it is highly expressed in U118MG but not in U87MG cells (Fig 7B).	('U87MG', 'CellLine', 'CVCL:0022', (55, 60))	('U118MG', 'Var', (119, 125))	('U118MG', 'CellLine', 'CVCL:0633', (119, 125))	('MGMT', 'Gene', (47, 51))	('U118MG', 'CellLine', 'CVCL:0633', (65, 71))	('U87MG', 'CellLine', 'CVCL:0022', (137, 142))	('MGMT', 'Gene', '4255', (47, 51))
52636	26110872	Our data can be taken to demonstrate that PROG at high doses effectively inhibits the proliferation of grade IV human GBM U87MG and U118MG cells.	('proliferation', 'CPA', (86, 99))	('U87MG', 'CellLine', 'CVCL:0022', (122, 127))	('inhibits', 'NegReg', (73, 81))	('U118MG', 'Var', (132, 138))	('U118MG', 'CellLine', 'CVCL:0633', (132, 138))	('human', 'Species', '9606', (112, 117))	('PROG', 'Chemical', 'MESH:D011374', (42, 46))
52655	26110872	In brief, TMZ has been reported to induce cell death in different human GBM cell lines and our findings are in agreement with those observations.	('human', 'Species', '9606', (66, 71))	('TMZ', 'Chemical', 'MESH:D000077204', (10, 13))	('cell death', 'CPA', (42, 52))	('TMZ', 'Var', (10, 13))
52656	26110872	Interestingly, when TMZ (100 muM) was combined with PROG at low (5 muM) and high (80 muM) concentrations, there was ~30% and 49% more cell death in U87MG cells compared to TMZ alone after 6 days of exposure.	('muM', 'Gene', (29, 32))	('U87MG', 'Var', (148, 153))	('muM', 'Gene', (85, 88))	('cell death', 'CPA', (134, 144))	('muM', 'Gene', '56925', (67, 70))	('muM', 'Gene', '56925', (29, 32))	('muM', 'Gene', (67, 70))	('TMZ', 'Chemical', 'MESH:D000077204', (20, 23))	('PROG', 'Chemical', 'MESH:D011374', (52, 56))	('U87MG', 'CellLine', 'CVCL:0022', (148, 153))	('muM', 'Gene', '56925', (85, 88))	('TMZ', 'Chemical', 'MESH:D000077204', (172, 175))
52657	26110872	In the U118MG cells, the combination of TMZ and PROG at low and high concentrations produced ~24% and 58% more reduction respectively in cell viability compared to TMZ alone.	('reduction', 'NegReg', (111, 120))	('U118MG', 'Var', (7, 13))	('U118MG', 'CellLine', 'CVCL:0633', (7, 13))	('TMZ', 'Chemical', 'MESH:D000077204', (40, 43))	('TMZ', 'Chemical', 'MESH:D000077204', (164, 167))	('combination', 'Interaction', (25, 36))	('PROG', 'Chemical', 'MESH:D011374', (48, 52))	('cell viability', 'CPA', (137, 151))
52661	26110872	We speculate that the proliferative effects of low-dose PROG+TMZ in tumor cells makes them more chemosensitive for TMZ, resulting in more cell death.	('tumor', 'Disease', (68, 73))	('PROG', 'Chemical', 'MESH:D011374', (56, 60))	('more', 'PosReg', (91, 95))	('TMZ', 'Chemical', 'MESH:D000077204', (115, 118))	('chemosensitive for TMZ', 'MPA', (96, 118))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('proliferative', 'MPA', (22, 35))	('cell death', 'CPA', (138, 148))	('TMZ', 'Chemical', 'MESH:D000077204', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PROG+TMZ', 'Var', (56, 64))
52671	26110872	When one of the most cytotoxic doses of TMZ (100 muM) was combined with different low and high doses of PROG (5, 10, 20, 40, 80 muM), we obtained a significant reduction in the cytotoxicity of fibroblasts at all combinations except P5+TMZ100 compared to TMZ alone.	('cytotoxicity', 'Disease', (177, 189))	('reduction', 'NegReg', (160, 169))	('TMZ100', 'Chemical', '-', (235, 241))	('muM', 'Gene', '56925', (49, 52))	('muM', 'Gene', '56925', (128, 131))	('muM', 'Gene', (49, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (177, 189))	('TMZ', 'Chemical', 'MESH:D000077204', (235, 238))	('TMZ', 'Chemical', 'MESH:D000077204', (40, 43))	('muM', 'Gene', (128, 131))	('PROG', 'Chemical', 'MESH:D011374', (104, 108))	('TMZ', 'Chemical', 'MESH:D000077204', (254, 257))	('P5+TMZ100', 'Var', (232, 241))
52680	26110872	We speculate that this phenomenon may be the result of drug-drug interaction where TMZ blocked some of the PROG's signaling pathways, contributing to GBM cell death.	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('GBM cell death', 'CPA', (150, 164))	('TMZ', 'Var', (83, 86))	('blocked', 'NegReg', (87, 94))	('signaling pathways', 'Pathway', (114, 132))	('drug-drug interaction', 'Phenotype', 'HP:0020172', (55, 76))	('PROG', 'Chemical', 'MESH:D011374', (107, 111))
52688	26110872	This idea is supported by our recent findings showing that PROG induces cell death in p53 wild-type GBM cell lines (U87MG, U87dEGFR, U118MG) but not in p53 mutated cells (LN229).	('U118MG', 'Var', (133, 139))	('p53', 'Gene', '7157', (86, 89))	('U118MG', 'CellLine', 'CVCL:0633', (133, 139))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('U87MG', 'CellLine', 'CVCL:0022', (116, 121))	('LN229', 'CellLine', 'CVCL:0393', (171, 176))	('U87MG', 'Var', (116, 121))	('cell death', 'CPA', (72, 82))	('PROG', 'Chemical', 'MESH:D011374', (59, 63))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('p53', 'Gene', (86, 89))
52697	26110872	EGFR amplification occurs in ~40% of primary GBM, with overexpression in over 60% of cases.	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('primary GBM', 'Disease', (37, 48))
52698	26110872	Mutation and overexpression of EGFR has been linked to the development of more aggressive malignant phenotypes leading to increased resistance to treatment and poorer clinical outcomes.	('EGFR', 'Gene', '1956', (31, 35))	('linked', 'Reg', (45, 51))	('Mutation', 'Var', (0, 8))	('EGFR', 'Gene', (31, 35))	('resistance to treatment', 'MPA', (132, 155))	('overexpression', 'PosReg', (13, 27))	('increased', 'PosReg', (122, 131))
52702	26110872	Phosphorylated Akt (pAkt) further activates multiple downstream targets, including mTOR, which are involved in cellular processes like metabolism, cell proliferation, cell growth and apoptosis.	('Phosphorylated', 'Var', (0, 14))	('Akt', 'Gene', '207', (15, 18))	('mTOR', 'Gene', (83, 87))	('Akt', 'Gene', '207', (21, 24))	('Akt', 'Gene', (15, 18))	('Akt', 'Gene', (21, 24))	('activates', 'PosReg', (34, 43))	('mTOR', 'Gene', '2475', (83, 87))
52710	26110872	We also observed a significant decrease in cell viability in the P5+T100 group compared to the control group despite the fact that the expression of EGFR/pAkt/mTOR and PCNA remained unchanged.	('mTOR', 'Gene', (159, 163))	('EGFR', 'Gene', '1956', (149, 153))	('decrease', 'NegReg', (31, 39))	('mTOR', 'Gene', '2475', (159, 163))	('PCNA', 'Gene', (168, 172))	('EGFR', 'Gene', (149, 153))	('Akt', 'Gene', '207', (155, 158))	('P5+T100', 'Var', (65, 72))	('cell viability', 'CPA', (43, 57))	('PCNA', 'Gene', '5111', (168, 172))	('Akt', 'Gene', (155, 158))
52715	26110872	The sensitivity of GBM cells to TMZ is inhibited by the expression of MGMT.	('inhibited', 'NegReg', (39, 48))	('MGMT', 'Gene', (70, 74))	('sensitivity', 'MPA', (4, 15))	('MGMT', 'Gene', '4255', (70, 74))	('TMZ', 'Chemical', 'MESH:D000077204', (32, 35))	('expression', 'Var', (56, 66))
52785	25976744	The primary antibodies used were monoclonal anti-phospho-SAPK/JNK1/2 and anti-SAPK/JNK1/2 (1:1000; Cell Signaling; ordering numbers #4671S and #9258S, respectively) and anti-phospho-p38MAPK (1:500) and anti-p38MAPK (1:1000; Cell Signaling, ordering numbers #4511 L and #9212 L, respectively).	('Cell Signaling', 'CPA', (224, 238))	('JNK1/2', 'Gene', '5599;5601', (62, 68))	('JNK1/2', 'Gene', (62, 68))	('anti-phospho-p38MAPK', 'Var', (169, 189))	('#9258S', 'Var', (143, 149))	('JNK1/2', 'Gene', '5599;5601', (83, 89))	('SAPK', 'Gene', (78, 82))	('JNK1/2', 'Gene', (83, 89))	('Cell Signaling', 'CPA', (99, 113))	('SAPK', 'Gene', (57, 61))	('SAPK', 'Gene', '5601', (57, 61))	('anti-p38MAPK', 'Var', (202, 214))	('SAPK', 'Gene', '5601', (78, 82))
52811	25976744	U87 cells were treated for 30 min with increasing doses of POH (0.1, 0.5 and 1.5 mM), which showed that POH increased JNK1/2 phosphorylation in a dose-dependent manner (Figure 3A).	('POH', 'Chemical', 'MESH:C032208', (59, 62))	('POH', 'Chemical', 'MESH:C032208', (104, 107))	('increased', 'PosReg', (108, 117))	('POH', 'Var', (104, 107))	('JNK1/2', 'Gene', '5599;5601', (118, 124))	('JNK1/2', 'Gene', (118, 124))
52816	25976744	The activation of p38 was assayed under the same conditions in the U87 cell line, and 1.5 mM POH significantly increased p38 phosphorylation (Additional file 4).	('p38', 'Gene', (121, 124))	('p38', 'Gene', (18, 21))	('increased', 'PosReg', (111, 120))	('POH', 'Chemical', 'MESH:C032208', (93, 96))	('p38', 'Gene', '5594', (18, 21))	('POH', 'Var', (93, 96))	('p38', 'Gene', '5594', (121, 124))
52833	25976744	Using the U251 cell line, 0.5 mM POH also significantly increased the cell death (71.2% +- 7.9) (Figure 7B) compared to the control group (0.1% DMSO) (Figure 7A).	('POH', 'Var', (33, 36))	('U251', 'CellLine', 'CVCL:0021', (10, 14))	('increased', 'PosReg', (56, 65))	('DMSO', 'Chemical', 'MESH:D004121', (144, 148))	('POH', 'Chemical', 'MESH:C032208', (33, 36))	('cell death', 'CPA', (70, 80))
52840	25976744	JNK1/2 inhibition substantially reduced the amount of POH-induced apoptosis (Figure 8C and 9C).	('JNK1/2', 'Gene', '5599;5601', (0, 6))	('reduced', 'NegReg', (32, 39))	('POH', 'Chemical', 'MESH:C032208', (54, 57))	('JNK1/2', 'Gene', (0, 6))	('inhibition', 'Var', (7, 17))
52856	25976744	The cell viability was significantly decreased by POH only when a high concentration was used.	('cell viability', 'CPA', (4, 18))	('rat', 'Species', '10116', (78, 81))	('POH', 'Chemical', 'MESH:C032208', (50, 53))	('decreased', 'NegReg', (37, 46))	('POH', 'Var', (50, 53))
52869	25976744	At this point, it is important to emphasize that POH induces apoptosis in various tumor cells, including gliomas.	('apoptosis', 'CPA', (61, 70))	('POH', 'Chemical', 'MESH:C032208', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('POH', 'Var', (49, 52))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Disease', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('induces', 'Reg', (53, 60))
52870	25976744	It is known that POH preferentially inhibits the NKA alpha1 isoform, which modulates apoptosis, cell migration and proliferation and is overexpressed in the caveolae of GBM cells.	('alpha1', 'Gene', '146', (53, 59))	('cell migration', 'CPA', (96, 110))	('POH', 'Var', (17, 20))	('apoptosis', 'CPA', (85, 94))	('NKA', 'Gene', (49, 52))	('proliferation', 'CPA', (115, 128))	('alpha1', 'Gene', (53, 59))	('inhibits', 'NegReg', (36, 44))	('NKA', 'Gene', '6863', (49, 52))	('rat', 'Species', '10116', (122, 125))	('POH', 'Chemical', 'MESH:C032208', (17, 20))	('modulates', 'Reg', (75, 84))	('rat', 'Species', '10116', (104, 107))
52875	25976744	Additionally, POH increases the Bax expression in non-small cell lung cancers.	('cell lung cancers', 'Disease', (60, 77))	('Bax', 'Gene', (32, 35))	('POH', 'Chemical', 'MESH:C032208', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('increases', 'PosReg', (18, 27))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (54, 77))	('POH', 'Var', (14, 17))	('Bax', 'Gene', '581', (32, 35))	('cell lung cancers', 'Disease', 'MESH:D008175', (60, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('lung cancers', 'Phenotype', 'HP:0100526', (65, 77))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (50, 77))
52891	25976744	However, POH suppressed the level of pro-inflammatory cytokines in ischemia-reperfusion injury in rat brains.	('suppressed', 'NegReg', (13, 23))	('level of pro-inflammatory cytokines', 'MPA', (28, 63))	('POH', 'Chemical', 'MESH:C032208', (9, 12))	('ischemia-reperfusion injury', 'Disease', 'MESH:D015427', (67, 94))	('rat', 'Species', '10116', (98, 101))	('ischemia-reperfusion injury', 'Disease', (67, 94))	('POH', 'Var', (9, 12))
52907	25976744	As expected, POH induced apoptosis in GBM cells, though interestingly, JNK inhibition decreased the POH-induced apoptosis.	('inhibition', 'Var', (75, 85))	('JNK', 'Gene', (71, 74))	('decreased', 'NegReg', (86, 95))	('JNK', 'Gene', '5599', (71, 74))	('POH', 'Chemical', 'MESH:C032208', (13, 16))	('POH', 'Chemical', 'MESH:C032208', (100, 103))
52909	25976744	Inhibitors of this enzyme, particularly the cardiac glycoside UNBS1450 and the monoterpene POH, cause death in these tumor cells by autophagy and apoptosis induction, respectively.	('monoterpene POH', 'Chemical', '-', (79, 94))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('glycoside', 'Chemical', 'MESH:D006027', (52, 61))	('UNBS1450', 'Chemical', 'MESH:C510008', (62, 70))	('tumor', 'Disease', (117, 122))	('autophagy', 'CPA', (132, 141))	('apoptosis induction', 'CPA', (146, 165))	('UNBS1450', 'Var', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
52913	25976744	This hypothesis is supported by our observation that 1) Src inhibition and caveolae disruption blocked the phosphorylation of JNK, and 2) the induction of apoptosis was reduced by JNK inhibition.	('disruption', 'Var', (84, 94))	('JNK', 'Gene', (180, 183))	('blocked', 'NegReg', (95, 102))	('JNK', 'Gene', '5599', (180, 183))	('reduced', 'NegReg', (169, 176))	('JNK', 'Gene', (126, 129))	('Src', 'Gene', (56, 59))	('Src', 'Gene', '6714', (56, 59))	('phosphorylation', 'MPA', (107, 122))	('apoptosis', 'CPA', (155, 164))	('JNK', 'Gene', '5599', (126, 129))
52931	24732808	The signaling molecules in these pathways are either over-expressed, constitutively active or mutated in many cancer cells, and thus render niclosamide as a potential anticancer agent.	('mutated', 'Var', (94, 101))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('over-expressed', 'PosReg', (53, 67))	('niclosamide', 'Chemical', 'MESH:D009534', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
52943	24732808	More than 90% of colorectal cancers bear mutations that result in the activation of the Wnt/beta-catenin pathway.	('mutations', 'Var', (41, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('colorectal cancers', 'Disease', 'MESH:D015179', (17, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Wnt/beta-catenin pathway', 'Pathway', (88, 112))	('colorectal cancers', 'Disease', (17, 35))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('activation', 'PosReg', (70, 80))
52953	24732808	Niclosamide did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that niclosamide does not inhibit mTOR catalytic activity but rather inhibits signaling to mTORC1.	('mTOR', 'Gene', '2475', (28, 32))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', (28, 32))	('signaling', 'MPA', (174, 183))	('inhibits', 'NegReg', (165, 173))	('mTORC1', 'Gene', (187, 193))	('mTOR', 'Gene', '2475', (187, 191))	('mTOR', 'Gene', '2475', (56, 60))	('mTOR', 'Gene', (187, 191))	('niclosamide', 'Chemical', 'MESH:D009534', (101, 112))	('mTORC2', 'Gene', (28, 34))	('mTOR', 'Gene', (130, 134))	('inhibit', 'NegReg', (122, 129))	('mTORC1', 'Gene', '382056', (187, 193))	('mTOR', 'Gene', '2475', (130, 134))	('mTORC2', 'Gene', '74343', (28, 34))	('Niclosamide', 'Chemical', 'MESH:D009534', (0, 11))	('niclosamide', 'Var', (101, 112))
52954	24732808	Tuberous sclerosis complex (TSC2), a negative regulator of mTORC1, was not required for the inhibition of mTORC1 signaling by niclosamide, as niclosamide was able to suppress mTORC1 signaling in TSC2-deficient cells where mTORC1 activity was elevated.	('TSC2-deficient', 'Disease', 'MESH:C566021', (195, 209))	('niclosamide', 'Var', (142, 153))	('mTORC1', 'Gene', (59, 65))	('TSC2', 'Gene', '7249', (195, 199))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('TSC2', 'Gene', '7249', (28, 32))	('mTORC1', 'Gene', '382056', (59, 65))	('mTORC1', 'Gene', (175, 181))	('mTORC1', 'Gene', (106, 112))	('TSC2', 'Gene', (195, 199))	('mTORC1', 'Gene', '382056', (175, 181))	('mTORC1', 'Gene', '382056', (106, 112))	('TSC2', 'Gene', (28, 32))	('suppress', 'NegReg', (166, 174))	('mTORC1', 'Gene', (222, 228))	('mTORC1', 'Gene', '382056', (222, 228))	('Tuberous sclerosis', 'Disease', (0, 18))	('niclosamide', 'Chemical', 'MESH:D009534', (142, 153))	('TSC2-deficient', 'Disease', (195, 209))	('niclosamide', 'Chemical', 'MESH:D009534', (126, 137))
52959	24732808	Niclosamide inhibits the lysosomal degradative function likely by altering lysosomal permeability and the pH gradient, which is consistent with the finding that niclosamide can cause dispersion of protons from the lysosomes to the cytosol, leading to cytosolic acidification (Fig.	('lysosomal permeability', 'MPA', (75, 97))	('dispersion', 'MPA', (183, 193))	('pH gradient', 'MPA', (106, 117))	('niclosamide', 'Var', (161, 172))	('altering', 'Reg', (66, 74))	('lysosomal degradative function', 'MPA', (25, 55))	('inhibits', 'NegReg', (12, 20))	('niclosamide', 'Chemical', 'MESH:D009534', (161, 172))	('leading to', 'Reg', (240, 250))	('Niclosamide', 'Chemical', 'MESH:D009534', (0, 11))	('cytosolic acidification', 'MPA', (251, 274))
52981	24732808	In cancers, molecular genetic alterations cause increased levels of intracellular Notch-IC and subsequent constitutive activation of the Notch pathway.	('increased', 'PosReg', (48, 57))	('molecular genetic alterations', 'Var', (12, 41))	('Notch pathway', 'Pathway', (137, 150))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('activation', 'PosReg', (119, 129))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('levels', 'MPA', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
52982	24732808	Aberrant activation of this pathway contributes to tumorigenesis, and Notch inhibitory agents, such as gamma-secretase inhibitors, are being investigated as candidate cancer therapeutic agents.	('contributes', 'Reg', (36, 47))	('activation', 'PosReg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
52990	24732808	In addition, it was reported that inactivation of NF-kappaB by niclosamide caused mitochondrial damage and the generation of reactive oxygen species (ROS), leading to apoptosis of acute myelogenous leukemia cells.	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (180, 206))	('leading to', 'Reg', (156, 166))	('generation of reactive oxygen species', 'MPA', (111, 148))	('inactivation', 'Var', (34, 46))	('apoptosis', 'CPA', (167, 176))	('niclosamide', 'Chemical', 'MESH:D009534', (63, 74))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (125, 148))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (186, 206))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (180, 206))	('mitochondrial damage', 'CPA', (82, 102))	('acute myelogenous leukemia', 'Disease', (180, 206))	('NF-kappaB', 'Gene', '4790', (50, 59))	('leukemia', 'Phenotype', 'HP:0001909', (198, 206))	('NF-kappaB', 'Gene', (50, 59))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))
52991	24732808	performed a genome-wide gene expression array and demonstrated that niclosamide was able to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation in ovarian-cancer-initiating cells.	('niclosamide', 'Var', (68, 79))	('biogenesis', 'MPA', (151, 161))	('redox regulation', 'MPA', (167, 183))	('niclosamide', 'Chemical', 'MESH:D009534', (68, 79))	('ovarian-cancer', 'Disease', 'MESH:D010051', (187, 201))	('ovarian-cancer', 'Disease', (187, 201))	('metabolic pathways', 'Pathway', (109, 127))	('ovarian-cancer', 'Phenotype', 'HP:0100615', (187, 201))	('disrupt', 'NegReg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('biogenetics', 'MPA', (138, 149))
53007	24732808	synthesized a niclosamide analog - phosphate of niclosamide (p-niclosamide), and found p-niclosamide showed significant inhibition of xenograft tumor growth of acute myeloid leukemia HL-60 cells by suppressing the NF-kappaB pathway.	('HL-60', 'CellLine', 'CVCL:0002', (183, 188))	('suppressing', 'NegReg', (198, 209))	('niclosamide', 'Chemical', 'MESH:D009534', (14, 25))	('phosphate', 'Chemical', 'MESH:D010710', (35, 44))	('leukemia', 'Phenotype', 'HP:0001909', (174, 182))	('acute myeloid leukemia', 'Disease', (160, 182))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (166, 182))	('NF-kappaB', 'Gene', (214, 223))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (160, 182))	('niclosamide', 'Chemical', 'MESH:D009534', (89, 100))	('NF-kappaB', 'Gene', '4790', (214, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (160, 182))	('tumor', 'Disease', (144, 149))	('p-niclosamide', 'Chemical', '-', (87, 100))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('p-niclosamide', 'Var', (87, 100))	('niclosamide', 'Chemical', 'MESH:D009534', (48, 59))	('niclosamide', 'Chemical', 'MESH:D009534', (63, 74))	('inhibition', 'NegReg', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('p-niclosamide', 'Chemical', '-', (61, 74))
53035	24732808	Interestingly, niclosamide was one of the two top enriched compounds altering gene expression in the same direction as salinomycin, providing further evidence that niclosamide, like salinomycin, can work as a CSC killer.	('salinomycin', 'Chemical', 'MESH:C010327', (119, 130))	('niclosamide', 'Var', (164, 175))	('salinomycin', 'Chemical', 'MESH:C010327', (182, 193))	('altering', 'Reg', (69, 77))	('niclosamide', 'Chemical', 'MESH:D009534', (15, 26))	('niclosamide', 'Chemical', 'MESH:D009534', (164, 175))
53069	25010988	Modulation of PHD2 activity might be considered as a new way to inhibit glioblastoma progression.	('Modulation', 'Var', (0, 10))	('inhibit', 'NegReg', (64, 71))	('activity', 'MPA', (19, 27))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('PHD2', 'Gene', (14, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
53093	25010988	PHD2 knockdown caused a significant downregulation of HIF-1alpha expression and a marked reduction of HIF-1alpha protein glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('downregulation', 'NegReg', (36, 50))	('reduction of HIF-1alpha protein glioblastoma', 'Disease', 'MESH:D005909', (89, 133))	('knockdown', 'Var', (5, 14))	('reduction of HIF-1alpha protein glioblastoma', 'Disease', (89, 133))	('expression', 'MPA', (65, 75))	('HIF-1alpha', 'Gene', (54, 64))	('PHD2', 'Gene', (0, 4))
53094	25010988	The mRNA and the protein contents of HIF-2alpha were elevated in the PHD2 knockdown cells due to the downregulation of HIF-1alpha expression.	('downregulation', 'NegReg', (101, 115))	('expression', 'MPA', (130, 140))	('elevated', 'PosReg', (53, 61))	('HIF-2alpha', 'Gene', (37, 47))	('knockdown', 'Var', (74, 83))	('HIF-2alpha', 'Gene', '2034', (37, 47))	('HIF-1alpha', 'Gene', (119, 129))	('PHD2', 'Gene', (69, 73))
53097	25010988	Targeted modulation of PHD2 activity might be considered as new way to inhibit the progression of glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (98, 111))	('activity', 'MPA', (28, 36))	('inhibit', 'NegReg', (71, 78))	('Targeted modulation', 'Var', (0, 19))	('glioblastomas', 'Disease', 'MESH:D005909', (98, 111))	('modulation', 'Var', (9, 19))	('PHD2', 'Gene', (23, 27))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('glioblastomas', 'Disease', (98, 111))
53100	25010988	In all three glioblastoma cell lines, PHD2 knockdown caused a marked reduction of HIF-1alpha in hypoxia.	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('knockdown', 'Var', (43, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('reduction of HIF-1alpha in hypoxia', 'Disease', 'MESH:D000860', (69, 103))	('PHD2', 'Gene', (38, 42))	('reduction of HIF-1alpha in hypoxia', 'Disease', (69, 103))
53104	25010988	As shown in Figure 2a, the protein content of p50 in the PHD2 knockdown cells was markedly lower than in the control cells.	('lower', 'NegReg', (91, 96))	('p50', 'Gene', (46, 49))	('p50', 'Gene', '4790', (46, 49))	('PHD2', 'Gene', (57, 61))	('protein content', 'MPA', (27, 42))	('knockdown', 'Var', (62, 71))
53107	25010988	Quantitative RT-PCR showed that the gene expression of p50 was reduced in the PHD2 knockdown cells (Figure 2b).	('gene expression', 'MPA', (36, 51))	('reduced', 'NegReg', (63, 70))	('PHD2', 'Gene', (78, 82))	('p50', 'Gene', '4790', (55, 58))	('p50', 'Gene', (55, 58))	('knockdown', 'Var', (83, 92))
53114	25010988	As shown in Figure 4a, the gene expression of HIF-2alpha was significantly enhanced in the glioblastoma cells 48-72 h after PHD2 siRNA transfection (U87MG: 48 h, U138MG: 72 h).	('U87MG:', 'Var', (149, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('enhanced', 'PosReg', (75, 83))	('U87MG', 'CellLine', 'CVCL:0022', (149, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('HIF-2alpha', 'Gene', (46, 56))	('gene expression', 'MPA', (27, 42))	('U138MG', 'CellLine', 'CVCL:0020', (162, 168))	('HIF-2alpha', 'Gene', '2034', (46, 56))	('U138MG', 'Var', (162, 168))	('glioblastoma', 'Disease', (91, 103))
53115	25010988	A marked increase in HIF-2alpha protein level was also observed in the PHD2 knockdown cells (Figure 4b).	('HIF-2alpha', 'Gene', '2034', (21, 31))	('knockdown', 'Var', (76, 85))	('increase', 'PosReg', (9, 17))	('PHD2', 'Gene', (71, 75))	('HIF-2alpha', 'Gene', (21, 31))
53119	25010988	As shown in Figure 5, the expression of GLUT1 (Figure 5a) and VEGF-A (Figure 5b) was significantly upregulated in the PHD2 knockdown cells.	('expression', 'MPA', (26, 36))	('VEGF-A', 'Gene', '7422', (62, 68))	('GLUT1', 'Gene', (40, 45))	('upregulated', 'PosReg', (99, 110))	('PHD2', 'Gene', (118, 122))	('GLUT1', 'Gene', '6513', (40, 45))	('VEGF-A', 'Gene', (62, 68))	('knockdown', 'Var', (123, 132))
53127	25010988	As shown in Figure 6b, the apoptosis of the hypoxic glioblastoma cells was not significantly affected by PHD2.	('PHD2', 'Var', (105, 109))	('hypoxic glioblastoma', 'Disease', (44, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('hypoxic glioblastoma', 'Disease', 'MESH:D005909', (44, 64))
53137	25010988	As shown in Supplementary Figure S3, a knockdown of PHD1 led to an accumulation of HIF-1alpha in normoxic glioblastoma cells.	('HIF-1alpha', 'Protein', (83, 93))	('knockdown', 'Var', (39, 48))	('glioblastoma', 'Disease', (106, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (106, 118))	('PHD1', 'Gene', '112398', (52, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('PHD1', 'Gene', (52, 56))	('accumulation', 'PosReg', (67, 79))
53141	25010988	As shown in Supplementary Figure S4C, the gene expression of PHD3 was not significantly affected by PHD2 knockdown.	('PHD3', 'Gene', '112399', (61, 65))	('PHD3', 'Gene', (61, 65))	('knockdown', 'Var', (105, 114))	('PHD2', 'Gene', (100, 104))
53144	25010988	PHD2 knockdown led to a significant downregulation of HIF-1alpha expression and a marked reduction of HIF-1alpha protein in glioblastoma cells.	('downregulation', 'NegReg', (36, 50))	('protein', 'MPA', (113, 120))	('knockdown', 'Var', (5, 14))	('glioblastoma', 'Disease', (124, 136))	('reduction', 'NegReg', (89, 98))	('expression', 'MPA', (65, 75))	('HIF-1alpha', 'Gene', (54, 64))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('PHD2', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
53147	25010988	In the osteosarcoma cell line LM8, PHD2 knockdown also caused a reduction of the basal NFkappaB activity due to the suppressed expression of IkappaB kinase beta (IKKbeta).	('PHD2', 'Gene', (35, 39))	('basal', 'MPA', (81, 86))	('suppressed', 'NegReg', (116, 126))	('expression', 'MPA', (127, 137))	('osteosarcoma', 'Phenotype', 'HP:0002669', (7, 19))	('osteosarcoma', 'Disease', (7, 19))	('knockdown', 'Var', (40, 49))	('IKKbeta', 'Gene', (162, 169))	('NFkappaB', 'Protein', (87, 95))	('IkappaB kinase beta', 'Gene', '3551', (141, 160))	('IkappaB kinase beta', 'Gene', (141, 160))	('reduction', 'NegReg', (64, 73))	('IKKbeta', 'Gene', '3551', (162, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (7, 19))	('LM8', 'CellLine', 'CVCL:6669', (30, 33))
53148	25010988	In the colon carcinoma cell line HCT116 and the cervix carcinoma cell line HeLa, PHD2 was reported to decrease the basal activity of NFkappaB.	('colon carcinoma', 'Disease', 'MESH:D015179', (7, 22))	('cervix carcinoma', 'Disease', 'MESH:D002583', (48, 64))	('colon carcinoma', 'Disease', (7, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('decrease', 'NegReg', (102, 110))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (48, 64))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('PHD2', 'Var', (81, 85))	('basal', 'MPA', (115, 120))	('cervix carcinoma', 'Disease', (48, 64))	('HCT116', 'CellLine', 'CVCL:0291', (33, 39))	('NFkappaB', 'Protein', (133, 141))
53161	25010988	In the PHD2 knockdown glioblastoma cells, the mRNA and protein levels of HIF-2alpha were increased.	('HIF-2alpha', 'Gene', (73, 83))	('glioblastoma', 'Disease', (22, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('knockdown', 'Var', (12, 21))	('HIF-2alpha', 'Gene', '2034', (73, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('increased', 'PosReg', (89, 98))	('PHD2', 'Gene', (7, 11))
53162	25010988	Knockdown studies showed that the expression of HIF-2alpha in glioblastoma cells is constitutively suppressed by HIF-1alpha even under normoxic conditions.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('expression', 'MPA', (34, 44))	('suppressed', 'NegReg', (99, 109))	('HIF-2alpha', 'Gene', '2034', (48, 58))	('glioblastoma', 'Disease', (62, 74))	('HIF-1alpha', 'Var', (113, 123))	('HIF-2alpha', 'Gene', (48, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))
53167	25010988	The mRNA levels of GLUT1 and VEGF-A were significantly elevated in the PHD2 knockdown glioblastoma cells incubated in hypoxia.	('mRNA levels', 'MPA', (4, 15))	('GLUT1', 'Gene', '6513', (19, 24))	('knockdown', 'Var', (76, 85))	('hypoxia', 'Disease', 'MESH:D000860', (118, 125))	('PHD2', 'Gene', (71, 75))	('VEGF-A', 'Gene', '7422', (29, 35))	('VEGF-A', 'Gene', (29, 35))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('elevated', 'PosReg', (55, 63))	('GLUT1', 'Gene', (19, 24))	('hypoxia', 'Disease', (118, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
53169	25010988	The expression of hexokinase 2 (HK2) and phosphofructokinase (PFK), the pacemaker enzymes of glycolysis, was not affected in the PHD2 knockdown cells (Supplementary Figure S5), suggesting that PHD2 suppresses the glucose uptake of hypoxic glioblastoma cells without changing the rate of glycolysis.	('PHD2', 'Var', (193, 197))	('hexokinase 2', 'Gene', '3099', (18, 30))	('suppresses', 'NegReg', (198, 208))	('HK2', 'Gene', (32, 35))	('HK2', 'Gene', '3099', (32, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (239, 251))	('glucose uptake', 'MPA', (213, 227))	('hexokinase 2', 'Gene', (18, 30))	('hypoxic glioblastoma', 'Disease', 'MESH:D005909', (231, 251))	('hypoxic glioblastoma', 'Disease', (231, 251))	('glucose', 'Chemical', 'MESH:D005947', (213, 220))
53173	25010988	PHD2 knockdown caused a downregulation of BNIP3 expression in hypoxic glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('hypoxic glioblastoma', 'Disease', 'MESH:D005909', (62, 82))	('knockdown', 'Var', (5, 14))	('hypoxic glioblastoma', 'Disease', (62, 82))	('expression', 'MPA', (48, 58))	('downregulation', 'NegReg', (24, 38))	('BNIP3', 'Gene', (42, 47))	('BNIP3', 'Gene', '664', (42, 47))	('PHD2', 'Gene', (0, 4))
53176	25010988	PHD2 knockdown further resulted in a reduction of hypoxia-induced glioblastoma cell death, presumably due to the modulated expression of GLUT1, VEGF-A and BNIP3.	('BNIP3', 'Gene', '664', (155, 160))	('VEGF-A', 'Gene', '7422', (144, 150))	('VEGF-A', 'Gene', (144, 150))	('reduction', 'NegReg', (37, 46))	('knockdown', 'Var', (5, 14))	('hypoxia-induced glioblastoma cell death', 'Disease', (50, 89))	('GLUT1', 'Gene', (137, 142))	('GLUT1', 'Gene', '6513', (137, 142))	('PHD2', 'Gene', (0, 4))	('BNIP3', 'Gene', (155, 160))	('hypoxia-induced glioblastoma cell death', 'Disease', 'MESH:D005909', (50, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))
53189	25010988	Characterization of the interaction partners of PHD2 in NFkappaB pathway, the possible genetic abnormalities of PHD2 and the mechanisms by which HIF-1alpha suppresses HIF-2alpha gene expression in glioblastoma cells would be obligatory.	('suppresses', 'NegReg', (156, 166))	('interaction', 'Interaction', (24, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (197, 209))	('HIF-1alpha', 'Var', (145, 155))	('PHD2', 'Gene', (112, 116))	('genetic abnormalities', 'Disease', 'MESH:D030342', (87, 108))	('HIF-2alpha', 'Gene', (167, 177))	('expression', 'MPA', (183, 193))	('genetic abnormalities', 'Disease', (87, 108))	('HIF-2alpha', 'Gene', '2034', (167, 177))	('glioblastoma', 'Disease', (197, 209))	('glioblastoma', 'Disease', 'MESH:D005909', (197, 209))
53202	25010988	The following primers and assays were used: human GLUT1 forward, 5'-GGC CTT TTC GTT AAC CGC TT-3' human GLUT1 reverse, 5'-AGC ATC TCA AAG GAC TTG CCC-3' human L28 forward, 5'-ATG GTC GTG CGG AAC TGC T-3' human L28 reverse, 5'-TTG TAG CGG AAG GAA TTG CG-3' human VEGF-A forward, 5'-GCA GAA TCA TCA CGA AGT GG-3' human VEGF-A reverse, 5'-GCA TGG TGA TGT TGG ACT CC-3' Taqman Gene Expression Assay for HIF-1alpha (Hs00936368_m1), HIF-2alpha (Hs01026149_m1), BNIP3 (Hs00969293_mH), p50 (Hs00765730_m1).	('Hs00969293_mH', 'Var', (462, 475))	('human', 'Species', '9606', (44, 49))	('L28', 'Gene', '6158', (210, 213))	('GLUT1', 'Gene', '6513', (50, 55))	('HIF-2alpha', 'Gene', (427, 437))	('VEGF-A', 'Gene', '7422', (317, 323))	('VEGF-A', 'Gene', '7422', (262, 268))	('human', 'Species', '9606', (153, 158))	('BNIP3', 'Gene', (455, 460))	('GLUT1', 'Gene', '6513', (104, 109))	('Hs00765730_m1', 'Var', (483, 496))	('human', 'Species', '9606', (311, 316))	('human', 'Species', '9606', (256, 261))	('L28', 'Gene', '6158', (159, 162))	('Hs01026149_m1', 'Var', (439, 452))	('L28', 'Gene', (210, 213))	('BNIP3', 'Gene', '664', (455, 460))	('GLUT1', 'Gene', (50, 55))	('VEGF-A', 'Gene', (262, 268))	('HIF-2alpha', 'Gene', '2034', (427, 437))	('human', 'Species', '9606', (204, 209))	('VEGF-A', 'Gene', (317, 323))	('GLUT1', 'Gene', (104, 109))	('p50', 'Gene', '4790', (478, 481))	('L28', 'Gene', (159, 162))	('p50', 'Gene', (478, 481))	('human', 'Species', '9606', (98, 103))
53210	24203995	Specifically, we explore the role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis.	('tumour', 'Disease', (128, 134))	('invasion', 'CPA', (94, 102))	('rat', 'Species', '10116', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lipid', 'Chemical', 'MESH:D008055', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (68, 74))	('lipid biosynthesis', 'MPA', (46, 64))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('aberrant', 'Var', (37, 45))
53223	24203995	Finally, we will examine how deregulated lipid metabolism in cancer cells might contribute to the complex interactions between cancer cells and the variety of stromal cell types that are recruited into the tumour.	('deregulated', 'Var', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('interactions', 'Interaction', (106, 118))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (61, 67))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('lipid metabolism', 'MPA', (41, 57))	('lipid', 'Chemical', 'MESH:D008055', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumour', 'Disease', (206, 212))	('contribute', 'Reg', (80, 90))
53257	24203995	Aberrant activation of SREBPs can contribute to obesity, fatty liver disease and insulin resistance, and could also be involved in cancer development.	('cancer', 'Disease', (131, 137))	('obesity', 'Disease', (48, 55))	('involved', 'Reg', (119, 127))	('fatty liver', 'Phenotype', 'HP:0001397', (57, 68))	('Aberrant', 'Var', (0, 8))	('insulin', 'Gene', (81, 88))	('fatty liver disease', 'Disease', (57, 76))	('obesity', 'Phenotype', 'HP:0001513', (48, 55))	('contribute', 'Reg', (34, 44))	('insulin', 'Gene', '3630', (81, 88))	('insulin resistance', 'Phenotype', 'HP:0000855', (81, 99))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('liver disease', 'Phenotype', 'HP:0001392', (63, 76))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('obesity', 'Disease', 'MESH:D009765', (48, 55))	('SREBPs', 'Protein', (23, 29))	('fatty liver disease', 'Disease', 'MESH:D005234', (57, 76))
53268	24203995	An early study performed in the middle of the last century demonstrated that cancer tissues are able to generate lipids, including FAs and phospholipids, by de novo lipogenesis.	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('phospholipids', 'Chemical', 'MESH:D010743', (139, 152))	('lipids', 'Chemical', 'MESH:D008055', (146, 152))	('lipogenesis', 'Var', (165, 176))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FAs', 'Chemical', 'MESH:D005227', (131, 134))	('rat', 'Species', '10116', (66, 69))	('lipids', 'Chemical', 'MESH:D008055', (113, 119))
53272	24203995	Since this pivotal observation, numerous studies have confirmed that neoplastic tissues show aberrant activation of de novo lipogenesis and that inhibition of different enzymes within the FA biosynthesis pathway can block cancer cell growth (reviewed by).	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('de novo lipogenesis', 'MPA', (116, 135))	('cancer', 'Disease', (222, 228))	('activation', 'PosReg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('inhibition', 'Var', (145, 155))	('block', 'NegReg', (216, 221))
53279	24203995	Moreover, silencing of ACLY has been shown to block cancer cell growth both in vivo and in vitro.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('block', 'NegReg', (46, 51))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('ACLY', 'Gene', (23, 27))	('silencing', 'Var', (10, 19))
53283	24203995	Furthermore, dysregulation of the mevalonate pathway promotes cell transformation of primary mouse embryonic fibroblasts.	('cell transformation', 'CPA', (62, 81))	('mevalonate pathway', 'Pathway', (34, 52))	('promotes', 'PosReg', (53, 61))	('mouse', 'Species', '10090', (93, 98))	('dysregulation', 'Var', (13, 26))	('mevalonate', 'Chemical', 'MESH:D008798', (34, 44))
53284	24203995	In addition, mutant forms of the p53 tumour suppressor can induce SREBP-dependent expression of enzymes in the cholesterol biosynthesis pathway.	('mutant', 'Var', (13, 19))	('tumour', 'Disease', (37, 43))	('SREBP-dependent expression of', 'MPA', (66, 95))	('induce', 'PosReg', (59, 65))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('cholesterol', 'Chemical', 'MESH:D002784', (111, 122))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
53291	24203995	Furthermore, certain subtypes of glioblastoma multiforme (GBM) that express an activated mutant form of the epithelial growth factor receptor (EGFR) also display high levels of nuclear SREBP1.	('EGFR', 'Gene', (143, 147))	('epithelial growth factor receptor', 'Gene', (108, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (33, 56))	('nuclear SREBP1', 'MPA', (177, 191))	('activated', 'PosReg', (79, 88))	('EGFR', 'Gene', '1956', (143, 147))	('epithelial growth factor receptor', 'Gene', '1956', (108, 141))	('mutant', 'Var', (89, 95))	('glioblastoma multiforme', 'Disease', (33, 56))
53294	24203995	Despite the growing evidence demonstrating deregulated FA and cholesterol biosynthesis as features of cancer, the exact role of these metabolic alterations in the development and maintenance of the disease is not fully understood.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rat', 'Species', '10116', (148, 151))	('deregulated', 'Var', (43, 54))	('rat', 'Species', '10116', (36, 39))	('cholesterol biosynthesis', 'MPA', (62, 86))	('cholesterol', 'Chemical', 'MESH:D002784', (62, 73))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
53301	24203995	Alterations in FA saturation can dramatically alter these properties and affect many aspects of the cellular machinery.	('these properties', 'MPA', (52, 68))	('affect', 'Reg', (73, 79))	('cellular machinery', 'CPA', (100, 118))	('Alterations', 'Var', (0, 11))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (4, 7))	('alter', 'Reg', (46, 51))
53304	24203995	However, inhibition of FA desaturation following ablation of SCD causes ER stress, cell cycle inhibition and apoptosis in cancer cells.	('SCD', 'Gene', (61, 64))	('SCD', 'Gene', '6319', (61, 64))	('ER stress', 'MPA', (72, 81))	('rat', 'Species', '10116', (32, 35))	('cancer', 'Disease', (122, 128))	('apoptosis', 'CPA', (109, 118))	('FA desaturation', 'MPA', (23, 38))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cell cycle inhibition', 'CPA', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inhibition', 'Var', (9, 19))
53305	24203995	Inhibition of SCD can also impair cancer cell proliferation by activating AMPK.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('AMPK', 'Gene', '5562', (74, 78))	('AMPK', 'Gene', (74, 78))	('impair', 'NegReg', (27, 33))	('SCD', 'Gene', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('rat', 'Species', '10116', (53, 56))	('SCD', 'Gene', '6319', (14, 17))	('cancer', 'Disease', (34, 40))	('Inhibition', 'Var', (0, 10))
53306	24203995	Furthermore, depletion of SREBP1 and SREBP2 diminishes levels of monounsaturated FAs, resulting in mitochondrial dysfunction, the accumulation of ROS and ER stress in immortalised human epithelial cells.	('epithelia', 'Disease', 'None', (186, 195))	('epithelia', 'Disease', (186, 195))	('accumulation', 'PosReg', (130, 142))	('mitochondrial dysfunction', 'Disease', (99, 124))	('ROS', 'MPA', (146, 149))	('rat', 'Species', '10116', (75, 78))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (99, 124))	('human', 'Species', '9606', (180, 185))	('depletion', 'Var', (13, 22))	('ER stress', 'MPA', (154, 163))	('SREBP2', 'Gene', '6721', (37, 43))	('ROS', 'Chemical', 'MESH:D017382', (146, 149))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (99, 124))	('FAs', 'Chemical', 'MESH:D005227', (81, 84))	('SREBP2', 'Gene', (37, 43))	('levels of monounsaturated FAs', 'MPA', (55, 84))	('diminishes', 'NegReg', (44, 54))
53313	24203995	This molecule is produced by PI3K in response to growth factor signalling and mediates the recruitment and activation of Akt.	('PI3K', 'Var', (29, 33))	('Akt', 'Gene', '207', (121, 124))	('Akt', 'Gene', (121, 124))
53324	24203995	Aberrant activation of signalling pathways by oncogenes is likely to alter the abundance of multiple signalling lipids, thereby influencing numerous downstream processes that are crucial for cell transformation.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('signalling pathways', 'Pathway', (23, 42))	('influencing', 'Reg', (128, 139))	('alter', 'Reg', (69, 74))	('abundance of multiple signalling lipids', 'MPA', (79, 118))	('lipids', 'Chemical', 'MESH:D008055', (112, 118))
53331	24203995	Protein modification with saturated acyl chains can promote their association with cholesterol-rich membrane rafts, whereas unsaturated FAs exclude proteins from these structures.	('FAs', 'Chemical', 'MESH:D005227', (136, 139))	('association', 'Interaction', (66, 77))	('rat', 'Species', '10116', (30, 33))	('cholesterol-rich membrane rafts', 'MPA', (83, 114))	('rat', 'Species', '10116', (130, 133))	('cholesterol', 'Chemical', 'MESH:D002784', (83, 94))	('modification', 'Var', (8, 20))	('promote', 'PosReg', (52, 59))
53351	24203995	The following sections will discuss the potential impact of deregulated lipogenesis in the context of the complex interactions between cancer cells and the tumour microenvironment.	('cancer', 'Disease', (135, 141))	('tumour', 'Disease', (156, 162))	('deregulated', 'Var', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lipogenesis', 'MPA', (72, 83))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
53356	24203995	This disruption of normal mammary tissue architecture can be mediated by cancer-associated mutant forms of p53.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('mediated', 'Reg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutant', 'Var', (91, 97))
53357	24203995	The same study that demonstrated that mutant p53 proteins activate the mevalonate pathway by binding to SREBP (described above), also showed that inhibition of different enzymes within this pathway blocks the invasive morphology of breast cancer cells grown in 3D, potentially by interfering with geranyl-geranylation of small GTPases.	('breast cancer', 'Disease', (232, 245))	('invasive morphology', 'CPA', (209, 228))	('mevalonate', 'Chemical', 'MESH:D008798', (71, 81))	('binding', 'Interaction', (93, 100))	('mevalonate pathway', 'Pathway', (71, 89))	('inhibition', 'Var', (146, 156))	('small GTPases', 'Protein', (321, 334))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('mutant', 'Var', (38, 44))	('p53', 'Gene', '7157', (45, 48))	('proteins', 'Protein', (49, 57))	('geranyl-geranylation', 'MPA', (297, 317))	('activate', 'PosReg', (58, 66))	('rat', 'Species', '10116', (27, 30))	('interfering', 'NegReg', (280, 291))	('blocks', 'NegReg', (198, 204))	('p53', 'Gene', (45, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))
53358	24203995	Aberrant FA synthesis has also been linked to the disruption of cell polarity in epithelial tissues.	('Aberrant', 'Var', (0, 8))	('epithelia', 'Disease', 'None', (81, 90))	('epithelia', 'Disease', (81, 90))	('linked', 'Reg', (36, 42))	('FA synthesis', 'MPA', (9, 21))
53378	24203995	Prostaglandins are important modulators of the immune response, and inhibition of PGE2 synthesis using COX2 inhibitors in cervical cancer cells was shown to prevent the differentiation of monocytes into M2 macrophages.	('cancer', 'Disease', (131, 137))	('PGE2', 'Chemical', 'MESH:D015232', (82, 86))	('inhibition', 'Var', (68, 78))	('PGE2', 'Gene', (82, 86))	('prevent', 'NegReg', (157, 164))	('differentiation of monocytes into M2 macrophages', 'CPA', (169, 217))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Prostaglandins', 'Chemical', 'MESH:D011453', (0, 14))	('COX2', 'Gene', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('COX2', 'Gene', '4513', (103, 107))
53398	24203995	However, inhibition of FASN reduced proliferation and viability of rat aortic endothelial cells and human umbilical vein endothelial cells (RAECs and HUVECs), and blocked their capacity to form capillary-like structures in culture, suggesting that the inhibition of metastasis formation by orlistat is caused by its effects on endothelial cell metabolism.	('blocked', 'NegReg', (163, 170))	('reduced', 'NegReg', (28, 35))	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (43, 46))	('human', 'Species', '9606', (100, 105))	('orlistat', 'Chemical', 'MESH:D000077403', (290, 298))	('viability', 'CPA', (54, 63))	('proliferation', 'CPA', (36, 49))	('FASN', 'Protein', (23, 27))	('inhibition', 'Var', (9, 19))	('metastasis formation', 'CPA', (266, 286))
53419	24203995	As already discussed above, changes in lipid desaturation mediated by altered SCD expression could affect membrane fluidity and contribute to the induction of cancer cell migration, a process that is also regulated by hypoxia.	('cancer', 'Disease', (159, 165))	('SCD', 'Gene', '6319', (78, 81))	('altered', 'Var', (70, 77))	('expression', 'MPA', (82, 92))	('membrane fluidity', 'MPA', (106, 123))	('hypoxia', 'Disease', (218, 225))	('hypoxia', 'Disease', 'MESH:D000860', (218, 225))	('induction', 'Reg', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rat', 'Species', '10116', (174, 177))	('affect', 'Reg', (99, 105))	('lipid desaturation', 'MPA', (39, 57))	('changes', 'Reg', (28, 35))	('lipid', 'Chemical', 'MESH:D008055', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('SCD', 'Gene', (78, 81))	('rat', 'Species', '10116', (51, 54))
53453	33680951	Mutation of this gene caused defects in cephalic development of drosophila leading to a forkhead appearance and hence the name forkhead.	('drosophila', 'Species', '7227', (64, 74))	('forkhead', 'Gene', '43383', (88, 96))	('forkhead', 'Gene', '43383', (127, 135))	('Mutation', 'Var', (0, 8))	('defects', 'NegReg', (29, 36))	('forkhead', 'Gene', (127, 135))	('cephalic development of drosophila', 'CPA', (40, 74))	('forkhead', 'Gene', (88, 96))
53467	33680951	It is necessary to understand the various oncogenic pathways leading to the modulation of FOXM1 in response to environmental cues or oncogenic insults.	('FOXM1', 'Gene', '2305', (90, 95))	('modulation', 'Var', (76, 86))	('FOXM1', 'Gene', (90, 95))
53472	33680951	Copy number alteration was observed in 29% of malignant peripheral nerve sheath tumors (MPNSTs) and also in breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('Copy number alteration', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (46, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (46, 86))	('observed', 'Reg', (27, 35))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('MPNSTs', 'Phenotype', 'HP:0100697', (88, 94))	('malignant peripheral nerve sheath tumors', 'Disease', (46, 86))
53476	33680951	COSMIC database has revealed several mutations and gene amplifications of FOXM1 across various cancers ( Figure 1C ).	('FOXM1', 'Gene', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('FOXM1', 'Gene', '2305', (74, 79))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gene amplifications', 'Var', (51, 70))
53477	33680951	Most of these mutations may possibly alter the activity of FOXM1, but detailed studies need to be carried out to understand their effect at protein level, thereby the alterations in cellular physiology.	('activity', 'MPA', (47, 55))	('alter', 'Reg', (37, 42))	('cellular physiology', 'MPA', (182, 201))	('alterations', 'Reg', (167, 178))	('FOXM1', 'Gene', (59, 64))	('FOXM1', 'Gene', '2305', (59, 64))	('mutations', 'Var', (14, 23))
53490	33680951	RASSF1A, which is mainly altered via hypermethylation, protein degradation and point mutation has been widely observed in various cancers such as liver, breast, colon and bladder cancer.	('observed', 'Reg', (110, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('RASSF1A', 'Gene', (0, 7))	('point mutation', 'Var', (79, 93))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Disease', (130, 137))	('protein degradation', 'MPA', (55, 74))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('breast', 'Disease', (153, 159))	('RASSF1A', 'Gene', '11186', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('liver', 'Disease', (146, 151))	('colon and bladder cancer', 'Disease', 'MESH:D001749', (161, 185))
53493	33680951	Presence of this positive FOXM1 and MET feedback loop accelerate pancreatic ductal adenocarcinoma (PDA) development.	('accelerate', 'PosReg', (54, 64))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (65, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('FOXM1', 'Gene', '2305', (26, 31))	('FOXM1', 'Gene', (26, 31))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('pancreatic ductal adenocarcinoma', 'Disease', (65, 97))	('Presence', 'Var', (0, 8))
53513	33680951	A shorter overall survival was observed in glioblastoma multiforme (GBM) patients with the expression of alpha6-integrin, ZEB1/YAP1, FGFR1 and FOXM1.	('alpha6-integrin', 'Protein', (105, 120))	('FGFR1', 'Gene', (133, 138))	('YAP1', 'Gene', '10413', (127, 131))	('FGFR1', 'Gene', '2260', (133, 138))	('expression', 'Var', (91, 101))	('glioblastoma multiforme', 'Disease', (43, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('ZEB1', 'Gene', '6935', (122, 126))	('shorter', 'NegReg', (2, 9))	('ZEB1', 'Gene', (122, 126))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (43, 66))	('FOXM1', 'Gene', (143, 148))	('overall survival', 'MPA', (10, 26))	('patients', 'Species', '9606', (73, 81))	('FOXM1', 'Gene', '2305', (143, 148))	('YAP1', 'Gene', (127, 131))
53531	33680951	Colorectal cancer cell proliferation was also enhanced in the background of Hh signaling and FOXM1 expression.	('FOXM1', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('expression', 'Var', (99, 109))	('enhanced', 'PosReg', (46, 54))	('Colorectal cancer', 'Disease', (0, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('FOXM1', 'Gene', '2305', (93, 98))
53543	33680951	An increased incidence rate of cancer in colon, breast, prostate and ovarian has been inversely correlated with the vitamin D deficiency.	('vitamin', 'Gene', (116, 123))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('deficiency', 'Var', (126, 136))	('colon, breast, prostate and ovarian', 'Disease', 'MESH:D011471', (41, 76))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('vitamin D', 'Chemical', 'MESH:D014807', (116, 125))
53550	33680951	Accumulation FOXM1A and downregulation of both FOXM1B and FOXM1C have been observed upon knockdown of SRp20.	('SRp20', 'Gene', '6428', (102, 107))	('SRp20', 'Gene', (102, 107))	('downregulation', 'NegReg', (24, 38))	('FOXM1', 'Gene', (47, 52))	('FOXM1', 'Gene', '2305', (47, 52))	('FOXM1', 'Gene', (13, 18))	('FOXM1', 'Gene', '2305', (13, 18))	('knockdown', 'Var', (89, 98))	('FOXM1', 'Gene', '2305', (58, 63))	('FOXM1', 'Gene', (58, 63))
53553	33680951	Inhibition of USP39 by siRNA has downregulated FOXM1 and in turn led to tumor volume reduction in xenograft model of HCC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('HCC', 'Phenotype', 'HP:0001402', (117, 120))	('USP39', 'Gene', '10713', (14, 19))	('tumor', 'Disease', (72, 77))	('USP39', 'Gene', (14, 19))	('FOXM1', 'Gene', (47, 52))	('reduction', 'NegReg', (85, 94))	('FOXM1', 'Gene', '2305', (47, 52))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('downregulated', 'NegReg', (33, 46))
53563	33680951	So it would be speculated that the deregulation on these molecules in cancer may affect the expression of FOXM1 transcription factor.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('deregulation', 'Var', (35, 47))	('FOXM1', 'Gene', (106, 111))	('affect', 'Reg', (81, 87))	('FOXM1', 'Gene', '2305', (106, 111))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('expression', 'MPA', (92, 102))
53571	33680951	Another mechanism of FOXM1 miRNA downregulation is by the hypermethylation of its own promoter.	('hypermethylation', 'Var', (58, 74))	('downregulation', 'NegReg', (33, 47))	('miRNA', 'MPA', (27, 32))	('FOXM1', 'Gene', (21, 26))	('FOXM1', 'Gene', '2305', (21, 26))
53574	33680951	The drug resistance phenotype in cancer cells has been observed to be reversed by the overexpression of miRNA 134, whereas miRNA 320 enhanced radiosensitivity by directly targeting FOXM1.	('cancer', 'Disease', (33, 39))	('targeting', 'Reg', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('drug resistance', 'Phenotype', 'HP:0020174', (4, 19))	('miRNA', 'Var', (104, 109))	('radiosensitivity', 'MPA', (142, 158))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('FOXM1', 'Gene', (181, 186))	('drug resistance', 'MPA', (4, 19))	('miRNA 320', 'Var', (123, 132))	('overexpression', 'PosReg', (86, 100))	('FOXM1', 'Gene', '2305', (181, 186))	('enhanced', 'PosReg', (133, 141))
53582	33680951	Apart from these, many lncRNA like H19, LINC00339, LINC01410, Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), SBF2-AS1, FBXL19-AS1, MEG3, TRPM2-AS, MFI2-AS1, NNT-AS1, CCAL, modulate the expression of FOXM1 via miR-342-3p and miR-194, miR-145, miR-3619, miR-320a, miR-361-5p, miR-876-5p, miR-612, miR-194-5p, miR-134, miR-22, and miR-149 respectively in various cancers.	('AS1', 'Gene', '5729', (170, 173))	('H19', 'Gene', '283120', (35, 38))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (165, 173))	('miR-194-5p', 'Var', (313, 323))	('lung adenocarcinoma', 'Disease', (84, 103))	('miR-149', 'Gene', '406941', (346, 353))	('miR-194', 'Var', (242, 249))	('miR-342-3p', 'Var', (227, 237))	('miR-145', 'Gene', '406937', (251, 258))	('FBXL19', 'Gene', (137, 143))	('NNT-AS1', 'Gene', '100652772', (175, 182))	('miR-361', 'Gene', (260, 267))	('AS1', 'Gene', (132, 135))	('TRPM2-AS', 'Gene', (155, 163))	('miR-145', 'Gene', (251, 258))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('MALAT1', 'Gene', (118, 124))	('miR-361', 'Gene', '494323', (280, 287))	('SBF2-AS1', 'Gene', (127, 135))	('cancers', 'Disease', 'MESH:D009369', (378, 385))	('AS1', 'Gene', (179, 182))	('FOXM1', 'Gene', (217, 222))	('miR-876', 'Gene', (292, 299))	('AS1', 'Gene', '5729', (144, 147))	('LINC01410', 'Gene', (51, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('MEG3', 'Gene', (149, 153))	('FBXL19', 'Gene', '54620', (137, 143))	('AS1', 'Gene', (170, 173))	('miR-22', 'Gene', (334, 340))	('miR-22', 'Gene', '407004', (334, 340))	('miR-3619', 'Gene', (260, 268))	('MALAT1', 'Gene', '378938', (118, 124))	('NNT-AS1', 'Gene', (175, 182))	('miR-612', 'Gene', '693197', (304, 311))	('SBF2-AS1', 'Gene', '283104;81846;5729', (127, 135))	('miR-134', 'Gene', (325, 332))	('miR-3619', 'Gene', '100500828', (260, 268))	('miR-320a', 'Gene', (270, 278))	('LINC00339', 'Gene', '29092', (40, 49))	('TRPM2-AS', 'Gene', '101928607', (155, 163))	('miR-361', 'Gene', (280, 287))	('AS1', 'Gene', '5729', (132, 135))	('LINC00339', 'Gene', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('H19', 'Gene', (35, 38))	('MFI2-AS1', 'Gene', (165, 173))	('miR-149', 'Gene', (346, 353))	('miR-612', 'Gene', (304, 311))	('expression', 'MPA', (203, 213))	('modulate', 'Reg', (190, 198))	('MEG3', 'Gene', '55384', (149, 153))	('miR-134', 'Gene', '406924', (325, 332))	('cancers', 'Phenotype', 'HP:0002664', (378, 385))	('miR-361', 'Gene', '494323', (260, 267))	('LINC01410', 'Gene', '103352539', (51, 60))	('miR-876', 'Gene', '100126310', (292, 299))	('miR-320a', 'Gene', '407037', (270, 278))	('AS1', 'Gene', (144, 147))	('FOXM1', 'Gene', '2305', (217, 222))	('AS1', 'Gene', '5729', (179, 182))	('cancers', 'Disease', (378, 385))
53585	33680951	As FOXM1 plays a major role in many cellular processes, any deregulation in its activity by way of faulty PTMs may facilitate the process of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('facilitate', 'PosReg', (115, 125))	('tumor', 'Disease', (141, 146))	('activity', 'MPA', (80, 88))	('deregulation', 'Var', (60, 72))	('FOXM1', 'Gene', '2305', (3, 8))	('FOXM1', 'Gene', (3, 8))
53589	33680951	A proteomic study had revealed K278 and K282 as the plausible sites of methylation on FOXM1.	('FOXM1', 'Gene', (86, 91))	('K278', 'Var', (31, 35))	('FOXM1', 'Gene', '2305', (86, 91))	('K282', 'Var', (40, 44))
53600	33680951	When cells enter S and G2 phase, Cyclin E/A and CDK2 complex phosphorylates FOXM1C at Thr600, Thr611 and Ser638 and regulate the transcriptional activity.	('FOXM1', 'Gene', '2305', (76, 81))	('Ser638', 'Chemical', '-', (105, 111))	('Cyclin', 'Gene', (33, 39))	('FOXM1', 'Gene', (76, 81))	('regulate', 'Reg', (116, 124))	('CDK2', 'Gene', (48, 52))	('Thr611', 'Chemical', '-', (94, 100))	('Thr611', 'Var', (94, 100))	('Thr600', 'Var', (86, 92))	('Cyclin', 'Gene', '5111', (33, 39))	('Thr600', 'Chemical', '-', (86, 92))	('CDK2', 'Gene', '1017', (48, 52))	('Ser638', 'Var', (105, 111))	('transcriptional activity', 'MPA', (129, 153))
53601	33680951	Three potential CDK 1/2 sites were observed in the FOXM1B protein which includes amino acid residues at 585, 596 and 657.	('FOXM1B', 'Gene', (51, 57))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('596', 'Var', (109, 112))
53602	33680951	Among these T596 residue has been recognized as a critical CDK1 phosphorylation site within the activation domain of FOXM1B.	('T596', 'Chemical', '-', (12, 16))	('T596 residue', 'Var', (12, 24))	('FOXM1B', 'Gene', (117, 123))	('CDK1', 'Gene', (59, 63))	('CDK1', 'Gene', '983', (59, 63))
53604	33680951	Mutation of T596 abolishes binding to CBP and inhibits transcriptional activity of FOXM1B.	('T596', 'Chemical', '-', (12, 16))	('CBP', 'Gene', '1387', (38, 41))	('CBP', 'Gene', (38, 41))	('binding', 'Interaction', (27, 34))	('Mutation', 'Var', (0, 8))	('transcriptional activity', 'MPA', (55, 79))	('inhibits', 'NegReg', (46, 54))	('FOXM1B', 'Gene', (83, 89))	('abolishes', 'NegReg', (17, 26))	('T596', 'Gene', (12, 16))
53606	33680951	Mutation of the Cyclin-binding motif (Leu-641-Ala) has resulted in the elimination of both CDK1 and CDK2 binding.	('Cyclin', 'Gene', '5111', (16, 22))	('CDK2', 'Gene', (100, 104))	('CDK1', 'Gene', '983', (91, 95))	('Cyclin', 'Gene', (16, 22))	('CDK1', 'Gene', (91, 95))	('elimination', 'NegReg', (71, 82))	('CDK2', 'Gene', '1017', (100, 104))	('Leu-641-Ala', 'Mutation', 'p.L641A', (38, 49))	('Leu-641-Ala', 'Var', (38, 49))	('binding', 'Interaction', (105, 112))
53607	33680951	Phosphorylation of S251 in the forkhead box domain of FOXM1B stands as a critical event for activation of its transcriptional activity at the G2/M phase by CDK1.	('CDK1', 'Gene', '983', (156, 160))	('FOXM1B', 'Gene', (54, 60))	('S251', 'Var', (19, 23))	('activation', 'PosReg', (92, 102))	('Phosphorylation', 'Var', (0, 15))	('transcriptional activity', 'MPA', (110, 134))	('forkhead', 'Gene', '43383', (31, 39))	('forkhead', 'Gene', (31, 39))	('CDK1', 'Gene', (156, 160))
53614	33680951	FOXM1 has two potential PBD-binding sites (T596 and S678) at its C terminal region and phosphorylate S715 and S724 present within the TAD region of FOXM1.	('FOXM1', 'Gene', '2305', (148, 153))	('FOXM1', 'Gene', (148, 153))	('T596', 'Chemical', '-', (43, 47))	('S724', 'Var', (110, 114))	('S678', 'Var', (52, 56))	('FOXM1', 'Gene', '2305', (0, 5))	('T596', 'Var', (43, 47))	('FOXM1', 'Gene', (0, 5))	('PBD-binding', 'Interaction', (24, 35))	('S715', 'Var', (101, 105))
53624	33680951	At the onset of DNA damage, phosphorylation of FOXM1 by CHK2 kinase ensures a proper DNA damage response through the stabilization of FOXM1.	('phosphorylation', 'Var', (28, 43))	('ensures', 'PosReg', (68, 75))	('DNA damage response', 'MPA', (85, 104))	('FOXM1', 'Gene', (47, 52))	('FOXM1', 'Gene', (134, 139))	('FOXM1', 'Gene', '2305', (47, 52))	('FOXM1', 'Gene', '2305', (134, 139))	('stabilization', 'MPA', (117, 130))
53625	33680951	In FOXM1B, S361 residue marks the phosphorylation site for CHK2 and has been established to be conserved between mouse and humans.	('FOXM1B', 'Gene', (3, 9))	('S361 residue', 'Var', (11, 23))	('humans', 'Species', '9606', (123, 129))	('mouse', 'Species', '10090', (113, 118))	('phosphorylation site', 'MPA', (34, 54))
53627	33680951	FOXM1C has two such sequences around T160 and S190 at the N terminal region.	('S190', 'Var', (46, 50))	('FOXM1', 'Gene', '2305', (0, 5))	('T160', 'Var', (37, 41))	('FOXM1', 'Gene', (0, 5))
53628	33680951	Likewise, protein kinase CK2 recognizes the motif S/T-X-X-E/D.	('S/T-X-X-E/D', 'Var', (50, 61))	('protein kinase CK2', 'Gene', '1457', (10, 28))	('protein kinase CK2', 'Gene', (10, 28))
53629	33680951	Phosphorylation of FOXM1C by CK2 at residues T27 and S28 results in its activation by removing the inhibitory phosphorylation.	('activation', 'PosReg', (72, 82))	('removing', 'NegReg', (86, 94))	('inhibitory phosphorylation', 'MPA', (99, 125))	('CK2', 'Protein', (29, 32))	('S28', 'Var', (53, 56))	('FOXM1', 'Gene', (19, 24))	('FOXM1', 'Gene', '2305', (19, 24))	('Phosphorylation', 'MPA', (0, 15))
53632	33680951	Acetylation of FOXM1 by p300/CBP at lysines K63, K422, K440, K603 and K614 has been noted to be essential for its transactivation of the target genes.	('K440', 'Var', (55, 59))	('p300', 'Gene', (24, 28))	('transactivation', 'MPA', (114, 129))	('FOXM1', 'Gene', '2305', (15, 20))	('K614', 'Var', (70, 74))	('FOXM1', 'Gene', (15, 20))	('lysines', 'Chemical', 'MESH:D008239', (36, 43))	('CBP', 'Gene', (29, 32))	('Acetylation', 'MPA', (0, 11))	('p300', 'Gene', '2033', (24, 28))	('K422', 'Var', (49, 53))	('CBP', 'Gene', '1387', (29, 32))	('K603', 'Var', (61, 65))
53634	33680951	Apart from its increased transcriptional activity, acetylation of FOXM1 resulted in stabilization of the protein.	('FOXM1', 'Gene', (66, 71))	('acetylation', 'Var', (51, 62))	('stabilization', 'MPA', (84, 97))	('transcriptional activity', 'MPA', (25, 49))	('increased', 'PosReg', (15, 24))	('protein', 'Protein', (105, 112))	('FOXM1', 'Gene', '2305', (66, 71))
53641	33680951	Tumor growth potential was significantly reduced in acetylation deficient mutants compared to wildtype FOXM1.	('FOXM1', 'Gene', '2305', (103, 108))	('reduced', 'NegReg', (41, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor growth potential', 'CPA', (0, 22))	('mutants', 'Var', (74, 81))	('FOXM1', 'Gene', (103, 108))	('acetylation', 'MPA', (52, 63))
53642	33680951	SUMOylation is a highly dynamic and reversible post translational modification that modulates FOXM1 activity in a context dependent manner.	('SUMOylation', 'Var', (0, 11))	('FOXM1', 'Gene', (94, 99))	('FOXM1', 'Gene', '2305', (94, 99))	('modulates', 'Reg', (84, 93))	('activity', 'MPA', (100, 108))
53645	33680951	SUMOylation of psiKXE motifs on the transactivation domain of FOXM1C promoted cytoplasmic accumulation and degradation by APCCdh ubiquitin ligase in breast cancer cells.	('SUMOylation', 'Var', (0, 11))	('degradation', 'MPA', (107, 118))	('FOXM1', 'Gene', '2305', (62, 67))	('psiKXE motifs', 'Disease', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cytoplasmic accumulation', 'MPA', (78, 102))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('promoted', 'PosReg', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('psiKXE motifs', 'Disease', 'None', (15, 28))	('breast cancer', 'Disease', (149, 162))	('FOXM1', 'Gene', (62, 67))
53651	33680951	demonstrated transcriptional activation of FOXM1 by SUMO2 in wild type compared to the SUMOylation deficient FOXM1 mutant.	('activation', 'PosReg', (29, 39))	('SUMO2', 'Gene', (52, 57))	('SUMO2', 'Gene', '6613', (52, 57))	('mutant', 'Var', (115, 121))	('FOXM1', 'Gene', (43, 48))	('FOXM1', 'Gene', '2305', (43, 48))	('FOXM1', 'Gene', (109, 114))	('transcriptional', 'MPA', (13, 28))	('FOXM1', 'Gene', '2305', (109, 114))
53652	33680951	Their results indicated that SUMOylation blocks the dimerization of FOXM1, thereby relieving FOXM1 auto repression.	('FOXM1', 'Gene', (93, 98))	('dimerization', 'MPA', (52, 64))	('relieving', 'NegReg', (83, 92))	('blocks', 'NegReg', (41, 47))	('SUMOylation', 'Var', (29, 40))	('auto repression', 'MPA', (99, 114))	('FOXM1', 'Gene', '2305', (68, 73))	('FOXM1', 'Gene', (68, 73))	('FOXM1', 'Gene', '2305', (93, 98))
53673	33680951	Apart from this, its role in execution of mitosis by genes such as BUBR1, NEK2, Aurora A/B, KIF4A, CENP-A/B/E/F, CEP55, BORA and CDCA2/8 ensures high fidelity of cell division process (genome instability and mutation).	('cell division', 'CPA', (162, 175))	('mitosis', 'Disease', 'None', (42, 49))	('CEP55', 'Gene', (113, 118))	('Aurora A/B', 'Gene', '6790;9212', (80, 90))	('KIF4A', 'Gene', (92, 97))	('BORA', 'Gene', '79866', (120, 124))	('BUBR1', 'Gene', '701', (67, 72))	('BUBR1', 'Gene', (67, 72))	('NEK2', 'Gene', (74, 78))	('BORA', 'Gene', (120, 124))	('mutation', 'Var', (208, 216))	('CENP-A/B/E/F', 'Gene', (99, 111))	('NEK2', 'Gene', '4751', (74, 78))	('CEP55', 'Gene', '55165', (113, 118))	('mitosis', 'Disease', (42, 49))	('Aurora A/B', 'Gene', (80, 90))	('CENP-A/B/E/F', 'Gene', '1058;1059;1062;1063', (99, 111))	('KIF4A', 'Gene', '24137', (92, 97))	('CDCA2/8', 'Gene', (129, 136))	('CDCA2/8', 'Gene', '157313;55143', (129, 136))
53677	33680951	It has been found that FOXM1 depletion sensitizes the cells to premature senescence thus slowing down cancer progression.	('depletion', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('sensitizes', 'Reg', (39, 49))	('FOXM1', 'Gene', '2305', (23, 28))	('FOXM1', 'Gene', (23, 28))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('slowing down', 'NegReg', (89, 101))
53690	33680951	FOXM1 interaction with MELK, PIN1 and pSTAT3 induced neurosphere development, BRAFV600E stimulated melanoma progression and radioresistance in glioblastoma respectively.	('MELK', 'Gene', '9833', (23, 27))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('STAT3', 'Gene', (39, 44))	('FOXM1', 'Gene', '2305', (0, 5))	('PIN1', 'Gene', '5300', (29, 33))	('interaction', 'Interaction', (6, 17))	('STAT3', 'Gene', '6774', (39, 44))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('PIN1', 'Gene', (29, 33))	('stimulated', 'PosReg', (88, 98))	('induced', 'PosReg', (45, 52))	('MELK', 'Gene', (23, 27))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('BRAFV600E', 'Var', (78, 87))	('FOXM1', 'Gene', (0, 5))	('radioresistance', 'CPA', (124, 139))	('glioblastoma', 'Disease', (143, 155))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('melanoma', 'Disease', (99, 107))	('neurosphere development', 'CPA', (53, 76))
53692	33680951	Nucleophosmin (NPN) was shown to sustain FOXM1 nuclear localization in cancer cells, whose mutation in AML interestingly led to FOXM1 inactivation by cytoplasmic shuttling.	('FOXM1', 'Gene', (41, 46))	('mutation', 'Var', (91, 99))	('AML', 'Disease', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('FOXM1', 'Gene', '2305', (128, 133))	('cancer', 'Disease', (71, 77))	('FOXM1', 'Gene', (128, 133))	('FOXM1', 'Gene', '2305', (41, 46))	('Nucleophosmin', 'Gene', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Nucleophosmin', 'Gene', '4869', (0, 13))	('NPN', 'Gene', '4869', (15, 18))	('AML', 'Disease', 'MESH:D015470', (103, 106))	('inactivation', 'NegReg', (134, 146))	('nuclear localization', 'MPA', (47, 67))	('NPN', 'Gene', (15, 18))
53710	33680951	In this review, we have addressed various regulatory pathways and mechanisms by which FOXM1 is altered and its implications in modulating different hallmarks of cancer.	('FOXM1', 'Gene', (86, 91))	('modulating', 'Reg', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('altered', 'Var', (95, 102))	('FOXM1', 'Gene', '2305', (86, 91))
53762	32823792	The Cancer Genome Atlas has revolutionised research on the GBM genome by revealing different mutations in tumour suppressor genes and oncogenes specific to different GBM variants.	('mutations', 'Var', (93, 102))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('variants', 'Var', (170, 178))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('tumour', 'Disease', (106, 112))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('GBM', 'Phenotype', 'HP:0012174', (166, 169))
53763	32823792	Additionally, the same project described three major pathways that are usually involved in GBM pathogenesis:the tumour protein p53 (P53) pathway, the receptor tyrosine kinase/Ras/phosphoinositide 3-kinase (PI3K) signalling pathway and the retinoblastoma (RB) pathway:whose mutations lead to the excessive proliferation of tumour cells by augmenting cell lifespan via apoptosis inhibition and increasing the proliferation rate.	('tumour', 'Disease', 'MESH:D009369', (322, 328))	('lead to', 'Reg', (283, 290))	('retinoblastoma', 'Phenotype', 'HP:0009919', (239, 253))	('RB', 'Disease', 'MESH:D012175', (255, 257))	('tumour', 'Disease', (322, 328))	('p53', 'Gene', '7157', (127, 130))	('GBM', 'Phenotype', 'HP:0012174', (91, 94))	('RB', 'Phenotype', 'HP:0009919', (255, 257))	('increasing', 'PosReg', (392, 402))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('P53', 'Gene', (132, 135))	('p53', 'Gene', (127, 130))	('retinoblastoma', 'Gene', (239, 253))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('augmenting', 'NegReg', (338, 348))	('proliferation rate', 'CPA', (407, 425))	('P53', 'Gene', '7157', (132, 135))	('cell lifespan', 'CPA', (349, 362))	('apoptosis inhibition', 'CPA', (367, 387))	('mutations', 'Var', (273, 282))	('tumour', 'Phenotype', 'HP:0002664', (322, 328))	('retinoblastoma', 'Gene', '5925', (239, 253))
53766	32823792	Primary (de novo) GBM has the highest incidence (accounting for 90% of all GBMs), affects older patients, and is most frequently associated with epidermal growth factor receptor (EGFR) overexpression (amplification of genes on chromosome 7), platelet-derived growth factor receptor (PDGFR) amplification (on chromosome 4), cyclin-dependent kinase inhibitor 2 A/B (CDKN2A/B) deletion (on chromosome 1), phosphate and tensin homologue (PTEN) mutations (on chromosome 10) and telomerase reverse transcriptase (TERT) promoter, among other factors.	('EGFR', 'Gene', (179, 183))	('mutations', 'Var', (440, 449))	('associated', 'Reg', (129, 139))	('TERT', 'Gene', (507, 511))	('amplification', 'Var', (290, 303))	('PTEN', 'Gene', (434, 438))	('TERT', 'Gene', '7015', (507, 511))	('deletion', 'Var', (374, 382))	('phosphate and tensin homologue', 'Gene', '5728', (402, 432))	('2 A/B', 'Var', (357, 362))	('GBM', 'Phenotype', 'HP:0012174', (75, 78))	('telomerase reverse transcriptase', 'Gene', '7015', (473, 505))	('PTEN', 'Gene', '5728', (434, 438))	('overexpression', 'PosReg', (185, 199))	('EGFR', 'Gene', '1956', (179, 183))	('CDKN2A/B', 'Gene', (364, 372))	('PDGFR', 'Gene', (283, 288))	('epidermal growth factor receptor', 'Gene', (145, 177))	('PDGFR', 'Gene', '5159', (283, 288))	('Primary', 'Disease', (0, 7))	('patients', 'Species', '9606', (96, 104))	('GBM', 'Phenotype', 'HP:0012174', (18, 21))	('platelet-derived growth factor receptor', 'Gene', '5159', (242, 281))	('epidermal growth factor receptor', 'Gene', '1956', (145, 177))	('2 A/B', 'SUBSTITUTION', 'None', (357, 362))	('platelet-derived growth factor receptor', 'Gene', (242, 281))	('telomerase reverse transcriptase', 'Gene', (473, 505))	('CDKN2A/B', 'Gene', '1029;1030', (364, 372))
53767	32823792	Secondary GBM derives from lower-grade gliomas, affects the younger population, has a more favourable prognosis and is commonly related to loss of chromosome 19q, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation (on chromosome 10q26), TP53 and isocitrate dehydrogenase 1 (IDH1) mutations.	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('TP53', 'Gene', (253, 257))	('MGMT', 'Gene', (203, 207))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('TP53', 'Gene', '7157', (253, 257))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (163, 201))	('IDH1', 'Gene', (290, 294))	('loss', 'Var', (139, 143))	('GBM', 'Phenotype', 'HP:0012174', (10, 13))	('isocitrate dehydrogenase 1', 'Gene', (262, 288))	('isocitrate dehydrogenase 1', 'Gene', '3417', (262, 288))	('related', 'Reg', (128, 135))	('MGMT', 'Gene', '4255', (203, 207))	('O6-methylguanine-DNA-methyltransferase', 'Gene', (163, 201))	('Secondary GBM', 'Disease', (0, 13))	('gliomas', 'Disease', (39, 46))	('IDH1', 'Gene', '3417', (290, 294))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))	('mutations', 'Var', (296, 305))
53768	32823792	For instance, EGFR amplification is found in approximately half of GBM patients.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('amplification', 'Var', (19, 32))	('patients', 'Species', '9606', (71, 79))	('GBM', 'Disease', (67, 70))	('found', 'Reg', (36, 41))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
53769	32823792	Among its mutations, the most significant variant is EGFRvIII, which contributes to resistance to apoptotic stimuli and chemotherapy.	('resistance to apoptotic stimuli', 'MPA', (84, 115))	('significant', 'Reg', (30, 41))	('contributes', 'Reg', (69, 80))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('variant', 'Var', (42, 49))
53773	32823792	Consequently, its mutation supports excessive tumour proliferation.	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('mutation', 'Var', (18, 26))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
53776	32823792	MGMT promoter methylation silences the MGMT gene, which provides an improved survival rate due to the increased response to temozolomide.	('MGMT', 'Gene', (0, 4))	('silences', 'NegReg', (26, 34))	('survival rate', 'CPA', (77, 90))	('MGMT', 'Gene', '4255', (39, 43))	('temozolomide', 'Chemical', 'MESH:D000077204', (124, 136))	('methylation', 'Var', (14, 25))	('MGMT', 'Gene', (39, 43))	('MGMT', 'Gene', '4255', (0, 4))	('increased', 'PosReg', (102, 111))	('improved', 'PosReg', (68, 76))	('response to temozolomide', 'MPA', (112, 136))
53777	32823792	Perhaps one of the most acknowledged mutations, IDH1, facilitates better GBM description due to the consensus among histological, immunohistochemical, grading and molecular classifications.	('GBM description', 'CPA', (73, 88))	('IDH1', 'Gene', '3417', (48, 52))	('mutations', 'Var', (37, 46))	('IDH1', 'Gene', (48, 52))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('facilitates', 'PosReg', (54, 65))
53779	32823792	The IDH1 mutation impedes the DNA repair process of tumour cells, thereby increasing DNA damage and eventually inducing an apoptotic action.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('increasing', 'PosReg', (74, 84))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('DNA repair process', 'CPA', (30, 48))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('inducing', 'Reg', (111, 119))	('IDH1', 'Gene', (4, 8))	('DNA damage', 'MPA', (85, 95))	('impedes', 'NegReg', (18, 25))	('tumour', 'Disease', (52, 58))	('apoptotic action', 'MPA', (123, 139))
53781	32823792	Additionally, the IDH1 mutation represents the most reliable factor in diagnosing secondary GBM.	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('mutation', 'Var', (23, 31))	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', (18, 22))	('secondary GBM', 'Disease', (82, 95))
53783	32823792	The proneural type is frequently associated with the IDH1 mutation and promoter methylation, which results in a favourable response to chemo- and radiotherapy.	('IDH1', 'Gene', (53, 57))	('promoter methylation', 'Var', (71, 91))	('mutation', 'Var', (58, 66))	('IDH1', 'Gene', '3417', (53, 57))	('associated', 'Reg', (33, 43))	('proneural type', 'Disease', (4, 18))
53784	32823792	Nevertheless, the mesenchymal subgroup is linked to intratumoural necrosis and PTEN mutation, thereby yielding the highest invasive capacity and the poorest prognosis.	('tumour', 'Disease', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('necrosis', 'Disease', (66, 74))	('invasive', 'MPA', (123, 131))	('PTEN', 'Gene', '5728', (79, 83))	('necrosis', 'Disease', 'MESH:D009336', (66, 74))	('intratumoural necrosis', 'Phenotype', 'HP:0010885', (52, 74))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('PTEN', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
53789	32823792	These molecules include cancer effectors (e.g., mutant oncoproteins, oncogenic transcripts and microRNAs) that promote tumour development.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutant', 'Var', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('oncoproteins', 'Protein', (55, 67))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (119, 125))	('promote', 'PosReg', (111, 118))
53800	32823792	PTEN is usually localised either in the nucleus or in the cytoplasm of cells and the absence of nuclear PTEN has been linked to tumour aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (135, 149))	('absence', 'Var', (85, 92))	('linked', 'Reg', (118, 124))	('PTEN', 'Gene', '5728', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour aggressiveness', 'Disease', (128, 149))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', (104, 108))	('tumour aggressiveness', 'Disease', 'MESH:D009369', (128, 149))	('PTEN', 'Gene', '5728', (104, 108))
53813	32823792	Novel discoveries regarding chemoresistance-inducing miR might offer valuable opportunities for scientists to benefit from the reverse of this process: loading miR anti-sense nucleotides into exosomes to target GBM cells and convert their phenotype into a chemosensitive one.	('miR', 'Gene', (160, 163))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('GBM', 'Phenotype', 'HP:0012174', (211, 214))	('phenotype', 'MPA', (239, 248))	('convert', 'Reg', (225, 232))	('anti-sense nucleotides', 'Var', (164, 186))	('miR', 'Gene', '220972', (160, 163))
53821	32823792	showed that exosomes released by GBMs induce a reorganisation of both the cytoskeleton and the inflammatory properties of monocytes, which ultimately augments immune tolerance towards the tumour.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('GBM', 'Phenotype', 'HP:0012174', (33, 36))	('augments', 'NegReg', (150, 158))	('GBMs', 'Var', (33, 37))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))
53864	32823792	For example, EGFRvIII is associated with the 'classical' subtype of GBM, which tends to be highly tolerant to temozolomide, while the IDH1 mutation is linked to the 'proneural' subtype, which is associated with more favourable outcomes.	('mutation', 'Var', (139, 147))	('associated', 'Reg', (25, 35))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('tolerant to temozolomide', 'MPA', (98, 122))	('temozolomide', 'Chemical', 'MESH:D000077204', (110, 122))	('IDH1', 'Gene', (134, 138))	('IDH1', 'Gene', '3417', (134, 138))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('GBM', 'Disease', (68, 71))
53896	31614872	The majority of grade I is benign and counts almost 80% of all meningiomas.	('meningiomas', 'Disease', 'MESH:D008579', (63, 74))	('grade I', 'Var', (16, 23))	('meningiomas', 'Phenotype', 'HP:0002858', (63, 74))	('meningioma', 'Phenotype', 'HP:0002858', (63, 73))	('meningiomas', 'Disease', (63, 74))
53904	31614872	Circulating miRNAs were found in almost all human body fluids including CSF and they seem to be highly stable and resist extreme conditions Moreover, several studies have shown that deregulated levels of CSF miRNAs are associated with malignant tumors of CNS.	('human', 'Species', '9606', (44, 49))	('associated with', 'Reg', (219, 234))	('malignant tumors', 'Disease', (235, 251))	('malignant tumors', 'Disease', 'MESH:D009369', (235, 251))	('levels', 'MPA', (194, 200))	('deregulated', 'Var', (182, 193))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('malignant tumors of CNS', 'Phenotype', 'HP:0100836', (235, 258))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors of CNS', 'Phenotype', 'HP:0100006', (245, 258))
53917	31614872	Based on the fold-change, significance specificity, and uniqueness for various tumor types, we selected 9 miRNAs (let-7a, let-7b, miR-10a, miR-10b, miR-21-3p, miR-30e, miR-140, miR-196a and miR-196b) to be validated in CSF specimens of independent groups of patients (41 GBMs, 8 low-grade gliomas, 44 meningiomas, 12 brain metastases and 21 non-tumor patients).	('non-tumor', 'Disease', (341, 350))	('metastases', 'Disease', (323, 333))	('miR-196b', 'Gene', (190, 198))	('tumor', 'Disease', (345, 350))	('miR-10a', 'Gene', '406902', (130, 137))	('miR-21-3p', 'Gene', '406995', (148, 157))	('GBM', 'Disease', (271, 274))	('gliomas', 'Disease', (289, 296))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('miR-140', 'Gene', (168, 175))	('GBM', 'Disease', 'MESH:D005909', (271, 274))	('let-7b', 'Gene', (122, 128))	('patients', 'Species', '9606', (258, 266))	('miR-140', 'Gene', '406932', (168, 175))	('meningiomas', 'Disease', 'MESH:D008579', (301, 312))	('gliomas', 'Disease', 'MESH:D005910', (289, 296))	('miR-30e', 'Gene', (159, 166))	('miR-10a', 'Gene', (130, 137))	('tumor', 'Disease', (79, 84))	('let-7a', 'Var', (114, 120))	('miR-10b', 'Gene', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('meningioma', 'Phenotype', 'HP:0002858', (301, 311))	('non-tumor', 'Disease', 'MESH:C580335', (341, 350))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('miR-196b', 'Gene', '442920', (190, 198))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-10b', 'Gene', '406903', (139, 146))	('patients', 'Species', '9606', (351, 359))	('miR-30e', 'Gene', '407034', (159, 166))	('meningiomas', 'Phenotype', 'HP:0002858', (301, 312))	('gliomas', 'Phenotype', 'HP:0009733', (289, 296))	('miR-21-3p', 'Gene', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('miR-196a', 'Var', (177, 185))	('meningiomas', 'Disease', (301, 312))	('metastases', 'Disease', 'MESH:D009362', (323, 333))	('let-7b', 'Gene', '406884', (122, 128))
53939	31614872	Specifically, our results indicate that let-7c, miR-140 and miR-196a show significantly different levels in glioblastoma and low-grade glioma patients' CSF.	('glioma', 'Disease', (135, 141))	('miR-196a', 'Var', (60, 68))	('miR-140', 'Gene', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('let-7c', 'Gene', (40, 46))	('glioblastoma', 'Disease', (108, 120))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('patients', 'Species', '9606', (142, 150))	('let-7c', 'Gene', '406885', (40, 46))	('miR-140', 'Gene', '406932', (48, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
53944	31614872	Among all, miR-196a and miR-196b showed increased expression levels in GBMs relative to both anaplastic astrocytomas and normal brain tissues, which is consistent with our results since both miRNAs had significantly higher levels in CSFs from GBM patients than from non-tumor donors.	('levels', 'MPA', (223, 229))	('CSFs', 'MPA', (233, 237))	('GBM', 'Disease', 'MESH:D005909', (243, 246))	('miR-196b', 'Gene', (24, 32))	('miR-196b', 'Gene', '442920', (24, 32))	('astrocytomas', 'Disease', 'MESH:D001254', (104, 116))	('GBM', 'Disease', (71, 74))	('expression levels', 'MPA', (50, 67))	('patients', 'Species', '9606', (247, 255))	('higher', 'PosReg', (216, 222))	('GBM', 'Disease', (243, 246))	('astrocytomas', 'Disease', (104, 116))	('increased', 'PosReg', (40, 49))	('non-tumor', 'Disease', (266, 275))	('miR-196a', 'Var', (11, 19))	('GBM', 'Disease', 'MESH:D005909', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('non-tumor', 'Disease', 'MESH:C580335', (266, 275))
53946	31614872	Another two studies described increasing tissue expression levels of miR-196a upon progression of low-grade gliomas to the GBM.	('gliomas', 'Disease', 'MESH:D005910', (108, 115))	('GBM', 'Disease', 'MESH:D005909', (123, 126))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('gliomas', 'Disease', (108, 115))	('increasing', 'PosReg', (30, 40))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('miR-196a', 'Var', (69, 77))	('GBM', 'Disease', (123, 126))	('tissue expression levels', 'MPA', (41, 65))
53993	31216715	In addition to this, there are weak emissions from the NO-gamma band (226 nm, 236 nm, 247 nm 258 nm) and OH radical (309 nm).	('309', 'Var', (117, 120))	('emissions', 'MPA', (36, 45))	('OH radical', 'Chemical', '-', (105, 115))	('226', 'Var', (70, 73))
54002	31216715	Flow cytometry analysis showed that the number of CD86 (M1 macrophage marker)-positive cells was significantly higher in PMA treated plasma-treated macrophages than the CD163 (M2 macrophage marker) population when compared with only PMA treated groups (Figure 2C,D).	('PMA', 'Chemical', 'MESH:D013755', (121, 124))	('PMA', 'Var', (121, 124))	('CD163', 'Gene', '9332', (169, 174))	('higher', 'PosReg', (111, 117))	('PMA', 'Chemical', 'MESH:D013755', (233, 236))	('CD86', 'Gene', (50, 54))	('CD163', 'Gene', (169, 174))
54015	31216715	On the other hand, MTT assays showed that a single plasma exposure had the least effect on cell death in U251MG and U87MG solid cancer cells (Figure 3A,B).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('U251MG', 'CellLine', 'CVCL:0021', (105, 111))	('cell death', 'CPA', (91, 101))	('MTT', 'Chemical', 'MESH:C070243', (19, 22))	('U87MG', 'CellLine', 'CVCL:0022', (116, 121))	('U87MG', 'Var', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
54024	31216715	Plasma-activated macrophages directly affected the cell viability and ATP content of U251MG and U87MG cells compared with those observed in the co-culture condition with supernatant medium (Figure 3F,G).	('U87MG', 'Var', (96, 101))	('U251MG', 'Var', (85, 91))	('U251MG', 'CellLine', 'CVCL:0021', (85, 91))	('cell viability', 'CPA', (51, 65))	('affected', 'Reg', (38, 46))	('ATP', 'Chemical', 'MESH:D000255', (70, 73))	('ATP', 'MPA', (70, 73))	('U87MG', 'CellLine', 'CVCL:0022', (96, 101))
54033	31216715	Our data demonstrate that differentiation of human macrophages into pro-inflammatory M1 with plasma leads to apoptotic cell death through inducing genes involved in DNA damage checkpoint and cell cycle arrest which could be capable of inhibiting glioma cell growth for anti-tumor approaches.	('inducing', 'PosReg', (138, 146))	('apoptotic cell death', 'CPA', (109, 129))	('inhibiting', 'NegReg', (235, 245))	('glioma', 'Disease', (246, 252))	('arrest', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('human', 'Species', '9606', (45, 50))	('genes', 'Var', (147, 152))	('cell cycle', 'CPA', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('arrest', 'Disease', 'MESH:D006323', (202, 208))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))
54051	31216715	Accordingly, we observed protein expression of epithelial marker E-cadherin was upregulated in U251MG cells in the co-culture condition.	('U251MG', 'CellLine', 'CVCL:0021', (95, 101))	('U251MG', 'Var', (95, 101))	('protein expression', 'MPA', (25, 43))	('upregulated', 'PosReg', (80, 91))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))
54052	31216715	Also, the protein expression of N-cadherin and Vimentin, mesenchymal markers, were downregulated in U251MG cells after co-culture with plasma-stimulated macrophages (Figure 5F).	('protein expression', 'MPA', (10, 28))	('N-cadherin', 'Protein', (32, 42))	('Vimentin', 'Gene', '7431', (47, 55))	('downregulated', 'NegReg', (83, 96))	('U251MG', 'Var', (100, 106))	('U251MG', 'CellLine', 'CVCL:0021', (100, 106))	('Vimentin', 'Gene', (47, 55))
54069	31216715	Moreover, we have extracted the patient prognosis survival data from TCGA survival database and confirmed that high expression of TNF-alpha improves glioma patient's survival (Figure 7G).	('TNF-alpha', 'Gene', (130, 139))	('high expression', 'Var', (111, 126))	('glioma', 'Disease', (149, 155))	('improves', 'PosReg', (140, 148))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))	('patient', 'Species', '9606', (32, 39))	('patient', 'Species', '9606', (156, 163))
54079	31216715	Here, we found that cold plasma exposure could stimulate the expression of both CD86 and CD163 markers in THP-1 cells; however, CD86 expression was significantly higher than CD163 expression (Figure 2).	('CD163', 'Gene', '9332', (89, 94))	('THP-1', 'Gene', '2736', (106, 111))	('expression', 'MPA', (133, 143))	('THP-1', 'Gene', (106, 111))	('CD163', 'Gene', '9332', (174, 179))	('higher', 'PosReg', (162, 168))	('stimulate', 'PosReg', (47, 56))	('CD86', 'Var', (128, 132))	('CD163', 'Gene', (89, 94))	('CD86', 'Gene', (80, 84))	('CD163', 'Gene', (174, 179))	('expression', 'MPA', (61, 71))
54109	31216715	THP-1, U251MG and U87MG cells were obtained from Korean Cell Line Bank (Seoul, Korea) and cultured as per the supplier's instructions.	('THP-1', 'Gene', (0, 5))	('U251MG', 'Var', (7, 13))	('U251MG', 'CellLine', 'CVCL:0021', (7, 13))	('U87MG', 'CellLine', 'CVCL:0022', (18, 23))	('U87MG', 'Var', (18, 23))	('THP-1', 'Gene', '2736', (0, 5))
54137	31216715	Tissue sections were immunostained overnight at 4  C with the E-cadherin antibody (1:400; abcam, Cambridge, UK), N-cadherin (1:400; abcam) antibody.	('E-cadherin', 'Gene', '999', (62, 72))	('1:400', 'Var', (125, 130))	('E-cadherin', 'Gene', (62, 72))
54164	31137689	Tumor debulking is usually referred to as "maximal safe resection", implying a high risk of cognitive loss following the surgical procedure and incomplete removal of the tumor.	('cognitive loss', 'Phenotype', 'HP:0100543', (92, 106))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cognitive loss', 'Disease', 'MESH:D003072', (92, 106))	('tumor', 'Disease', (170, 175))	('cognitive loss', 'Disease', (92, 106))	('Tumor', 'Var', (0, 5))
54176	31137689	It is believed that all these proteins have a pivotal role in determining BBB function and a specific work performed on claudin-5 demonstrated that inhibiting its expression increased BBB permeability for molecules as large as 800 kDa.	('BBB permeability for molecules', 'MPA', (184, 214))	('claudin-5', 'Gene', (120, 129))	('inhibiting', 'Var', (148, 158))	('expression', 'MPA', (163, 173))	('claudin-5', 'Gene', '7122', (120, 129))	('increased', 'PosReg', (174, 183))
54203	31137689	More importantly, they showed that the osmotic BBB opening could induce caveolae-mediated transcytosis of the carriers while having a low toxicity profile.	('osmotic', 'Var', (39, 46))	('toxicity', 'Disease', 'MESH:D064420', (138, 146))	('opening', 'Disease', 'MESH:D005597', (51, 58))	('induce', 'Reg', (65, 71))	('toxicity', 'Disease', (138, 146))	('opening', 'Disease', (51, 58))	('caveolae-mediated transcytosis', 'CPA', (72, 102))
54210	31137689	The study concluded that high acoustic pressure and microbubble doses could cause brain hemorrhage, tissue necrosis, cell apoptosis, astroglial activation, and glial scarring.	('brain hemorrhage', 'Phenotype', 'HP:0001342', (82, 98))	('astroglial activation', 'CPA', (133, 154))	('microbubble doses', 'Var', (52, 69))	('necrosis', 'Disease', (107, 115))	('cell apoptosis', 'CPA', (117, 131))	('necrosis', 'Disease', 'MESH:D009336', (107, 115))	('brain hemorrhage', 'Disease', (82, 98))	('cause', 'Reg', (76, 81))	('scarring', 'Phenotype', 'HP:0100699', (166, 174))	('tissue necrosis', 'Phenotype', 'HP:0010885', (100, 115))	('glial scarring', 'CPA', (160, 174))	('brain hemorrhage', 'Disease', 'MESH:D020300', (82, 98))
54229	31137689	Different studies in the last decades demonstrated that, compared to the patients that received only placebo treatment, Gliadel  was efficient in increasing, by several weeks, the overall survival of the patients.	('patients', 'Species', '9606', (204, 212))	('increasing', 'PosReg', (146, 156))	('Gliadel', 'Chemical', 'MESH:C574855', (120, 127))	('Gliadel', 'Var', (120, 127))	('patients', 'Species', '9606', (73, 81))
54238	31137689	In an attempt to define the patient population that more likely could benefit from Gliadel , the group of Urbschat demonstrated that high expression of miRNA-181d is associated with low overall and progression-free survival of the patients, even though more investigations are necessary to understand the mechanism of this phenomenon.	('overall', 'CPA', (186, 193))	('miRNA-181d', 'Var', (152, 162))	('patients', 'Species', '9606', (231, 239))	('low', 'NegReg', (182, 185))	('Gliadel', 'Chemical', 'MESH:C574855', (83, 90))	('patient', 'Species', '9606', (28, 35))	('progression-free survival', 'CPA', (198, 223))	('patient', 'Species', '9606', (231, 238))
54247	31137689	CED was investigated for the delivery of various agents, such as conventional chemotherapy, cytotoxin-ligand conjugates targeting cell surface receptors, antisense oligonucleotides, and nanovectors.	('antisense oligonucleotides', 'Var', (154, 180))	('oligonucleotides', 'Chemical', 'MESH:D009841', (164, 180))	('CED', 'Disease', 'MESH:D003966', (0, 3))	('CED', 'Disease', (0, 3))
54265	31137689	The antibody for TfR OX26 was shown to favor BBB transcytosis of therapeutics and nanoparticles, but recent evidence contradicted this data, highlighting the need of more research to understand this phenomenon.	('favor', 'PosReg', (39, 44))	('BBB transcytosis of', 'MPA', (45, 64))	('TfR', 'Gene', (17, 20))	('antibody', 'Var', (4, 12))	('TfR', 'Gene', '7037', (17, 20))
54275	31137689	After intravenous injection, it was shown to increase BBB permeability probably by increasing the size-selective pathway, and enhancing the delivery of antisense oligonucleotides with no toxic effects.	('antisense', 'Var', (152, 161))	('enhancing', 'PosReg', (126, 135))	('BBB permeability', 'MPA', (54, 70))	('size-selective pathway', 'Pathway', (98, 120))	('delivery', 'MPA', (140, 148))	('oligonucleotides', 'Chemical', 'MESH:D009841', (162, 178))	('increasing', 'PosReg', (83, 93))	('increase', 'PosReg', (45, 53))
54278	31137689	Intravenous treatments with lysophosphatidic acid can transiently (20 min post administration) increase BBB permeability for small and large molecules including Gd-DTPA, the infrared dye 800cwPEG, and Rhodamine 800 (often used to measure the activity of the efflux pump P-gp).	('PEG', 'Chemical', 'MESH:D011092', (192, 195))	('BBB permeability for', 'MPA', (104, 124))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (28, 49))	('increase', 'PosReg', (95, 103))	('Gd-DTPA', 'MPA', (161, 168))	('lysophosphatidic acid', 'Var', (28, 49))	('Gd-DTPA', 'Chemical', 'MESH:D019786', (161, 168))	('Rhodamine 800', 'Chemical', 'MESH:C105720', (201, 214))
54281	31137689	This ion is at the base of the TJ ultrastructure and when released in the cell cytoplasm can affect their tightness probably by increasing the expression of e-NOS and n-NOS with the parallel decrease in nuclear expression of the transcription factor ZONAB and decrease of the mRNA and protein expression of claudin-5 and occludin (Figure 6).	('claudin-5', 'Gene', '7122', (307, 316))	('n-NOS', 'Var', (167, 172))	('increasing', 'PosReg', (128, 138))	('expression', 'MPA', (143, 153))	('occludin', 'Gene', '100506658', (321, 329))	('decrease', 'NegReg', (260, 268))	('affect', 'Reg', (93, 99))	('tightness', 'Disease', 'MESH:C536920', (106, 115))	('nuclear expression', 'MPA', (203, 221))	('ZONAB', 'Gene', (250, 255))	('occludin', 'Gene', (321, 329))	('e-NOS', 'Gene', '4846', (157, 162))	('ZONAB', 'Gene', '8531', (250, 255))	('claudin-5', 'Gene', (307, 316))	('tightness', 'Disease', (106, 115))	('e-NOS', 'Gene', (157, 162))	('decrease', 'NegReg', (191, 199))
54295	31137689	The group of Huang demonstrated that brain cancer overexpressed secreted protein acidic and rich in cysteine (SPARC) and GP-60, increasing the albumin endothelial transcytosis and cancer uptake, respectively (Figure 7).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('brain cancer', 'Phenotype', 'HP:0030692', (37, 49))	('cancer', 'Disease', (43, 49))	('secreted protein acidic and rich in cysteine', 'Gene', '6678', (64, 108))	('GP-60', 'Var', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('brain cancer', 'Disease', (37, 49))	('overexpressed', 'PosReg', (50, 63))	('albumin endothelial', 'MPA', (143, 162))	('SPARC', 'Gene', '6678', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('increasing', 'PosReg', (128, 138))	('brain cancer', 'Disease', 'MESH:D001932', (37, 49))	('SPARC', 'Gene', (110, 115))	('cancer', 'Disease', (180, 186))
54304	31137689	In this scenario, HEK 293 EBNA modified to release endostatin were encapsulated in an alginate scaffold prior to brain implantation, inhibiting in vivo GBM-induced angiogenesis process, while polymeric biodegradable scaffolds seeded with stem cells overexpressing secretable tumor necrosis factor apoptosis-inducing ligand were implanted to inhibit brain tumor growth.	('inhibiting', 'NegReg', (133, 143))	('tumor', 'Disease', (275, 280))	('EBNA', 'Chemical', '-', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('inhibit', 'NegReg', (341, 348))	('HEK 293', 'CellLine', 'CVCL:0045', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('GBM-induced angiogenesis process', 'CPA', (152, 184))	('modified', 'Var', (31, 39))	('brain tumor', 'Phenotype', 'HP:0030692', (349, 360))	('endostatin', 'Gene', '80781', (51, 61))	('brain tumor', 'Disease', (349, 360))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('brain tumor', 'Disease', 'MESH:D001932', (349, 360))	('alginate', 'Chemical', 'MESH:D000464', (86, 94))	('endostatin', 'Gene', (51, 61))	('necrosis', 'Disease', 'MESH:D009336', (281, 289))	('tumor', 'Disease', (355, 360))	('necrosis', 'Disease', (281, 289))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
54309	31137689	Engineering efforts have yielded several AAV variants that can efficiently transduce the CNS via systemic delivery in adult mice.	('variants', 'Var', (45, 53))	('AAV', 'Gene', (41, 44))	('transduce', 'Reg', (75, 84))	('mice', 'Species', '10090', (124, 128))
54322	29720725	miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158.	('inhibition', 'NegReg', (141, 151))	('rat', 'Species', '10116', (70, 73))	('G protein coupled-receptor (GPR) 158', 'Gene', '57512', (155, 191))	('CCND1', 'Gene', (98, 103))	('miR-449a', 'Var', (0, 8))	('suppressing', 'NegReg', (108, 119))	('downregulation', 'NegReg', (80, 94))	('neural phenotypes', 'CPA', (120, 137))	('inhibiting', 'NegReg', (40, 50))
54323	29720725	GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('lower', 'NegReg', (146, 151))	('promotes', 'PosReg', (7, 15))	('GPR158', 'Var', (0, 6))	('glioblastoma', 'Disease', (242, 254))	('astrocytomas', 'Disease', (166, 178))	('induces', 'Reg', (53, 60))	('apoptosis', 'CPA', (61, 70))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (126, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (242, 254))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('IDH', 'Gene', (228, 231))	('glioma', 'Disease', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('glioma', 'Disease', 'MESH:D005910', (137, 143))	('IDH', 'Gene', (155, 158))	('glioma', 'Disease', (16, 22))	('astrocytomas', 'Disease', 'MESH:D001254', (166, 178))	('oligodendrogliomas', 'Disease', (126, 144))	('IDH', 'Gene', '3417', (228, 231))	('glioma', 'Disease', 'MESH:D005910', (16, 22))	('malignant form of glioma', 'Phenotype', 'HP:0012174', (202, 226))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('IDH', 'Gene', '3417', (155, 158))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('glioma', 'Disease', (220, 226))	('glioblastoma', 'Disease', 'MESH:D005909', (242, 254))
54324	29720725	The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.	('GPR158', 'Var', (128, 134))	('GPR158', 'Gene', (19, 25))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('patient', 'Species', '9606', (62, 69))	('human', 'Species', '9606', (162, 167))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('gliomas', 'Disease', (168, 175))
54326	29720725	The identification of mutations in two isocitrate dehydrogenase genes, IDH1 and IDH2, in gliomas was a major discovery, leading to a biomarker-defined glioma classification, IDH and ATRX-mutant astrocytomas and glioblastomas and IDH-mutant 1p/19q codeleted oligodendrogliomas.	('glioma', 'Disease', (268, 274))	('gliomas', 'Disease', (268, 275))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('IDH2', 'Gene', '3418', (80, 84))	('leading to', 'Reg', (120, 130))	('ATRX', 'Gene', (182, 186))	('IDH', 'Gene', (71, 74))	('glioma', 'Disease', 'MESH:D005910', (268, 274))	('ATRX', 'Gene', '546', (182, 186))	('astrocytomas', 'Disease', 'MESH:D001254', (194, 206))	('IDH', 'Gene', (174, 177))	('oligodendrogliomas', 'Disease', (257, 275))	('gliomas', 'Disease', 'MESH:D005910', (268, 275))	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('glioblastomas', 'Disease', (211, 224))	('IDH', 'Gene', (80, 83))	('IDH1', 'Gene', (71, 75))	('IDH', 'Gene', (229, 232))	('gliomas', 'Disease', (89, 96))	('glioma', 'Disease', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('IDH', 'Gene', '3417', (71, 74))	('rat', 'Species', '10116', (45, 48))	('IDH', 'Gene', '3417', (174, 177))	('glioblastomas', 'Disease', 'MESH:D005909', (211, 224))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (268, 275))	('mutations', 'Var', (22, 31))	('IDH', 'Gene', '3417', (80, 83))	('IDH1', 'Gene', '3417', (71, 75))	('IDH', 'Gene', '3417', (229, 232))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('glioma', 'Disease', (151, 157))	('astrocytomas', 'Disease', (194, 206))	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (257, 275))	('glioblastomas', 'Phenotype', 'HP:0012174', (211, 224))	('IDH2', 'Gene', (80, 84))
54328	29720725	The only prognostic biomarker in GBM is the methylation of MGMT but is has no diagnostic value.	('GBM', 'Disease', (33, 36))	('MGMT', 'Gene', (59, 63))	('methylation', 'Var', (44, 55))	('MGMT', 'Gene', '4255', (59, 63))
54329	29720725	To identify additional biomarkers of diagnostic and/or prognostic value, we used a mouse model of intrinsic brain tumours generated by Cre-mediated inactivation of Ptenlox/lox and p53lox/lox genes or of Rblox/lox and p53lox/lox genes in the neurogenic cell population of the subventricular zone (SVZ) of the brain, previously in-depth molecularly characterized.	('lox', 'Gene', '16948', (205, 208))	('lox', 'Gene', '16948', (220, 223))	('inactivation', 'Var', (148, 160))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('lox', 'Gene', '16948', (172, 175))	('lox', 'Gene', (205, 208))	('lox', 'Gene', '16948', (187, 190))	('intrinsic brain tumours', 'Disease', (98, 121))	('intrinsic brain tumours', 'Disease', 'MESH:D020919', (98, 121))	('lox', 'Gene', '16948', (209, 212))	('lox', 'Gene', (172, 175))	('lox', 'Gene', (220, 223))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('lox', 'Gene', (187, 190))	('rat', 'Species', '10116', (126, 129))	('lox', 'Gene', (209, 212))	('mouse', 'Species', '10090', (83, 88))	('lox', 'Gene', '16948', (168, 171))	('lox', 'Gene', '16948', (224, 227))	('lox', 'Gene', '16948', (183, 186))	('brain tumours', 'Phenotype', 'HP:0030692', (108, 121))	('lox', 'Gene', (168, 171))	('lox', 'Gene', (224, 227))	('lox', 'Gene', (183, 186))	('brain tumour', 'Phenotype', 'HP:0030692', (108, 120))
54334	29720725	It was selected for subsequent analysis as a tumour suppressive role of miR-449a has been suggested in a number of malignancies, most notably in prostate cancer by targeting classical proto-oncogenes CCND1, c-Myc and HDAC-1.	('miR-449a', 'Var', (72, 80))	('CCND1', 'Gene', (200, 205))	('c-Myc', 'Gene', (207, 212))	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('HDAC-1', 'Gene', '3065', (217, 223))	('c-Myc', 'Gene', '4609', (207, 212))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('targeting', 'Reg', (164, 173))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('prostate cancer', 'Disease', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('malignancies', 'Disease', (115, 127))	('tumour', 'Disease', (45, 51))	('HDAC-1', 'Gene', (217, 223))
54336	29720725	A role of miR-449a targeting MYC-associated zinc finger proteins has been suggested in glioblastoma.	('MYC-associated zinc finger proteins', 'Protein', (29, 64))	('glioblastoma', 'Disease', (87, 99))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('miR-449a', 'Var', (10, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))
54339	29720725	miR-449a targets a site in the 3' UTR of the CCND1 transcript, and miR-449a significantly reduces Cyclin D1 protein in PC-3 cells.	('CCND1', 'Gene', (45, 50))	('Cyclin D1', 'Gene', '595', (98, 107))	('reduces', 'NegReg', (90, 97))	('Cyclin D1', 'Gene', (98, 107))	('miR-449a', 'Var', (67, 75))	('PC-3', 'CellLine', 'CVCL:0035', (119, 123))
54340	29720725	Here, we identify a new target of miR-449a, the G-protein coupled receptor 158 (GPR158), a member of a large group of cell surface proteins exerting a range of diverse cellular functions.	('G-protein coupled receptor 158', 'Gene', '57512', (48, 78))	('GPR158', 'Gene', (80, 86))	('miR-449a', 'Var', (34, 42))	('G-protein coupled receptor 158', 'Gene', (48, 78))
54344	29720725	Here we show a target dependent effect of miR-449a, inhibiting growth and migration by downregulating CCND1 and suppressing neural differentiation by inhibiting GPR158.	('neural differentiation', 'CPA', (124, 146))	('inhibiting', 'NegReg', (150, 160))	('downregulating', 'NegReg', (87, 101))	('rat', 'Species', '10116', (77, 80))	('suppressing', 'NegReg', (112, 123))	('inhibiting', 'NegReg', (52, 62))	('CCND1', 'Gene', (102, 107))	('GPR158', 'Gene', (161, 167))	('miR-449a', 'Var', (42, 50))
54345	29720725	In human gliomas, high levels of miR-449a and low expression of GPR158 are associated with higher malignancy and poorer survival.	('low', 'NegReg', (46, 49))	('poorer', 'NegReg', (113, 119))	('gliomas', 'Disease', (9, 16))	('higher', 'PosReg', (91, 97))	('GPR158', 'Gene', (64, 70))	('human', 'Species', '9606', (3, 8))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('miR-449a', 'Var', (33, 41))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('expression', 'MPA', (50, 60))	('malignancy', 'Disease', (98, 108))
54352	29720725	miR-449a is enriched in astrocytes, whereas miR-219 and miR-338 are essential for oligodendrocyte differentiation.	('miR-338', 'Gene', '442906', (56, 63))	('miR-338', 'Gene', (56, 63))	('miR-219', 'Gene', (44, 51))	('miR-219', 'Gene', '407002', (44, 51))	('miR-449a', 'Var', (0, 8))
54353	29720725	Considering that miR-449a is involved in the regulatory network of RB and P53, it was a promising candidate and most likely relevant to the brain tumour phenotype.	('P53', 'Gene', (74, 77))	('brain tumour', 'Disease', (140, 152))	('P53', 'Gene', '7157', (74, 77))	('RB', 'Disease', 'MESH:D012175', (67, 69))	('brain tumour', 'Disease', 'MESH:D001932', (140, 152))	('brain tumour', 'Phenotype', 'HP:0030692', (140, 152))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('miR-449a', 'Var', (17, 25))	('involved', 'Reg', (29, 37))
54354	29720725	To identify DE genes between the two tumour types, we retrieved the top 1000 DE-genes ranked by logarithmic fold change (glioma/PNET) from our published Exon Microarray dataset (GSE42515), and matched them against the 101 putative targets, following permissive filtration criteria: (i) miR-449a is highly expressed in PNETs, expecting downregulated targets; (ii) DE-genes with p > 0.05 were also considered to minimize false negative calls.	('miR-449a', 'Var', (286, 294))	('downregulated', 'NegReg', (335, 348))	('tumour', 'Disease', (37, 43))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('rat', 'Species', '10116', (265, 268))	('glioma', 'Disease', (121, 127))
54356	29720725	To identify candidates regulated by miR-449a, we analysed Rb/p53 (miR-449ahigh), Pten/p53 (miR-449alow), and Rb/p53antagomir mBTSCs (miR-449alow), and selected those targets which were upregulated in miR-449alow mBTSCs.	('mir', 'Gene', (121, 124))	('Rb/p53', 'Gene', '7157', (109, 115))	('mir', 'Gene', '220972', (121, 124))	('Rb/p53', 'Gene', (109, 115))	('upregulated', 'PosReg', (185, 196))	('Rb/p53', 'Gene', '7157', (58, 64))	('Rb/p53', 'Gene', (58, 64))	('miR-449alow', 'Var', (200, 211))
54360	29720725	We then confirmed a functional link between miR-449a and its target Gpr158 by two functionally independent approaches: a modified hybrid Argonaute 2 (AGO2) pulldown assay and a luciferase reporter assay.	('AGO2', 'Gene', (150, 154))	('miR-449a', 'Var', (44, 52))	('Argonaute 2', 'Gene', '27161', (137, 148))	('AGO2', 'Gene', '27161', (150, 154))	('Argonaute 2', 'Gene', (137, 148))
54363	29720725	2e), demonstrating direct regulation of Gpr158 expression by miR-449a.	('rat', 'Species', '10116', (12, 15))	('miR-449a', 'Var', (61, 69))	('regulation', 'Reg', (26, 36))	('expression', 'MPA', (47, 57))	('Gpr158', 'Gene', (40, 46))
54370	29720725	To test if these were miR-449a-mediated effects, miR-449a antagomir or mimics were introduced into mBTSCs.	('miR-449a', 'Var', (49, 57))	('mir', 'Gene', (64, 67))	('mir', 'Gene', '220972', (64, 67))
54372	29720725	In a 3D collagen matrix tumour invasion assay, inhibition of miR-449a expression in Rb/p53 cells increased cell migration, whereas miR-449 mimics in Pten/p53 cells slowed down migration (Fig.	('Rb/p53', 'Gene', '7157', (84, 90))	('rat', 'Species', '10116', (179, 182))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('increased', 'PosReg', (97, 106))	('rat', 'Species', '10116', (115, 118))	('migration', 'CPA', (176, 185))	('slowed down', 'NegReg', (164, 175))	('inhibition', 'Var', (47, 57))	('Rb/p53', 'Gene', (84, 90))	('miR-449', 'Gene', '723868', (61, 68))	('miR-449', 'Gene', (131, 138))	('cell migration', 'CPA', (107, 121))	('expression', 'MPA', (70, 80))	('tumour invasion', 'Disease', 'MESH:D009361', (24, 39))	('miR-449', 'Gene', (61, 68))	('miR-449', 'Gene', '723868', (131, 138))	('tumour invasion', 'Disease', (24, 39))
54374	29720725	In conclusion, in stem cell medium, miR-449ahigh mBTSC grow slower than miR-449alow mBTSC, suggesting a suppressive role of miR-449a on proliferation, migration and invasion.	('migration', 'CPA', (151, 160))	('miR-449ahigh', 'Var', (36, 48))	('slower', 'NegReg', (60, 66))	('rat', 'Species', '10116', (154, 157))	('invasion', 'CPA', (165, 173))	('rat', 'Species', '10116', (143, 146))	('grow', 'CPA', (55, 59))	('suppressive', 'NegReg', (104, 115))	('proliferation', 'CPA', (136, 149))
54375	29720725	First we confirmed the known effect of miR-449a to downregulate Ccnd1.	('Ccnd1', 'Gene', '595', (64, 69))	('downregulate', 'NegReg', (51, 63))	('Ccnd1', 'Gene', (64, 69))	('miR-449a', 'Var', (39, 47))
54383	29720725	Unexpectedly, overexpression of Gpr158 in Rb/p53 and Pten/p53 mBTSC, resulted in slower growth of both cell lines, whereby Pten/p53 cells always proliferated and migrated faster than Rb/p53 cells (Figs.	('growth', 'MPA', (88, 94))	('slower', 'NegReg', (81, 87))	('Rb/p53', 'Gene', (183, 189))	('migrated', 'CPA', (162, 170))	('rat', 'Species', '10116', (152, 155))	('rat', 'Species', '10116', (165, 168))	('proliferated', 'CPA', (145, 157))	('Rb/p53', 'Gene', '7157', (42, 48))	('Pten/p53', 'Gene', (53, 61))	('Gpr158', 'Var', (32, 38))	('Rb/p53', 'Gene', (42, 48))	('faster', 'PosReg', (171, 177))	('overexpression', 'PosReg', (14, 28))	('Rb/p53', 'Gene', '7157', (183, 189))
54384	29720725	4g-i), i.e., Gpr158 further reduces proliferation and migration.	('reduces', 'NegReg', (28, 35))	('rat', 'Species', '10116', (43, 46))	('rat', 'Species', '10116', (57, 60))	('Gpr158', 'Var', (13, 19))	('proliferation', 'CPA', (36, 49))
54385	29720725	This is seemingly incompatible with the finding that miR-449a inhibits Gpr158, as both miR-449ahigh Rb/p53 and miR-449alow Pten/p53 cells show further reduction of proliferation, i.e., in the same direction as miR-449a treatment.	('proliferation', 'CPA', (164, 177))	('miR-449alow', 'Var', (111, 122))	('inhibits', 'NegReg', (62, 70))	('rat', 'Species', '10116', (171, 174))	('miR-449ahigh', 'Var', (87, 99))	('Rb/p53', 'Gene', '7157', (100, 106))	('Rb/p53', 'Gene', (100, 106))	('reduction', 'NegReg', (151, 160))
54387	29720725	Indeed siRNA knock-down of Gpr158 in naive, adherently growing murine neural stem/progenitor cells (mNSPC) (Supplementary Figure 1B) showed global reduction of expression levels of the majority of genes associated with neural differentiation/neurogenesis (Supplementary Figure 1C), of which Nrp1, S100alpha6 and Tnr were significant.	('knock-down', 'Var', (13, 23))	('Gpr158', 'Gene', (27, 33))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (108, 131))	('Nrp1', 'Gene', '18186', (291, 295))	('expression levels', 'MPA', (160, 177))	('Supplementary Figure 1B', 'Disease', (108, 131))	('reduction', 'NegReg', (147, 156))	('Nrp1', 'Gene', (291, 295))	('murine', 'Species', '10090', (63, 69))
54389	29720725	There is significant up-regulation of the proneural markers Map2, Sox2, and Pdgfra, and of three extracellular matrix-associated genes Filamin A (Flna), Netrin 1 (Ntn1), and Pleiotrophin (Ptn), and downregulation upon Gpr158 knock-down (Fig.	('up-regulation', 'PosReg', (21, 34))	('Netrin 1', 'Gene', (153, 161))	('Flna', 'Gene', '2316', (146, 150))	('Ptn', 'Gene', '5764', (188, 191))	('Netrin 1', 'Gene', '9423', (153, 161))	('knock-down', 'Var', (225, 235))	('Pleiotrophin', 'Gene', '5764', (174, 186))	('Ntn1', 'Gene', '9423', (163, 167))	('Flna', 'Gene', (146, 150))	('Filamin A', 'Gene', '2316', (135, 144))	('Map2', 'Gene', (60, 64))	('Pdgfra', 'Gene', (76, 82))	('Filamin A', 'Gene', (135, 144))	('Ntn1', 'Gene', (163, 167))	('Ptn', 'Gene', (188, 191))	('Pleiotrophin', 'Gene', (174, 186))	('Gpr158', 'Gene', (218, 224))	('downregulation', 'NegReg', (198, 212))
54391	29720725	4l), whilst Gpr158 siRNA knockdown increased proliferation (p < 0.05, Figs.	('rat', 'Species', '10116', (52, 55))	('increased', 'PosReg', (35, 44))	('proliferation', 'CPA', (45, 58))	('knockdown', 'Var', (25, 34))	('Gpr158', 'Gene', (12, 18))
54393	29720725	Consistent with this observation, also GPR158 knockdown in three human GBM primary cultures significantly reduced apoptosis (Fig.	('human', 'Species', '9606', (65, 70))	('GPR158', 'Gene', (39, 45))	('knockdown', 'Var', (46, 55))	('reduced', 'NegReg', (106, 113))	('apoptosis', 'CPA', (114, 123))
54394	29720725	4r), and in keeping, overexpression of GPR158 in two human GBM primary cultures induced apoptosis (Fig.	('induced', 'Reg', (80, 87))	('apoptosis', 'CPA', (88, 97))	('GPR158', 'Var', (39, 45))	('overexpression', 'PosReg', (21, 35))	('human', 'Species', '9606', (53, 58))
54397	29720725	We identified that miR-449a has distinct, target-dependent (i.e., CCND1 and GPR158) effects on cellular growth, migration and differentiation.	('cellular growth', 'CPA', (95, 110))	('differentiation', 'CPA', (126, 141))	('rat', 'Species', '10116', (115, 118))	('miR-449a', 'Var', (19, 27))	('migration', 'CPA', (112, 121))	('effects', 'Reg', (84, 91))	('GPR158', 'Gene', (76, 82))
54398	29720725	Under growth-promoting conditions in EGF, FGF enriched serum-free medium, miR-449a suppresses Ccnd1 and inhibits migration and invasion, suggestive of a tumour-suppressive effect.	('tumour', 'Disease', (153, 159))	('Ccnd1', 'Gene', (94, 99))	('inhibits', 'NegReg', (104, 112))	('miR-449a', 'Var', (74, 82))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('rat', 'Species', '10116', (116, 119))	('Ccnd1', 'Gene', '595', (94, 99))	('suppresses', 'NegReg', (83, 93))
54400	29720725	Therefore, we first determined Gpr158 and Ccnd1 expression in Pten/p53 or Rb/p53 mBTSC, under proliferative (serum-free, EGF, FGF enriched) and differentiating (3% FBS) conditions.	('rat', 'Species', '10116', (101, 104))	('Gpr158', 'Gene', (31, 37))	('Rb/p53', 'Gene', '7157', (74, 80))	('Rb/p53', 'Gene', (74, 80))	('Ccnd1', 'Gene', '595', (42, 47))	('Ccnd1', 'Gene', (42, 47))	('Pten/p53', 'Var', (62, 70))
54410	29720725	5d4) conspicuously retained their expression of DCX, suggesting a direct effect of miR-449a to suppress neural differentiation.	('DCX', 'Gene', (48, 51))	('suppress', 'NegReg', (95, 103))	('DCX', 'Gene', '1641', (48, 51))	('miR-449a', 'Var', (83, 91))	('neural differentiation', 'CPA', (104, 126))
54413	29720725	In conclusion, the neurogenic effect of Gpr158 can be antagonised by mir-449a.	('Gpr158', 'Var', (40, 46))	('mir-449a', 'Gene', '723868', (69, 77))	('mir-449a', 'Gene', (69, 77))	('neurogenic', 'CPA', (19, 29))
54415	29720725	Under these conditions, downregulation of Ccnd1 explains the miR-449a-induced reduction of growth and migration.	('rat', 'Species', '10116', (105, 108))	('reduction', 'NegReg', (78, 87))	('downregulation', 'NegReg', (24, 38))	('Ccnd1', 'Gene', '595', (42, 47))	('miR-449a-induced', 'Var', (61, 77))	('Ccnd1', 'Gene', (42, 47))
54416	29720725	We further confirmed the interaction of miR-449a with Ccnd1 and Gpr158 in vivo.	('Gpr158', 'Gene', (64, 70))	('Ccnd1', 'Gene', '595', (54, 59))	('interaction', 'Interaction', (25, 36))	('miR-449a', 'Var', (40, 48))	('Ccnd1', 'Gene', (54, 59))
54417	29720725	Allografts of Rb/p53 (miR-449ahigh), Pten/p53 (miR-449alow), and Rb/p53ant (miR-449alow) were generated in NOD-SCID immunodeficient mice.	('Rb/p53', 'Gene', (14, 20))	('miR-449ahigh', 'Var', (22, 34))	('NOD-SCID immunodeficient', 'Disease', (107, 131))	('NOD-SCID immunodeficient', 'Disease', 'MESH:D020191', (107, 131))	('rat', 'Species', '10116', (98, 101))	('miR-449alow', 'Var', (47, 58))	('mice', 'Species', '10090', (132, 136))	('Rb/p53', 'Gene', '7157', (65, 71))	('Rb/p53', 'Gene', '7157', (14, 20))	('miR-449alow', 'Var', (76, 87))	('Rb/p53', 'Gene', (65, 71))
54418	29720725	Pten/p53 allografts have a (pro)-neural phenotype and diffusely infiltrate the CNS.	('Pten/p53', 'Gene', (0, 8))	('allografts', 'Var', (9, 19))	('rat', 'Species', '10116', (70, 73))
54423	29720725	In conclusion, miR-449a directly downregulates Gpr158 and Ccnd1 in vivo (Figs.	('downregulates', 'NegReg', (33, 46))	('Gpr158', 'Gene', (47, 53))	('miR-449a', 'Var', (15, 23))	('Ccnd1', 'Gene', '595', (58, 63))	('Ccnd1', 'Gene', (58, 63))
54425	29720725	To correlate GPR158 expression with clinically, diagnostically and biologically relevant tumour entities, we defined oligodendrogliomas (O, n = 83) as IDH mutant, 1p/19q co-deleted tumours, and astrocytomas (A, n = 138) as IDH mutant, ATRX mutant tumours with no 1p/19q codeletion.	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('astrocytomas', 'Disease', 'MESH:D001254', (194, 206))	('tumours', 'Disease', (247, 254))	('tumour entities', 'Disease', 'MESH:D009369', (89, 104))	('ATRX', 'Gene', (235, 239))	('IDH', 'Gene', (151, 154))	('ATRX', 'Gene', '546', (235, 239))	('IDH', 'Gene', (223, 226))	('tumours', 'Phenotype', 'HP:0002664', (247, 254))	('1p/19q', 'Var', (163, 169))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (117, 135))	('tumours', 'Disease', 'MESH:D009369', (247, 254))	('tumour entities', 'Disease', (89, 104))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('IDH', 'Gene', '3417', (151, 154))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('IDH', 'Gene', '3417', (223, 226))	('tumours', 'Disease', (181, 188))	('oligodendrogliomas', 'Disease', (117, 135))	('astrocytomas', 'Disease', (194, 206))	('tumours', 'Phenotype', 'HP:0002664', (181, 188))	('tumours', 'Disease', 'MESH:D009369', (181, 188))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))
54428	29720725	IDH wild-type high grade gliomas with 7p gain, 10q loss, EGFR amplification and TERT promoter mutation were considered as GBM (corresponding to WHO grade IV) (n = 146).	('IDH', 'Gene', (0, 3))	('gain', 'PosReg', (41, 45))	('loss', 'NegReg', (51, 55))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('EGFR', 'Gene', '1956', (57, 61))	('amplification', 'Var', (62, 75))	('TERT', 'Gene', (80, 84))	('EGFR', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (80, 84))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))	('gliomas', 'Disease', (25, 32))
54433	29720725	In 29 other TCGA tumour entities (Supplementary Figure 3D), with the exception of pheochromocytoma and paraganglioma, the remaining tumours types expressed very little or no GPR158.	('tumour entities', 'Disease', (17, 32))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('paraganglioma', 'Disease', 'MESH:D010235', (103, 116))	('tumours', 'Disease', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('pheochromocytoma', 'Disease', (82, 98))	('GPR158', 'Var', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (103, 116))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (82, 98))	('pheochromocytoma', 'Disease', 'MESH:D010673', (82, 98))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('paraganglioma', 'Disease', (103, 116))	('tumour entities', 'Disease', 'MESH:D009369', (17, 32))
54438	29720725	Thus, the expression of CCND1 remains largely independent of the tumour subtypes, supporting the notion that GPR158 may have a role as biomarker that is independent from the miR-449a target CCND1.	('GPR158', 'Var', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('CCND1', 'Gene', (24, 29))	('tumour', 'Disease', (65, 71))
54444	29720725	First we separated the 25 NHNN patients of whom we had miR-449a expression values into 2 groups (above and below median) and found significantly better survival in the miR-449alow group (p = 0.004) (Fig.	('miR-449a', 'Var', (55, 63))	('survival', 'MPA', (152, 160))	('patients', 'Species', '9606', (31, 39))	('rat', 'Species', '10116', (13, 16))	('miR-449alow', 'Var', (168, 179))	('better', 'PosReg', (145, 151))
54446	29720725	Then we accessed the TCGA repository, retrieved and quantified GPR158 mRNA expression levels as per rsem (Supplementary table 3), and assigned patients to 4 strata according to their GPR158 rsem level (<=500 (Interval 1), >500 <= 1000 (Interval 2), >1000 <= 1500 (Interval 3) and >1500 (Interval 4)).	('>1500', 'Var', (280, 285))	('patients', 'Species', '9606', (143, 151))	('>1000 <= 1500', 'Var', (249, 262))	('<=500', 'Var', (202, 207))	('>500 <= 1000', 'Var', (222, 234))	('GPR158', 'Gene', (63, 69))	('rat', 'Species', '10116', (159, 162))
54448	29720725	Patients with high GPR158 expression were younger than those with low expression, consistent with IDH mutant tumours occurring in younger patients are also being associated with better survival.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('GPR158', 'Gene', (19, 25))	('better', 'PosReg', (178, 184))	('tumours', 'Disease', (109, 116))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('IDH', 'Gene', (98, 101))	('patients', 'Species', '9606', (138, 146))	('IDH', 'Gene', '3417', (98, 101))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
54449	29720725	To identify if GPR158 has a prognostic role within either IDH wild-type or IDH mutant subgroups, we then grouped patients according to the IDH mutation status.	('IDH', 'Gene', '3417', (58, 61))	('GPR158', 'Gene', (15, 21))	('patients', 'Species', '9606', (113, 121))	('mutant', 'Var', (79, 85))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', (139, 142))	('IDH', 'Gene', '3417', (75, 78))	('IDH', 'Gene', (58, 61))	('IDH', 'Gene', '3417', (139, 142))
54450	29720725	Although not reaching significance in the IDH mutant cohort, GPR158high tumours showed an obvious tendency to longer survival (p = 0.057; Fig.	('IDH', 'Gene', (42, 45))	('IDH', 'Gene', '3417', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('GPR158high', 'Var', (61, 71))	('tumours', 'Disease', (72, 79))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('longer', 'PosReg', (110, 116))
54451	29720725	However, in the IDHwt eGBM subgroup, GPR158high tumours showed no different survival from GPR158low tumours, as only few patients were available in the GPR158high group.	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('tumours', 'Disease', (100, 107))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('GPR158low tumours', 'Disease', 'MESH:D009369', (90, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('GPR158high', 'Var', (37, 47))	('IDH', 'Gene', (16, 19))	('IDH', 'Gene', '3417', (16, 19))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('GPR158low tumours', 'Disease', (90, 107))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('patients', 'Species', '9606', (121, 129))
54452	29720725	We assessed the prognostic value of GPR158 in the four subtypes of GBM and found significantly longer survival of GPR158high patients in the proneural and neural groups (Fig.	('survival', 'MPA', (102, 110))	('GPR158high', 'Var', (114, 124))	('longer', 'PosReg', (95, 101))	('patients', 'Species', '9606', (125, 133))
54453	29720725	In summary, in both the NHNN and the TCGA glioma cohorts, we confirmed that higher GPR158 transcript and protein expression levels correlate with better survival, and patients with GPR158high IDHwt GBM responded significantly better to chemotherapy compared to patients with GPR158low tumours (Fig.	('IDH', 'Gene', '3417', (192, 195))	('tumours', 'Phenotype', 'HP:0002664', (285, 292))	('glioma', 'Disease', 'MESH:D005910', (42, 48))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('glioma', 'Disease', (42, 48))	('better', 'PosReg', (226, 232))	('GPR158high', 'Var', (181, 191))	('patients', 'Species', '9606', (167, 175))	('tumour', 'Phenotype', 'HP:0002664', (285, 291))	('GPR158low tumours', 'Disease', (275, 292))	('higher', 'PosReg', (76, 82))	('GPR158low tumours', 'Disease', 'MESH:D009369', (275, 292))	('patients', 'Species', '9606', (261, 269))	('better', 'PosReg', (146, 152))	('IDH', 'Gene', (192, 195))
54455	29720725	miR-449a belongs to the miR-34/449 family, and shares with miRNA-34, 449b, and 449c seed sequences, secondary structures, and downstream targets, including CCND1 and E2F transcription factor 5 (E2F5).	('E2F transcription factor 5', 'Gene', (166, 192))	('E2F transcription factor 5', 'Gene', '1875', (166, 192))	('miR-34', 'Gene', (24, 30))	('miR-449a', 'Var', (0, 8))	('E2F5', 'Gene', (194, 198))	('miR-34', 'Gene', '407040', (24, 30))	('E2F5', 'Gene', '1875', (194, 198))
54458	29720725	2e and 4a-f) and we identified a new target, G-protein coupled receptor 158 (GPR158) which is downregulated by miR-449a (Figs.	('miR-449a', 'Var', (111, 119))	('G-protein coupled receptor 158', 'Gene', '57512', (45, 75))	('GPR158', 'Gene', (77, 83))	('downregulated', 'NegReg', (94, 107))	('G-protein coupled receptor 158', 'Gene', (45, 75))
54461	29720725	We show here that miR-449a has target-dependent effects on cell migration, proliferation and differentiation, mediated by CCND1 or GPR158 (Fig.	('rat', 'Species', '10116', (67, 70))	('effects', 'Reg', (48, 55))	('differentiation', 'CPA', (93, 108))	('cell migration', 'CPA', (59, 73))	('CCND1', 'Gene', (122, 127))	('rat', 'Species', '10116', (82, 85))	('proliferation', 'CPA', (75, 88))	('GPR158', 'Gene', (131, 137))	('miR-449a', 'Var', (18, 26))
54462	29720725	miR-449a inhibits CCND1 under proliferative conditions in stem cell medium (serum free, EGF, FGF supplemented), reducing proliferation and migration (Figs.	('reducing', 'NegReg', (112, 120))	('proliferation', 'CPA', (121, 134))	('rat', 'Species', '10116', (142, 145))	('rat', 'Species', '10116', (37, 40))	('migration', 'CPA', (139, 148))	('inhibits', 'NegReg', (9, 17))	('miR-449a', 'Var', (0, 8))	('CCND1', 'Gene', (18, 23))	('rat', 'Species', '10116', (128, 131))
54466	29720725	4k-o, and Supplementary Figure 2), whilst miR-449a antagomir restores a neural phenotype (Fig.	('miR-449a', 'Var', (42, 50))	('restores', 'PosReg', (61, 69))	('mir', 'Gene', (57, 60))	('mir', 'Gene', '220972', (57, 60))
54467	29720725	This antagonistic effect between mir-449a and GPR158 was consistently found in conditions promoting neural (FBS, Fig.	('mir-449a', 'Gene', '723868', (33, 41))	('mir-449a', 'Gene', (33, 41))	('GPR158', 'Var', (46, 52))
54469	29720725	miR-449a has an inhibitory effect on migration and invasion in vitro in some cancer types and Figs.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('rat', 'Species', '10116', (40, 43))	('migration', 'CPA', (37, 46))	('miR-449a', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasion', 'CPA', (51, 59))	('inhibitory', 'NegReg', (16, 26))
54470	29720725	In vivo, miR-449a has a tumour suppressive effect in some cancers, such as hepatocellular carcinoma,, or lung cancer, but not in others, where an association with cancer progression was found, such as breast or colorectal cancer.	('breast or colorectal cancer', 'Disease', (201, 228))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (110, 116))	('miR-449a', 'Var', (9, 17))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', (58, 65))	('tumour', 'Disease', (24, 30))	('hepatocellular carcinoma', 'Disease', (75, 99))	('cancer', 'Disease', (163, 169))	('lung cancer', 'Disease', (105, 116))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('breast or colorectal cancer', 'Disease', 'MESH:D015179', (201, 228))
54474	29720725	CCND1 can have context-depending roles in vitro and in vivo: It is one of the major regulators of the cell-cycle progression, can act as an oncogene, and aberrant expression is commonly seen in human cancers.	('aberrant', 'Var', (154, 162))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('human', 'Species', '9606', (194, 199))	('CCND1', 'Gene', (0, 5))
54476	29720725	4a-c, 5a and 9a), and is modulated by miR-449a expression, i.e., is higher in Pten/p53 mBTSC (miR-449alow) than in Rb/p53 mBTSC (miR-449ahigh) (Figs.	('Rb/p53', 'Gene', (115, 121))	('miR-449a', 'Gene', (38, 46))	('higher', 'PosReg', (68, 74))	('Pten/p53', 'Var', (78, 86))	('Rb/p53', 'Gene', '7157', (115, 121))	('miR-449alow', 'Var', (94, 105))
54477	29720725	4c and 5a) and in miR-449ahigh experimental tumours, Ccnd1 is downregulated (Fig.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('Ccnd1', 'Gene', '595', (53, 58))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('downregulated', 'NegReg', (62, 75))	('tumours', 'Disease', (44, 51))	('Ccnd1', 'Gene', (53, 58))	('miR-449ahigh', 'Var', (18, 30))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
54480	29720725	This is consistent with our observation of higher expression of neural markers, and of GPR158 and CCND1 in miR-449alow tumours developing from allografted Pten/p53 cells and from Rb/p53 cells treated with miR-449a antagomir (Fig.	('miR-449alow', 'Var', (107, 118))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('Rb/p53', 'Gene', (179, 185))	('higher', 'PosReg', (43, 49))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('mir', 'Gene', '220972', (220, 223))	('CCND1', 'Gene', (98, 103))	('tumours', 'Disease', (119, 126))	('Rb/p53', 'Gene', '7157', (179, 185))	('mir', 'Gene', (220, 223))	('expression', 'MPA', (50, 60))	('GPR158', 'Gene', (87, 93))
54483	29720725	Of translational importance, miR-449a expression correlates with tumour grade (Fig.	('expression', 'MPA', (38, 48))	('miR-449a', 'Var', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))
54488	29720725	Correlation of GPR158 expression levels to GBM, stratified according to the molecular subtypes further supports this notion, as GPR158 expression is highest in the proneural subtypes (a class that is enriched for IDH mutations and PDGFR amplifications), and decreases in classical (enriched for EGFR amplified and CDKN2A mutant tumours) and mesenchymal subtypes, which are most commonly NF1 mutated (Supplementary Figure 3c).	('PDGFR', 'Gene', (231, 236))	('PDGFR', 'Gene', '5159', (231, 236))	('tumours', 'Disease', (328, 335))	('NF1', 'Gene', '4763', (387, 390))	('IDH', 'Gene', (213, 216))	('CDKN2A', 'Gene', '1029', (314, 320))	('decreases', 'NegReg', (258, 267))	('tumours', 'Phenotype', 'HP:0002664', (328, 335))	('tumours', 'Disease', 'MESH:D009369', (328, 335))	('NF1', 'Gene', (387, 390))	('GPR158', 'Gene', (128, 134))	('expression', 'MPA', (135, 145))	('EGFR', 'Gene', (295, 299))	('IDH', 'Gene', '3417', (213, 216))	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('highest', 'Reg', (149, 156))	('CDKN2A', 'Gene', (314, 320))	('mesenchymal subtypes', 'CPA', (341, 361))	('rat', 'Species', '10116', (50, 53))	('mutant', 'Var', (321, 327))	('EGFR', 'Gene', '1956', (295, 299))
54497	29720725	We show that miR-449 directly targets and downregulates CCND1, resulting in reduced proliferation in vitro, and GPR158, antagonising neural differentiation and apoptosis in glioma stem cells.	('apoptosis', 'CPA', (160, 169))	('antagonising', 'NegReg', (120, 132))	('rat', 'Species', '10116', (91, 94))	('glioma', 'Disease', (173, 179))	('GPR158', 'Var', (112, 118))	('neural differentiation', 'CPA', (133, 155))	('miR-449', 'Gene', '723868', (13, 20))	('reduced', 'NegReg', (76, 83))	('proliferation', 'CPA', (84, 97))	('downregulates', 'NegReg', (42, 55))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('CCND1', 'Gene', (56, 61))	('miR-449', 'Gene', (13, 20))
54498	29720725	High miR-449a expression levels correlate with shorter survival, whilst high GPR158 expression is associated experimentally with neural phenotypes, cell differentiation and clinically with lower glioma grades and better patient survival and may serve as predictive biomarker.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('shorter', 'NegReg', (47, 54))	('expression levels', 'MPA', (14, 31))	('better', 'PosReg', (213, 219))	('GPR158', 'Gene', (77, 83))	('lower', 'NegReg', (189, 194))	('patient', 'Species', '9606', (220, 227))	('glioma', 'Disease', (195, 201))	('expression', 'MPA', (84, 94))	('high', 'Var', (72, 76))	('glioma', 'Disease', 'MESH:D005910', (195, 201))
54504	29720725	Pair-wise RNA samples labelled with Hy3 or Hy5 dye were hybridized to the miRCURY LNA microRNA Array 7 (Exiqon).	('Hy3', 'Gene', (36, 39))	('Hy3', 'Gene', '6085', (36, 39))	('Hy5 dye', 'Var', (43, 50))
54519	29720725	Further instructive information can be found on this informal resource http://www.biology-pages.info/L/LimitingDilution.html Murine brain tumour stem cells of the Rb/p53 or Pten/p53 genotypes transduced with lentivirus expressing GPR158 or GFP as control, containing puromycin a selection marker (4 weeks selection).	('brain tumour', 'Disease', 'MESH:D001932', (132, 144))	('brain tumour', 'Phenotype', 'HP:0030692', (132, 144))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('brain tumour', 'Disease', (132, 144))	('puromycin a', 'Chemical', '-', (267, 278))	('Murine', 'Species', '10090', (125, 131))	('GPR158', 'Var', (230, 236))	('Rb/p53', 'Gene', '7157', (163, 169))	('Rb/p53', 'Gene', (163, 169))
54521	29720725	After 48 h differentiation cells were fixed and stained for doublecortin (DCX, ab18723, 1:800, Abcam) and GFAP (ab4674, 1:1000, Abcam), followed by secondary antibodies conjugated with Alexa dyes.	('Alexa dyes', 'Chemical', '-', (185, 195))	('DCX', 'Gene', '1641', (74, 77))	('doublecortin', 'Gene', '1641', (60, 72))	('GFAP', 'Gene', (106, 110))	('doublecortin', 'Gene', (60, 72))	('1:800', 'Var', (88, 93))	('GFAP', 'Gene', '2670', (106, 110))	('DCX', 'Gene', (74, 77))
54540	29758120	The clonogenic assay of U87MG demonstrated the radiosensitizing effect of eribulin.	('radiosensitizing effect', 'MPA', (47, 70))	('rat', 'Species', '10116', (37, 40))	('U87MG', 'Var', (24, 29))	('U87MG', 'CellLine', 'CVCL:0022', (24, 29))	('eribulin', 'Chemical', 'MESH:C490954', (74, 82))
54548	29758120	Radiation suppresses the growth of GBM and prolongs the survival of patients with GBM, and, therefore, it is central to the treatment of GBM.8 Radiosensitization by arresting the cell cycle in M-phase has been shown to increase the efficacy of radiation.	('cell cycle', 'CPA', (179, 189))	('GBM', 'Phenotype', 'HP:0012174', (137, 140))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('patients', 'Species', '9606', (68, 76))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('Radiosensitization', 'Var', (143, 161))	('M-phase', 'CPA', (193, 200))	('increase', 'PosReg', (219, 227))
54558	29758120	The human glioma cell lines U87MG, U118MG and U251MG were provided by Professor Collins, University of Cambridge, UK.	('U251MG', 'CellLine', 'CVCL:0021', (46, 52))	('human', 'Species', '9606', (4, 9))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('U118MG', 'Var', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('U118MG', 'CellLine', 'CVCL:0633', (35, 41))	('U87MG', 'CellLine', 'CVCL:0022', (28, 33))	('U251MG', 'Var', (46, 52))	('glioma', 'Disease', (10, 16))
54589	29758120	We then assessed the death rate of U87MG and U251MG cells upon exposure to eribulin and/or irradiation (Figure 1C).	('U87MG', 'Var', (35, 40))	('eribulin', 'Chemical', 'MESH:C490954', (75, 83))	('U251MG', 'Var', (45, 51))	('U251MG', 'CellLine', 'CVCL:0021', (45, 51))	('rat', 'Species', '10116', (27, 30))	('U87MG', 'CellLine', 'CVCL:0022', (35, 40))
54597	29758120	Death rates of neither U87MG nor U251MG cells treated with a combination of eribulin (5 nmol/L) and irradiation were reduced by addition of pan-caspase inhibitor z-VAD-FMK (VAD), while cisplatin (CDDP)-induced caspase-dependent cell death was significantly reduced (P < .01, t test).	('VAD', 'Chemical', 'MESH:C041041', (164, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('z-VAD-FMK', 'Var', (162, 171))	('U87MG', 'CellLine', 'CVCL:0022', (23, 28))	('reduced', 'NegReg', (117, 124))	('z-VAD-FMK', 'Chemical', 'MESH:C096713', (162, 171))	('VAD', 'Chemical', 'MESH:C041041', (173, 176))	('eribulin', 'Chemical', 'MESH:C490954', (76, 84))	('rat', 'Species', '10116', (6, 9))	('U251MG', 'CellLine', 'CVCL:0021', (33, 39))	('CDDP', 'Chemical', 'MESH:D002945', (196, 200))	('U251MG', 'Var', (33, 39))
54675	28550091	Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit alpha2 (IL13Ralpha2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity.	('HER2', 'Gene', (97, 101))	('glioma', 'Disease', 'MESH:D005910', (245, 251))	('EGFR', 'Gene', '1956', (107, 111))	('IL13 receptor subunit alpha2', 'Gene', '3598', (53, 81))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('EGFR', 'Gene', '1956', (125, 129))	('IL13 receptor subunit alpha2', 'Gene', (53, 81))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EGFR', 'Gene', (107, 111))	('glioma', 'Disease', (245, 251))	('EGFR', 'Gene', (125, 129))	('variant III', 'Var', (112, 123))	('tumor', 'Disease', (149, 154))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('CAR', 'Gene', '13052', (9, 12))	('CAR', 'Gene', (9, 12))
54676	28550091	Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function.	('enhance', 'PosReg', (58, 65))	('IL15', 'Gene', (25, 29))	('CAR', 'Gene', '13052', (66, 69))	('CAR', 'Gene', (66, 69))	('Transgenic expression', 'Var', (0, 21))
54681	28550091	IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Ralpha2-CAR T-cell viability in the absence of exogenous cytokines or antigen.	('increased', 'PosReg', (65, 74))	('IL15', 'Gene', (49, 53))	('expression', 'Var', (54, 64))	('CAR', 'Gene', '13052', (87, 90))	('CAR', 'Gene', (87, 90))
54683	28550091	Gliomas recurring after 40 days after T-cell injection had downregulated IL13Ralpha2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence.	('expression', 'MPA', (85, 95))	('variants', 'Var', (126, 134))	('loss', 'NegReg', (121, 125))	('downregulated', 'NegReg', (59, 72))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('IL13Ralpha2', 'Gene', (73, 84))	('Gliomas', 'Disease', (0, 7))
54691	28550091	In contrast, CD19-specific CAR T cells showed potent antitumor activity for B-cell-derived hematologic malignancies.	('hematologic malignancies', 'Disease', 'MESH:D019337', (91, 115))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CAR', 'Gene', '13052', (27, 30))	('CAR', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('hematologic malignancies', 'Disease', (91, 115))	('CD19-specific', 'Var', (13, 26))	('tumor', 'Disease', (57, 62))
54693	28550091	Genetic modification strategies being pursued to overcome this obstacle include expression of cytokines (e.g., IL12, IL15), or manipulation of cytokine receptors (e.g., TGFbeta, IL4, or PD-1) to block inhibitory signals in the tumor microenvironment or convert inhibitory into stimulatory signals.	('block', 'NegReg', (195, 200))	('IL4', 'Gene', (178, 181))	('IL4', 'Gene', '3565', (178, 181))	('tumor', 'Disease', (227, 232))	('IL15', 'Gene', (117, 121))	('inhibitory signals', 'MPA', (201, 219))	('TGFbeta', 'Gene', '7040', (169, 176))	('manipulation', 'Var', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('PD-1', 'Gene', (186, 190))	('inhibitory', 'MPA', (261, 271))	('TGFbeta', 'Gene', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
54717	28550091	U373 cells and recurrent tumors were analyzed for IL13Ralpha2, HER2, and EphA2 expression using anti-IL13Ralpha2, HER2-APC (BD Biosciences), and anti-EphA2 antibodies (R&D Systems, Inc.), respectively.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('EphA2', 'Gene', (73, 78))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('HER2-APC', 'Disease', (114, 122))	('HER2-APC', 'Disease', 'MESH:D011125', (114, 122))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('anti-IL13Ralpha2', 'Var', (96, 112))
54764	28550091	IL15, IL13Ralpha2-CAR.Delta.IL15, IL13Ralpha2-CAR.IL15, or non-transduced T cells were cultured with Raji (IL13Ralpha1-/IL13Ralpha2-), 293T (IL13Ralpha1+/IL13Ralpha2-), or U373 (IL13Ralpha1+/IL13Ralpha2+) cells, or media alone.	('CAR', 'Gene', '13052', (18, 21))	('CAR', 'Gene', (18, 21))	('IL13Ralpha1-/IL13Ralpha2-', 'Var', (107, 132))	('293T', 'CellLine', 'CVCL:0063', (135, 139))	('CAR', 'Gene', '13052', (46, 49))	('CAR', 'Gene', (46, 49))
54767	28550091	Target cells that were only positive for IL13Ralpha1 (293T cells) or negative for IL13Ralpha1 and IL13Ralpha2 (Raji) did not induce significant IL15 production in any of the tested T-cell populations.	('293T', 'CellLine', 'CVCL:0063', (54, 58))	('IL13Ralpha1', 'Var', (41, 52))	('induce', 'Reg', (125, 131))	('IL15 production', 'MPA', (144, 159))
54771	28550091	To determine the benefits of transgenic IL15 expression on the effector function of CAR T cells, IL13Ralpha2-CAR and IL13Ralpha2-CAR.IL15 T cells were stimulated every 7 days with U373 or 293T cells without exogenous cytokines.	('CAR', 'Gene', '13052', (109, 112))	('CAR', 'Gene', (109, 112))	('CAR', 'Gene', (129, 132))	('transgenic', 'Var', (29, 39))	('CAR', 'Gene', '13052', (129, 132))	('IL15', 'Gene', (40, 44))	('293T', 'CellLine', 'CVCL:0063', (188, 192))	('expression', 'Var', (45, 55))	('CAR', 'Gene', '13052', (84, 87))	('CAR', 'Gene', (84, 87))
54798	28550091	Tumors that recurred within 20 days after T-cell injection were IL13Ralpha2 positive, whereas more than 80% of cells in tumors that recurred after day 40 were IL13Ralpha2 negative (Fig.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('IL13Ralpha2', 'Var', (64, 75))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
54806	28550091	Recurring tumors presented as antigen loss variants, highlighting the need to target multiple TAAs once the effector function of monospecific T cells is optimized.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('variants', 'Var', (43, 51))	('antigen', 'Protein', (30, 37))	('loss', 'NegReg', (38, 42))
54812	28550091	We did not observe autonomous growth of IL13Ralpha2-CAR.IL15, IL13Ralpha2-CAR.Delta.IL15, or IL15 T cells, which is in agreement with previous studies; however, baseline IL15 expression enhanced T-cell survival in the absence of antigen.	('CAR', 'Gene', (74, 77))	('IL15', 'Gene', (170, 174))	('CAR', 'Gene', '13052', (52, 55))	('T-cell survival', 'CPA', (195, 210))	('CAR', 'Gene', (52, 55))	('enhanced', 'PosReg', (186, 194))	('baseline', 'Var', (161, 169))	('CAR', 'Gene', '13052', (74, 77))
54814	28550091	Repeat stimulation resulted in an enrichment of T cells expressing IL15 and IL13Ralpha2-CARs with approximately 100% of T cells expressing both transgenes after six stimulations.	('CAR', 'Gene', (88, 91))	('IL15', 'Var', (67, 71))	('CAR', 'Gene', '13052', (88, 91))
54827	28550091	For example, transgenic expression of IL12 enhanced effector function and antitumor activity of MUC-16-CAR T cells, as judged by increased T-cell persistence and prolonged survival of tumor-bearing mice.	('enhanced', 'PosReg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('mice', 'Species', '10090', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('IL12', 'Gene', (38, 42))	('survival', 'CPA', (172, 180))	('increased', 'PosReg', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (184, 189))	('T-cell persistence', 'CPA', (139, 157))	('prolonged', 'PosReg', (162, 171))	('effector function', 'CPA', (52, 69))	('MUC-16-CAR T', 'CellLine', 'CVCL:4140', (96, 108))	('tumor', 'Disease', (78, 83))	('transgenic expression', 'Var', (13, 34))
54828	28550091	In addition, transgenic expression of IL12 in VEGF-CAR T cells enhanced their antitumor activity by reversing the immunosuppressive tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('enhanced', 'PosReg', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IL12', 'Gene', (38, 42))	('VEGF', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('VEGF', 'Gene', '7422', (46, 50))	('CAR', 'Gene', '13052', (51, 54))	('CAR', 'Gene', (51, 54))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('transgenic expression', 'Var', (13, 34))	('tumor', 'Disease', (82, 87))	('immunosuppressive tumor', 'Disease', (114, 137))	('immunosuppressive tumor', 'Disease', 'MESH:D009369', (114, 137))
54829	28550091	Finally, transgenic expression of IL15 in GD2-CAR NKT cells rendered NKT resistant to hypoxia and tumor-associated macrophages resulting in improved activity against neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (166, 179))	('IL15', 'Gene', (34, 38))	('improved', 'PosReg', (140, 148))	('neuroblastoma', 'Disease', (166, 179))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (166, 179))	('activity', 'MPA', (149, 157))	('transgenic expression', 'Var', (9, 30))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('CAR', 'Gene', '13052', (46, 49))	('tumor', 'Disease', (98, 103))	('CAR', 'Gene', (46, 49))
54830	28550091	Our study extends these findings to glioma and highlights that improving T-cell persistence by transgenic expression of IL15 leaves T cells vulnerable to other mechanisms of immune escape.	('glioma', 'Disease', (36, 42))	('T-cell persistence', 'CPA', (73, 91))	('improving', 'PosReg', (63, 72))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('IL15', 'Gene', (120, 124))	('transgenic expression', 'Var', (95, 116))
54835	28550091	On the basis of our findings, we favor targeting IL13Ralpha2 and EphA2 with CAR T cells to prevent immune escape.	('CAR', 'Gene', (76, 79))	('IL13Ralpha2', 'Var', (49, 60))	('CAR', 'Gene', '13052', (76, 79))
54843	28550091	In conclusion, we showed that transgenic expression of IL15 in IL13Ralpha2-CAR T cells enhanced their effector function, resulting in improved antiglioma activity in vitro and in vivo.	('improved', 'PosReg', (134, 142))	('IL15', 'Gene', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('effector', 'MPA', (102, 110))	('enhanced', 'PosReg', (87, 95))	('transgenic expression', 'Var', (30, 51))	('CAR', 'Gene', '13052', (75, 78))	('CAR', 'Gene', (75, 78))	('glioma', 'Disease', (147, 153))
54848	28550091	The emergence of antigen loss variants highlights the need to target multiple tumor antigens.	('variants', 'Var', (30, 38))	('antigen', 'Protein', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('loss', 'NegReg', (25, 29))
54910	27507538	The mice received four consecutive viral doses at 2.5x106 IU, 1.5x106 IU, 2x106 IU and 2.5x106 IU per 62.5 mm2 tumor volume respectively at 3, 4 and 2 day intervals.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mice', 'Species', '10090', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('2x106 IU', 'Var', (74, 82))	('tumor', 'Disease', (111, 116))	('2.5x106 IU', 'Var', (87, 97))
54913	27507538	The mice received four consecutive viral doses at 5x104 IU, 2x104 IU, 4x104 IU and 4x104 IU per 62.5 mm2 tumor volume respectively 4, 3 and 2 day intervals.	('mice', 'Species', '10090', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('4x104 IU', 'Var', (83, 91))
54914	27507538	9 week old athymic nude mice were injected subcutaneously with 1 x 106 stably transduced A2780 containing lentiviral-vectors expressing scramble miRNA (both scramble miR construct and anti-miR construct) (5 mice), miR-31/-128 (5 mice), miR-31/-128 +PVRL4 (5 mice) and anti-miRs-31/128 (5 mice).	('miR', 'Gene', (236, 239))	('miR', 'Gene', (214, 217))	('miR', 'Gene', (189, 192))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', '220972', (273, 276))	('mice', 'Species', '10090', (258, 262))	('A2780 containing', 'Var', (89, 105))	('miR', 'Gene', (145, 148))	('mice', 'Species', '10090', (288, 292))	('miR', 'Gene', (273, 276))	('mice', 'Species', '10090', (207, 211))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', '220972', (236, 239))	('mice', 'Species', '10090', (24, 28))	('nude mice', 'Species', '10090', (19, 28))	('miR', 'Gene', '220972', (214, 217))	('miR', 'Gene', '220972', (189, 192))	('mice', 'Species', '10090', (229, 233))	('miR', 'Gene', (166, 169))
54916	27507538	A2780 cell xenografts are rapid growing tumors and thus reached IACUC approved tumor volumes before the opportunity to administer additional MV doses.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('MV', 'Species', '11234', (141, 143))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (40, 46))	('A2780', 'Var', (0, 5))
54919	27507538	PVRL4 luciferase wild-type 3'UTR expression clone and the mutant clones for miR-31 and miR-128 seed regions, containing firefly luciferase reporter gene and Renilla tracking gene, driven by the SV40 promoter (Genecopoeia) were transfected at 0.8 mug in to confluent 293T cells in 96 well plates using Lipofectamine 2000 (Invitrogen), following miRNA lenti-vectors transduction at MOI = 2.	('mutant', 'Var', (58, 64))	('miR', 'Gene', (87, 90))	('miR', 'Gene', '220972', (344, 347))	('293T', 'CellLine', 'CVCL:0063', (266, 270))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('miR', 'Gene', (344, 347))
55003	27507538	S13A) and A2780 (Fig.	('A2780', 'Var', (10, 15))	('S13A', 'Var', (0, 4))	('S13A', 'SUBSTITUTION', 'None', (0, 4))
55009	27507538	MV N-protein levels decreased significantly upon transfection with miR-31 (Fig.	('MV', 'Species', '11234', (0, 2))	('MV N-protein levels', 'MPA', (0, 19))	('miR-31', 'Var', (67, 73))	('decreased', 'NegReg', (20, 29))
55011	27507538	MV N-protein levels remained unchanged upon transfection with miR-31 (Fig.	('MV', 'Species', '11234', (0, 2))	('miR-31', 'Var', (62, 68))	('MV N-protein levels', 'MPA', (0, 19))
55016	27507538	S15 A, B and E-P) and A2780 (Fig.	('A2780', 'Var', (22, 27))	('E-P', 'Disease', (13, 16))	('E-P', 'Disease', 'MESH:C000656865', (13, 16))
55057	27507538	We further observed negative correlations between the expression levels of miR-31/-128 and PVRL4 protein levels in glioblastoma patient samples.	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('miR-31/-128', 'Var', (75, 86))	('negative', 'NegReg', (20, 28))	('PVRL4 protein levels', 'MPA', (91, 111))	('expression levels', 'MPA', (54, 71))	('patient', 'Species', '9606', (128, 135))	('glioblastoma', 'Disease', (115, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))
55061	27507538	Similarly, miR-31 has been identified to inhibit migration and proliferation while the loss of miR-31 increases tumor growth of glioblastoma cells.	('loss', 'Var', (87, 91))	('migration', 'CPA', (49, 58))	('increases tumor', 'Disease', (102, 117))	('increases tumor', 'Disease', 'MESH:D009369', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('inhibit', 'NegReg', (41, 48))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('miR-31', 'Gene', (95, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
55064	27507538	MiR-128 can be down-regulated due to loss of heterozygosity in chromosome 3p, the loci for miR-128-2, as observed in several cancers including neuroblastoma/glioblastoma and breast cancer.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('MiR', 'Gene', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('MiR', 'Gene', '220972', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-128-2', 'Gene', (91, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('neuroblastoma/glioblastoma', 'Disease', (143, 169))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('down-regulated', 'NegReg', (15, 29))	('loss of heterozygosity', 'Var', (37, 59))	('neuroblastoma/glioblastoma', 'Disease', 'MESH:D005909', (143, 169))	('miR-128-2', 'Gene', '406916', (91, 100))
55065	27507538	Similarly, the miR-128 aberrations observed could be a result of DNA methylations of the miR-128 promoter region and point mutations.	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('point mutations', 'Var', (117, 132))	('aberrations', 'Var', (23, 34))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
55070	27507538	Altered miR-31 expressions could be due to regulation by TNF and BMP-2, epigenetic silencing due to promoter hypermethylation or demethylation of H3K4me3 by EMSY or post-transcriptional regulation.	('expressions', 'MPA', (15, 26))	('BMP-2', 'Gene', (65, 70))	('demethylation', 'Var', (129, 142))	('TNF', 'Gene', '7124', (57, 60))	('EMSY', 'Gene', '56946', (157, 161))	('BMP-2', 'Gene', '650', (65, 70))	('H3K4me3', 'Protein', (146, 153))	('EMSY', 'Gene', (157, 161))	('miR-31', 'Gene', (8, 14))	('epigenetic', 'MPA', (72, 82))	('promoter hypermethylation', 'Var', (100, 125))	('TNF', 'Gene', (57, 60))
55072	27507538	Cell culture and mouse xenograft data indicate that miR-31/-128 regulate MV infectivity and thus can have a significant impact on MV mediated tumor size.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('regulate', 'Reg', (64, 72))	('infect', 'Disease', (76, 82))	('mouse', 'Species', '10090', (17, 22))	('MV', 'Species', '11234', (73, 75))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('impact', 'Reg', (120, 126))	('infect', 'Disease', 'MESH:D007239', (76, 82))	('MV', 'Species', '11234', (130, 132))	('miR-31/-128', 'Var', (52, 63))
55100	26892186	We found that VOA exhibited greater growth suppression in p53 wild-type cells than p53 mutant cells and very low effect on fibroblasts and human glial HEB cells.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('mutant', 'Var', (87, 93))	('VOA', 'Chemical', '-', (14, 17))	('human', 'Species', '9606', (139, 144))	('p53', 'Gene', (58, 61))	('growth suppression', 'CPA', (36, 54))	('p53', 'Gene', '7157', (58, 61))
55101	26892186	Apoptosis was triggered by VOA with a caspase-dependent way in p53 wild-type A172 cells, while a caspase-independent way in p53 mutant U251 cells.	('p53', 'Gene', (124, 127))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('triggered', 'Reg', (14, 23))	('caspase', 'Gene', '841;842', (38, 45))	('p53', 'Gene', '7157', (124, 127))	('mutant', 'Var', (128, 134))	('U251', 'CellLine', 'CVCL:0021', (135, 139))	('caspase', 'Gene', '841;842', (97, 104))	('VOA', 'Chemical', '-', (27, 30))	('caspase', 'Gene', (38, 45))	('Apoptosis', 'CPA', (0, 9))	('caspase', 'Gene', (97, 104))
55105	26892186	Finally, blockage of autophagy potentiated the proapoptotic effect in both A172 and U251 cells, indicating a protective role of autophagy in VOA-induced cell death.	('autophagy', 'CPA', (21, 30))	('blockage', 'Var', (9, 17))	('proapoptotic effect', 'CPA', (47, 66))	('U251', 'CellLine', 'CVCL:0021', (84, 88))	('VOA', 'Chemical', '-', (141, 144))	('potentiated', 'PosReg', (31, 42))
55134	26892186	Furthermore, the clonogenic assay performed with a sustained treatment of A172 and U251 cells for two weeks also showed that the inhibition concentrations of VOA in A172 cells were significantly lower than that in U251 cells (Fig.	('VOA', 'Protein', (158, 161))	('U251', 'CellLine', 'CVCL:0021', (83, 87))	('A172', 'Var', (165, 169))	('lower', 'NegReg', (195, 200))	('VOA', 'Chemical', '-', (158, 161))	('inhibition', 'NegReg', (129, 139))	('rat', 'Species', '10116', (147, 150))	('U251', 'CellLine', 'CVCL:0021', (214, 218))
55171	26892186	Moreover, VOA decreased p53 expression level starting from 6 h treatment in A172 cells (Fig.	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))	('VOA', 'Var', (10, 13))	('decreased', 'NegReg', (14, 23))	('VOA', 'Chemical', '-', (10, 13))
55187	26892186	6B, VOA induced-decrease of p-mTOR and increase of p-AMPK were remarkably augmented after PFT-alpha pretreatment or si-p53 transfection in A172 cells.	('AMPK', 'Gene', '5562', (53, 57))	('mTOR', 'Gene', '2475', (30, 34))	('AMPK', 'Gene', (53, 57))	('transfection', 'Var', (123, 135))	('p53', 'Gene', '7157', (119, 122))	('VOA', 'Chemical', '-', (4, 7))	('increase', 'PosReg', (39, 47))	('induced-decrease', 'NegReg', (8, 24))	('augmented', 'PosReg', (74, 83))	('p53', 'Gene', (119, 122))	('mTOR', 'Gene', (30, 34))
55190	26892186	Taken together, these results revealed that p53 inhibition or knockdown could enhance the induction of apoptosis and autophagy by VOA in human glioma cells harboring wild-type p53.	('enhance', 'PosReg', (78, 85))	('human', 'Species', '9606', (137, 142))	('autophagy', 'CPA', (117, 126))	('p53', 'Gene', (176, 179))	('glioma', 'Disease', 'MESH:D005910', (143, 149))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('VOA', 'Chemical', '-', (130, 133))	('p53', 'Gene', '7157', (176, 179))	('inhibition', 'Var', (48, 58))	('apoptosis', 'CPA', (103, 112))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('glioma', 'Disease', (143, 149))	('knockdown', 'Var', (62, 71))
55196	26892186	7B), suggesting that inhibition of autophagy promotes the caspase-dependent apoptosis in p53 wild-type cells.	('caspase', 'Gene', '841;842', (58, 65))	('autophagy', 'CPA', (35, 44))	('caspase', 'Gene', (58, 65))	('inhibition', 'Var', (21, 31))	('promotes', 'PosReg', (45, 53))	('p53', 'Gene', (89, 92))	('p53', 'Gene', '7157', (89, 92))
55199	26892186	These results indicate that VOA-induced autophagy is a protective mechanism and blockage of autophagy aggravates the VOA-induced apoptosis.	('apoptosis', 'CPA', (129, 138))	('blockage', 'Var', (80, 88))	('VOA-induced', 'Disease', (117, 128))	('autophagy', 'CPA', (92, 101))	('VOA', 'Chemical', '-', (28, 31))	('VOA', 'Chemical', '-', (117, 120))	('aggravates', 'PosReg', (102, 112))
55201	26892186	However, 3-MA alone in both A172 and U251 also led to increased apoptotic cells compare to control.	('increased', 'PosReg', (54, 63))	('U251', 'Var', (37, 41))	('3-MA', 'Chemical', 'MESH:C025946', (9, 13))	('U251', 'CellLine', 'CVCL:0021', (37, 41))	('apoptotic cells', 'CPA', (64, 79))
55215	26892186	Interestingly, the cytotoxicity of VOA seems to be related to p53 status as p53 wild-type GBM cells (A172 and U87) are more sensitive to p53 mutant GBM cells (U251 and U118).	('cytotoxicity', 'Disease', (19, 31))	('mutant', 'Var', (141, 147))	('p53', 'Gene', (76, 79))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (76, 79))	('p53', 'Gene', '7157', (137, 140))	('U87', 'CellLine', 'CVCL:0022', (110, 113))	('VOA', 'Chemical', '-', (35, 38))	('cytotoxicity', 'Disease', 'MESH:D064420', (19, 31))	('U251', 'CellLine', 'CVCL:0021', (159, 163))	('p53', 'Gene', (137, 140))	('p53', 'Gene', '7157', (62, 65))	('sensitive', 'MPA', (124, 133))
55227	26892186	It is reasonable to assume that VOA-induced apoptotic signaling pathway may be dependent on p53 deficient/mutant status.	('deficient/mutant', 'NegReg', (96, 112))	('VOA-induced apoptotic signaling pathway', 'Pathway', (32, 71))	('deficient/mutant', 'Var', (96, 112))	('p53', 'Gene', (92, 95))	('p53', 'Gene', '7157', (92, 95))	('VOA', 'Chemical', '-', (32, 35))
55243	26892186	Similarly, our results showed that augment of both apoptosis and autophagy induced by VOA could be achieved by co-treatment of p53 inhibitor PFT-alpha in both A172 and U87 cells or transfection of p53 siRNA in A172 cells.	('autophagy', 'CPA', (65, 74))	('U87', 'CellLine', 'CVCL:0022', (168, 171))	('augment', 'PosReg', (35, 42))	('transfection', 'Var', (181, 193))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('VOA', 'Chemical', '-', (86, 89))	('apoptosis', 'CPA', (51, 60))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
55285	24077277	An R132H Mutation in Isocitrate Dehydrogenase 1 Enhances p21 Expression and Inhibits Phosphorylation of Retinoblastoma Protein in Glioma Cells Cytosolic isocitrate dehydrogenase 1 (IDH1) with an R132H mutation in brain tumors loses its enzymatic activity for catalyzing isocitrate to alpha-ketoglutarate (alpha-KG) and acquires new activity whereby it converts alpha-KG to 2-hydroxyglutarate.	('Inhibits', 'NegReg', (76, 84))	('Phosphorylation', 'MPA', (85, 100))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (284, 303))	('R132H', 'Mutation', 'rs121913500', (3, 8))	('isocitrate', 'Chemical', 'MESH:C034219', (153, 163))	('enzymatic activity', 'MPA', (236, 254))	('p21', 'Gene', (57, 60))	('R132H', 'Var', (195, 200))	('loses', 'NegReg', (226, 231))	('Glioma', 'Phenotype', 'HP:0009733', (130, 136))	('alpha-KG', 'Chemical', 'MESH:D007656', (361, 369))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('Isocitrate Dehydrogenase 1', 'Gene', '15926', (21, 47))	('IDH1', 'Gene', (181, 185))	('alpha-KG', 'Chemical', 'MESH:D007656', (305, 313))	('brain tumor', 'Phenotype', 'HP:0030692', (213, 224))	('Isocitrate Dehydrogenase 1', 'Gene', (21, 47))	('catalyzing isocitrate to alpha-ketoglutarate', 'MPA', (259, 303))	('isocitrate', 'Chemical', 'MESH:C034219', (270, 280))	('isocitrate dehydrogenase 1', 'Gene', (153, 179))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('R132H', 'Var', (3, 8))	('Retinoblastoma Protein in Glioma', 'Disease', 'MESH:D012175', (104, 136))	('isocitrate dehydrogenase 1', 'Gene', '15926', (153, 179))	('brain tumors', 'Disease', 'MESH:D001932', (213, 225))	('brain tumors', 'Phenotype', 'HP:0030692', (213, 225))	('p21', 'Gene', '1026', (57, 60))	('Expression', 'MPA', (61, 71))	('Retinoblastoma Protein in Glioma', 'Disease', (104, 136))	('IDH1', 'Gene', '3417', (181, 185))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (373, 391))	('R132H', 'Mutation', 'rs121913500', (195, 200))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (104, 118))	('brain tumors', 'Disease', (213, 225))	('Enhances', 'PosReg', (48, 56))
55286	24077277	The IDH1 mutation induces down-regulation of tricarboxylic acid cycle intermediates and up-regulation of lipid metabolism.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('lipid metabolism', 'MPA', (105, 121))	('up-regulation', 'PosReg', (88, 101))	('down-regulation', 'NegReg', (26, 41))	('IDH1', 'Gene', (4, 8))	('tricarboxylic acid cycle intermediates', 'MPA', (45, 83))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (45, 63))	('lipid', 'Chemical', 'MESH:D008055', (105, 110))
55289	24077277	Small interfering ribonucleic acid (siRNA) for SREBP1 specifically decreased p21 messenger RNA (mRNA) levels independent of the p53 pathway.	('decreased', 'NegReg', (67, 76))	('SREBP1', 'Gene', '6720', (47, 53))	('Small interfering', 'Var', (0, 17))	('SREBP1', 'Gene', (47, 53))
55290	24077277	In IDH1R132H-expressing U87 cells, phosphorylation of Retinoblastoma (Rb) protein also decreased.	('Retinoblastoma', 'Phenotype', 'HP:0009919', (54, 68))	('IDH1R132H-expressing', 'Var', (3, 23))	('Retinoblastoma', 'Gene', '5925', (54, 68))	('U87', 'Gene', '641648', (24, 27))	('decreased', 'NegReg', (87, 96))	('phosphorylation of', 'MPA', (35, 53))	('Retinoblastoma', 'Gene', (54, 68))	('U87', 'Gene', (24, 27))	('Rb', 'Gene', '5925', (70, 72))
55291	24077277	We propose that metabolic changes induced by the IDH1 mutation enhance p21 expression via SREBP1 and inhibit phosphorylation of Rb, which slows progressionof the cell cycle and may be associated with non-aggressive features of gliomas with an IDH1 mutation.	('enhance', 'PosReg', (63, 70))	('SREBP1', 'Gene', (90, 96))	('gliomas', 'Disease', (227, 234))	('IDH1', 'Gene', '3417', (49, 53))	('progressionof the cell cycle', 'CPA', (144, 172))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('phosphorylation', 'MPA', (109, 124))	('gliomas', 'Disease', 'MESH:D005910', (227, 234))	('Rb', 'Gene', '5925', (128, 130))	('inhibit', 'NegReg', (101, 108))	('IDH1', 'Gene', (243, 247))	('metabolic', 'MPA', (16, 25))	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('mutation', 'Var', (54, 62))	('slows', 'NegReg', (138, 143))	('IDH1', 'Gene', '3417', (243, 247))	('associated', 'Reg', (184, 194))	('SREBP1', 'Gene', '6720', (90, 96))	('IDH1', 'Gene', (49, 53))	('p21 expression', 'MPA', (71, 85))
55295	24077277	Genomic analysis of gliomas has identified mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes.	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('IDH1', 'Gene', (94, 98))	('IDH2', 'Gene', '3418', (103, 107))	('isocitrate dehydrogenase 1', 'Gene', (60, 86))	('IDH1', 'Gene', '3417', (94, 98))	('mutations', 'Var', (43, 52))	('isocitrate dehydrogenase 1', 'Gene', '15926', (60, 86))	('IDH2', 'Gene', (103, 107))	('gliomas', 'Disease', 'MESH:D005910', (20, 27))	('gliomas', 'Phenotype', 'HP:0009733', (20, 27))	('gliomas', 'Disease', (20, 27))
55297	24077277	A mutation affecting codon 132 of the IDH1 gene, located on chromosome 2q22, has been found in 12% of glioblastomas, resulting in an Arg to His substitution.	('Arg to His substitution', 'Var', (133, 156))	('mutation', 'Var', (2, 10))	('IDH1', 'Gene', '3417', (38, 42))	('glioblastomas', 'Phenotype', 'HP:0012174', (102, 115))	('glioblastomas', 'Disease', 'MESH:D005909', (102, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('glioblastomas', 'Disease', (102, 115))	('IDH1', 'Gene', (38, 42))	('Arg', 'Chemical', 'MESH:D001120', (133, 136))
55298	24077277	Notably, IDH mutations are detected in 95% of secondary gliomas (diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma.	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('IDH', 'Gene', (9, 12))	('detected', 'Reg', (27, 35))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('glioma', 'Disease', (169, 175))	('astrocytoma', 'Phenotype', 'HP:0009592', (73, 84))	('glioma', 'Disease', 'MESH:D005910', (169, 175))	('IDH', 'Gene', '3417', (9, 12))	('astrocytoma', 'Phenotype', 'HP:0009592', (134, 145))	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('astrocytoma', 'Phenotype', 'HP:0009592', (110, 121))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('mutations', 'Var', (13, 22))	('astrocytoma', 'Phenotype', 'HP:0009592', (197, 208))	('oligoastrocytoma', 'Disease', (105, 121))	('anaplastic oligoastrocytoma', 'Disease', (181, 208))	('gliomas', 'Disease', (56, 63))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('anaplastic astrocytoma', 'Disease', (123, 145))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
55299	24077277	The presence of the IDH1 mutation has been shown to be associated with a significantly better prognosis (IDH1 mutation versus wild IDH1; 31 months versus 15 months).	('IDH1', 'Gene', '3417', (20, 24))	('IDH1', 'Gene', (131, 135))	('IDH1', 'Gene', (105, 109))	('mutation', 'Var', (25, 33))	('IDH1', 'Gene', '3417', (131, 135))	('presence', 'Var', (4, 12))	('IDH1', 'Gene', '3417', (105, 109))	('better', 'PosReg', (87, 93))	('IDH1', 'Gene', (20, 24))
55300	24077277	IDH1R132H shows decreased enzymatic activity for isocitrate, leading to lower alpha-KG production.	('alpha-KG production', 'MPA', (78, 97))	('IDH1R132H', 'Var', (0, 9))	('isocitrate', 'Chemical', 'MESH:C034219', (49, 59))	('lower', 'NegReg', (72, 77))	('alpha-KG', 'Chemical', 'MESH:D007656', (78, 86))	('enzymatic activity for isocitrate', 'MPA', (26, 59))	('decreased', 'NegReg', (16, 25))
55302	24077277	In addition, levels of tricarboxylic acid (TCA) cycle intermediates were down-regulated and lipid metabolism was up-regulated in mutant IDH1-expressing cells.	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (23, 41))	('TCA', 'Chemical', 'MESH:D014233', (43, 46))	('lipid metabolism', 'MPA', (92, 108))	('IDH1', 'Gene', (136, 140))	('up-regulated', 'PosReg', (113, 125))	('IDH1', 'Gene', '3417', (136, 140))	('down-regulated', 'NegReg', (73, 87))	('lipid', 'Chemical', 'MESH:D008055', (92, 97))	('mutant', 'Var', (129, 135))
55303	24077277	The IDH mutation has also been related to the methylation status of CpG sites, in particular hypermethylation of the methyl guanine methyl transferase (MGMT) promoter.	('hypermethylation', 'MPA', (93, 109))	('IDH', 'Gene', '3417', (4, 7))	('mutation', 'Var', (8, 16))	('related', 'Reg', (31, 38))	('IDH', 'Gene', (4, 7))
55304	24077277	Although the mechanism for a favorable prognosis in IDHR132H gliomas has not been fully elucidated, these altered metabolism and methylation statuses are thought to be associated with nonaggressive features.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('metabolism', 'MPA', (114, 124))	('gliomas', 'Disease', (61, 68))	('IDHR132H', 'Var', (52, 60))	('gliomas', 'Disease', 'MESH:D005910', (61, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('methylation', 'MPA', (129, 140))
55314	24077277	In the present study, we explore the association between the IDH1 mutation and p21 activation via SREBP and propose a mechanism for a nonaggressive profile in gliomas bearing the IDH1 mutation.	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('p21', 'Gene', (79, 82))	('SREBP', 'Gene', (98, 103))	('activation', 'PosReg', (83, 93))	('IDH1', 'Gene', (61, 65))	('IDH1', 'Gene', (179, 183))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('mutation', 'Var', (66, 74))	('SREBP', 'Gene', '7555', (98, 103))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', '3417', (179, 183))	('mutation', 'Var', (184, 192))
55316	24077277	Site-directed mutagenesis was performed using the KOD-Plus-Mutagenesis Kit (Toyobo, Tokyo) to change G395 to A in IDH1, resulting in an R132H mutation.	('R132H', 'Mutation', 'rs121913500', (136, 141))	('IDH1', 'Gene', (114, 118))	('G395 to', 'Var', (101, 108))	('IDH1', 'Gene', '3417', (114, 118))	('G395 to A', 'Mutation', 'rs121913500', (101, 110))	('R132H', 'Var', (136, 141))
55330	24077277	ELISA kits were used for the measurement of p21 (#7167; Cell Signaling Technologies) and p53 protein (CY-7049; CycLex, Ina, Nagano).	('p53 protein', 'Protein', (89, 100))	('CY', 'Chemical', 'MESH:D003545', (102, 104))	('Ina', 'Gene', '9118', (119, 122))	('p21', 'Protein', (44, 47))	('CY-7049;', 'Var', (102, 110))	('Ina', 'Gene', (119, 122))
55335	24077277	The expression levels of enzymes involved in the TCA cycle downstream of alpha-KG appeared lower in IDH1R132H-transfected cells.	('lower', 'NegReg', (91, 96))	('TCA', 'Chemical', 'MESH:D014233', (49, 52))	('IDH1R132H-transfected', 'Var', (100, 121))	('expression levels of enzymes', 'MPA', (4, 32))	('alpha-KG', 'Chemical', 'MESH:D007656', (73, 81))
55337	24077277	However, the other TCA cycle enzymes upstream of alpha-KG were not affected by IDH1 mutation, probably due to relative depletion of alpha-KG in IDH1R132H-transfected cells by competitive inhibition by 2-HG.	('IDH1', 'Gene', '3417', (79, 83))	('TCA', 'Chemical', 'MESH:D014233', (19, 22))	('alpha-KG', 'Chemical', 'MESH:D007656', (132, 140))	('IDH1', 'Gene', (144, 148))	('depletion', 'MPA', (119, 128))	('alpha-KG', 'Chemical', 'MESH:D007656', (49, 57))	('IDH1', 'Gene', (79, 83))	('IDH1', 'Gene', '3417', (144, 148))	('mutation', 'Var', (84, 92))
55344	24077277	qRT-PCR analysis showed that IDH1R132H-transfected cells up-regulated SREBP1a, 1c, and 2 (Fig.	('up-regulated', 'PosReg', (57, 69))	('SREBP1a, 1c, and 2', 'Gene', '6720;6721', (70, 88))	('IDH1R132H-transfected', 'Var', (29, 50))
55349	24077277	These results indicated that the R132H mutation in IDH1 induced the expression of SREBPs and that SREBP1 enhanced the expression of p21 in IDH1R132H-transfected cells.	('SREBP1', 'Gene', (98, 104))	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', (139, 143))	('IDH1', 'Gene', (51, 55))	('R132H', 'Mutation', 'rs121913500', (143, 148))	('expression', 'MPA', (68, 78))	('SREBP', 'Gene', (98, 103))	('p21', 'Protein', (132, 135))	('SREBP', 'Gene', (82, 87))	('R132H', 'Var', (33, 38))	('induced', 'PosReg', (56, 63))	('IDH1', 'Gene', '3417', (139, 143))	('SREBP1', 'Gene', '6720', (98, 104))	('R132H', 'Mutation', 'rs121913500', (33, 38))	('SREBP', 'Gene', '7555', (98, 103))	('SREBP', 'Gene', '7555', (82, 87))	('expression', 'MPA', (118, 128))	('enhanced', 'PosReg', (105, 113))
55353	24077277	p21 protein inhibits the phosphorylation of Rb protein, one of the tumor suppressors.	('p21', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('phosphorylation', 'MPA', (25, 40))	('Rb', 'Gene', '5925', (44, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('inhibits', 'NegReg', (12, 20))	('tumor', 'Disease', (67, 72))
55356	24077277	Western blot analysis of Rb protein indicated that the level of the phosphorylated form, relative to total Rb protein, decreased in IDH1R132H-transfected cells (Fig.	('decreased', 'NegReg', (119, 128))	('IDH1R132H-transfected', 'Var', (132, 153))	('level', 'MPA', (55, 60))	('Rb', 'Gene', '5925', (25, 27))	('Rb', 'Gene', '5925', (107, 109))
55360	24077277	However, gliomas bearing the IDH1 mutation are associated with better outcomes.	('gliomas', 'Disease', (9, 16))	('IDH1', 'Gene', (29, 33))	('gliomas', 'Disease', 'MESH:D005910', (9, 16))	('gliomas', 'Phenotype', 'HP:0009733', (9, 16))	('mutation', 'Var', (34, 42))	('IDH1', 'Gene', '3417', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))
55361	24077277	The mutated IDH1 produces 2-HG from alpha-KG in the cytoplasm.	('mutated', 'Var', (4, 11))	('IDH1', 'Gene', '3417', (12, 16))	('alpha-KG', 'Chemical', 'MESH:D007656', (36, 44))	('IDH1', 'Gene', (12, 16))
55363	24077277	The present analyses confirmed that the TCA cycle was down-regulated in IDH1R132H-cells (Fig.	('TCA', 'Chemical', 'MESH:D014233', (40, 43))	('IDH1R132H-cells', 'Var', (72, 87))	('TCA cycle', 'Enzyme', (40, 49))	('down-regulated', 'NegReg', (54, 68))
55366	24077277	The R132H mutation in IDH1 induced shunting of carbons from glycolysis into de novo synthesis of lipid rather than into the TCA cycle.	('de novo synthesis of lipid', 'MPA', (76, 102))	('IDH1', 'Gene', (22, 26))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('TCA', 'Chemical', 'MESH:D014233', (124, 127))	('induced', 'Reg', (27, 34))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('IDH1', 'Gene', '3417', (22, 26))	('carbons', 'Chemical', 'MESH:D002244', (47, 54))	('shunting of carbons from glycolysis', 'MPA', (35, 70))	('R132H', 'Var', (4, 9))
55367	24077277	The enhanced lipid metabolism by the mutated IDH1can be relevant to increased SREBP expression.	('IDH1', 'Gene', '3417', (45, 49))	('lipid', 'Chemical', 'MESH:D008055', (13, 18))	('SREBP', 'Gene', (78, 83))	('enhanced', 'PosReg', (4, 12))	('lipid metabolism', 'MPA', (13, 29))	('SREBP', 'Gene', '7555', (78, 83))	('enhanced lipid metabolism', 'Phenotype', 'HP:0003077', (4, 29))	('IDH1', 'Gene', (45, 49))	('mutated', 'Var', (37, 44))	('increased', 'PosReg', (68, 77))
55369	24077277	Our data clearly showed that IDH1R132H induced increases in the mRNA levels of all SREBP family transcripts, 1a, 1c, and 2 (Fig.	('IDH1R132H', 'Var', (29, 38))	('SREBP', 'Gene', '7555', (83, 88))	('mRNA levels of', 'MPA', (64, 78))	('increases', 'PosReg', (47, 56))	('SREBP', 'Gene', (83, 88))
55372	24077277	In addition, it has been reported that glycolysis is enhanced in glioma with the IDH1 mutation, and that glycolysis suppresses p53.	('glioma', 'Disease', (65, 71))	('p53', 'MPA', (127, 130))	('glycolysis', 'MPA', (39, 49))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('suppresses', 'NegReg', (116, 126))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('IDH1', 'Gene', (81, 85))	('mutation', 'Var', (86, 94))	('IDH1', 'Gene', '3417', (81, 85))	('enhanced', 'PosReg', (53, 61))
55374	24077277	Recently, IDH1R132H has been reported to be associated with SREBP1a activation and cellular proliferation.	('associated', 'Reg', (44, 54))	('SREBP1a', 'Gene', '6720', (60, 67))	('IDH1R132H', 'Var', (10, 19))	('activation', 'PosReg', (68, 78))	('cellular proliferation', 'CPA', (83, 105))	('SREBP1a', 'Gene', (60, 67))
55375	24077277	However, the precise mechanism how IDH1R132H induces SREBP1a activation was not revealed.	('SREBP1a', 'Gene', (53, 60))	('IDH1R132H', 'Var', (35, 44))	('SREBP1a', 'Gene', '6720', (53, 60))
55376	24077277	Although IDH1R132H is associated with slow tumor progression, it is controversial whether IDH1R132H mutation induces or suppresses cell growth in cultured glioma cells.	('IDH1R132H', 'Gene', (90, 99))	('cell growth', 'CPA', (131, 142))	('suppresses', 'NegReg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('mutation', 'Var', (100, 108))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IDH1R132H', 'Var', (9, 18))	('tumor', 'Disease', (43, 48))	('glioma', 'Disease', (155, 161))
55378	24077277	In an attempt to demonstrate the direct association between the IDH1R132H and the retardation of cell growth, we analyzed the cell cycle profile of the transfected U87 cells.	('IDH1R132H', 'Var', (64, 73))	('U87', 'Gene', (164, 167))	('retardation', 'Disease', (82, 93))	('retardation', 'Disease', 'MESH:D008607', (82, 93))	('U87', 'Gene', '641648', (164, 167))
55381	24077277	Although the difference was not statistically significant, the U87 cells transfected with IDH1R132H plasmid tended to slower growth (Fig.	('U87', 'Gene', (63, 66))	('slower', 'NegReg', (118, 124))	('IDH1R132H plasmid', 'Var', (90, 107))	('U87', 'Gene', '641648', (63, 66))
55382	24077277	Accumulation of subtle growth retardation after a number of cell division in IDH1R132H glioma may lead to smaller tumor burden.	('subtle growth retardation', 'Disease', (16, 41))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('glioma', 'Disease', (87, 93))	('smaller', 'NegReg', (106, 113))	('subtle growth retardation', 'Disease', 'MESH:D006130', (16, 41))	('IDH1R132H', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('growth retardation', 'Phenotype', 'HP:0001510', (23, 41))	('tumor', 'Disease', (114, 119))	('subtle growth retardation', 'Phenotype', 'HP:0001530', (16, 41))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))
55385	24077277	Several reports implicate doxidative stress or methylation of the MGMT promoter portion in gliomas with the IDH1 mutation important for a nonaggressive profile.	('mutation', 'Var', (113, 121))	('implicate', 'Reg', (16, 25))	('IDH1', 'Gene', '3417', (108, 112))	('doxidative stress', 'Phenotype', 'HP:0025464', (26, 43))	('gliomas', 'Disease', (91, 98))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('methylation', 'Var', (47, 58))	('gliomas', 'Disease', 'MESH:D005910', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (91, 98))	('doxidative', 'MPA', (26, 36))	('IDH1', 'Gene', (108, 112))	('MGMT promoter', 'Gene', (66, 79))
55387	24077277	The R132H mutation in IDH1 appears to give rise to diverse metabolic changes, such as increased oxidative stress, inhibition of the TCA cycle, and enhanced lipid metabolism.	('lipid metabolism', 'MPA', (156, 172))	('lipid', 'Chemical', 'MESH:D008055', (156, 161))	('TCA cycle', 'Pathway', (132, 141))	('enhanced', 'PosReg', (147, 155))	('increased', 'PosReg', (86, 95))	('inhibition', 'NegReg', (114, 124))	('IDH1', 'Gene', (22, 26))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (86, 112))	('IDH1', 'Gene', '3417', (22, 26))	('enhanced lipid metabolism', 'Phenotype', 'HP:0003077', (147, 172))	('R132H', 'Mutation', 'rs121913500', (4, 9))	('TCA', 'Chemical', 'MESH:D014233', (132, 135))	('oxidative stress', 'MPA', (96, 112))	('R132H', 'Var', (4, 9))
55389	24077277	More detailed analysis of the metabolic changes induced by the IDH1 mutation will help us understand the mechanism of the low-grade malignant profile of an IDH1R132H glioma.	('IDH1', 'Gene', '3417', (63, 67))	('IDH1', 'Gene', (156, 160))	('mutation', 'Var', (68, 76))	('IDH1', 'Gene', '3417', (156, 160))	('glioma', 'Disease', (166, 172))	('glioma', 'Disease', 'MESH:D005910', (166, 172))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('IDH1', 'Gene', (63, 67))
55390	23686484	Profound impairment of adaptive immune responses by alkylating chemotherapy Cancer vaccines have overall had a record of failure as an adjuvant therapy for malignancies that are treated with alkylating chemotherapy, and the contribution of standard treatment to that failure remains unclear.	('malignancies', 'Disease', (156, 168))	('adaptive immune responses', 'CPA', (23, 48))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('impairment', 'NegReg', (9, 19))	('Profound impairment', 'Phenotype', 'HP:0002187', (0, 19))	('Cancer', 'Disease', (76, 82))	('malignancies', 'Disease', 'MESH:D009369', (156, 168))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('alkylating chemotherapy', 'Var', (52, 75))
55397	23686484	Tumors express mutant proteins termed "neo-antigens" that result from frameshift, gene fusion, and missense mutations.	('gene fusion', 'Var', (82, 93))	('missense mutations', 'Var', (99, 117))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('proteins', 'Protein', (22, 30))	('frameshift', 'Var', (70, 80))
55423	23686484	C57BL/6J (B6) mice, C57BL/6-Tg(TcraTcrb)1100Mjb/J (OT-I) and B6.PL-Thy1a/CyJ (Thy1.1+) mice were purchased from the Jackson Laboratory and used at 6-10 weeks of age.	('C57BL/6-Tg', 'Var', (20, 30))	('mice', 'Species', '10090', (14, 18))	('mice', 'Species', '10090', (87, 91))	('Thy1.1', 'Gene', '21838', (78, 84))	('Thy1.1', 'Gene', (78, 84))
55426	23686484	Cell number inoculated was 15,000 for GL261 and 30,000 for O94M2 and KM3M14.	('O94M2', 'Var', (59, 64))	('KM3M14', 'Var', (69, 75))	('GL261', 'Var', (38, 43))	('M2', 'CellLine', 'CVCL:U035', (62, 64))
55436	23686484	SIINFEKL and variant peptides (Anaspec) were dissolved in sterile water.	('water', 'Chemical', 'MESH:D014867', (66, 71))	('variant', 'Var', (13, 20))	('SIINFEKL', 'Disease', 'None', (0, 8))	('SIINFEKL', 'Disease', (0, 8))
55446	23686484	Low (25 mg/kg), intermediate (55 mg/kg), and high (80 mg/kg) dosages of temozolomide given daily for five days led to a transient reduction in lymphocyte counts similar in magnitude to that seen in patients treated with temozolomide (Table S1).	('55 mg/kg', 'Var', (30, 38))	('25 mg/kg', 'Var', (5, 13))	('temozolomide', 'Chemical', 'MESH:D000077204', (220, 232))	('patients', 'Species', '9606', (198, 206))	('temozolomide', 'Chemical', 'MESH:D000077204', (72, 84))	('reduction', 'NegReg', (130, 139))	('reduction in lymphocyte counts', 'Phenotype', 'HP:0001888', (130, 160))	('lymphocyte counts', 'CPA', (143, 160))
55454	23686484	B6 mice that were given intermediate dose temozolomide had significantly lower percentages of Kb-Ova-specific T cells elicited by a cluster of four vaccinations that began 80 days after the last dose of temozolomide relative to untreated, age matched controls, with a peak frequency of ~1% versus ~4.5% (Figure 2C).	('mice', 'Species', '10090', (3, 7))	('temozolomide', 'Chemical', 'MESH:D000077204', (203, 215))	('temozolomide', 'Chemical', 'MESH:D000077204', (42, 54))	('Kb-Ova-specific T cells', 'CPA', (94, 117))	('temozolomide', 'Var', (42, 54))	('lower', 'NegReg', (73, 78))
55459	23686484	We next quantified the impact of temozolomide on the efficacy of vaccines in tumor bearing animals using both model antigens and mutated tumor specific neo-antigens.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutated', 'Var', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('temozolomide', 'Chemical', 'MESH:D000077204', (33, 45))
55471	23686484	Similarly, we found that inhibition of spontaneous immune responses by temozolomide treatment could lead to a failure to reject a highly immunogenic B6 glioma line expressing the SV40 Large T antigen (Figure S1).	('temozolomide', 'Chemical', 'MESH:D000077204', (71, 83))	('glioma', 'Disease', (152, 158))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('SV40', 'Var', (179, 183))
55485	23686484	Temozolomide and cyclophosphamide lead to markedly and significantly lower peak levels of antigen specific CD8 T cells in the blood following vaccination (Figure 4E).	('lower', 'NegReg', (69, 74))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (17, 33))	('CD8', 'Gene', (107, 110))	('CD8', 'Gene', '925', (107, 110))	('cyclophosphamide', 'Var', (17, 33))	('Temozolomide', 'Chemical', 'MESH:D000077204', (0, 12))
55486	23686484	By contrast, in animals treated with carboplatin and doxorubicin the percentage of antigen specific CD8 T cells was incrementally lower and not significantly different from untreated controls.	('lower', 'NegReg', (130, 135))	('doxorubicin', 'Chemical', 'MESH:D004317', (53, 64))	('carboplatin', 'Chemical', 'MESH:D016190', (37, 48))	('CD8', 'Gene', (100, 103))	('doxorubicin', 'Var', (53, 64))	('CD8', 'Gene', '925', (100, 103))	('carboplatin', 'Var', (37, 48))
55499	23686484	Despite the fact that mice treated with low dose cyclophosphamide had a depletion of Treg cells as both a percentage of CD4 T cells and in absolute numbers (data not shown), we found that circulating leukocytes from mice vaccinated after cyclophosphamide elaborated significantly less IFN-gamma upon peptide stimulation than in mice receiving vaccine only (Figure 7A).	('CD4', 'Gene', (120, 123))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (49, 65))	('less', 'NegReg', (280, 284))	('mice', 'Species', '10090', (328, 332))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (238, 254))	('cyclophosphamide', 'Var', (49, 65))	('mice', 'Species', '10090', (216, 220))	('CD4', 'Gene', '12504', (120, 123))	('IFN-gamma', 'Gene', (285, 294))	('cyclophosphamide', 'Var', (238, 254))	('Treg', 'Chemical', '-', (85, 89))	('IFN-gamma', 'Gene', '15978', (285, 294))	('elaborated', 'MPA', (255, 265))	('mice', 'Species', '10090', (22, 26))	('depletion', 'MPA', (72, 81))
55501	23686484	We found that alkylating chemotherapy has a long lasting anti-proliferative effect on lymphocytes in mice, and this effect leads to inferior responses to cancer vaccines targeting mutated self antigens.	('responses', 'MPA', (141, 150))	('anti-proliferative effect', 'CPA', (57, 82))	('cancer', 'Disease', (154, 160))	('mutated', 'Var', (180, 187))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mice', 'Species', '10090', (101, 105))	('inferior', 'NegReg', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('alkylating', 'Var', (14, 24))
55508	23686484	This DNA damage is detected by proteins such as ATM which binds to double strand DNA breaks and autophosphorylates, in turn activating numerous downstream effectors involved in cell cycle arrest and apoptosis such as Chk2 kinase and p53.	('arrest', 'Disease', (188, 194))	('double strand', 'Var', (67, 80))	('Chk2', 'Gene', '50883', (217, 221))	('p53', 'Gene', '22060', (233, 236))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (177, 194))	('ATM', 'Gene', '11920', (48, 51))	('activating', 'PosReg', (124, 134))	('ATM', 'Gene', (48, 51))	('Chk2', 'Gene', (217, 221))	('arrest', 'Disease', 'MESH:D006323', (188, 194))	('p53', 'Gene', (233, 236))
55516	23686484	We have focused on tumor specific neo-antigens derived from mutated self proteins as well as exogenous model antigens, both of which are inherently immunogenic, i.e.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutated', 'Var', (60, 67))	('tumor', 'Disease', (19, 24))
55518	23686484	Similarly, clinical experience from vaccination with idiotypic immunoglobulin for lymphoma suggests that non-germline encoded epitopes from hypervariable regions are more immunogenic and stimulate CD4 and CD8 cells preferentially over framework regions.	('stimulate', 'PosReg', (187, 196))	('epitopes', 'Var', (126, 134))	('lymphoma', 'Disease', (82, 90))	('CD8', 'Gene', '925', (205, 208))	('lymphoma', 'Disease', 'MESH:D008223', (82, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('CD4', 'Gene', (197, 200))	('immunogenic', 'MPA', (171, 182))	('CD8', 'Gene', (205, 208))	('CD4', 'Gene', '12504', (197, 200))	('more', 'PosReg', (166, 170))
55519	23686484	Recent advances in bioinformatics have made prospective identification of immunogenic mutations possible, and is an active area of further research into personalized cancer vaccines.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
55520	23686484	For personalized cancer vaccines targeting tumor specific mutations to be successful, they should be administered in a protocol designed to maximize the quality and proliferative ability of responder lymphocytes.	('mutations', 'Var', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', (17, 23))	('tumor', 'Disease', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
55521	23686484	We demonstrated that the generation of T cell responses against mutated self proteins by cancer vaccines was inhibited by temozolomide in a mouse model of glioma (Figure 3E) and by cyclophosphamide in a mouse model of melanoma (Figure 7A).	('mouse', 'Species', '10090', (140, 145))	('mouse', 'Species', '10090', (203, 208))	('temozolomide', 'Chemical', 'MESH:D000077204', (122, 134))	('inhibited', 'NegReg', (109, 118))	('self proteins', 'Protein', (72, 85))	('melanoma', 'Disease', (218, 226))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('cancer', 'Disease', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('mutated', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('T cell responses', 'CPA', (39, 55))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (181, 197))	('glioma', 'Disease', (155, 161))
55632	34007747	Similarly, in relapsed metastatic pancreatic cancer, a nanoliposomal irinotecan and 5FU-based regimen in gemcitabine refractory patients had a response rate of 16% .	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('5FU', 'Chemical', 'MESH:D005472', (84, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('irinotecan', 'Chemical', 'MESH:D000077146', (69, 79))	('patients', 'Species', '9606', (128, 136))	('gemcitabine', 'Chemical', 'MESH:C056507', (105, 116))	('nanoliposomal', 'Var', (55, 68))	('pancreatic cancer', 'Disease', (34, 51))
55647	34007747	Another major challenge is the trafficking of the cytotoxic T cells to the solid tumor that is a highly regulated process and is typically altered by a mismatch of chemokine-chemokine receptors, downregulation of adhesion molecules, and abnormal vasculature by the tumor cells or stroma .	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', (265, 270))	('downregulation', 'NegReg', (195, 209))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('chemokine-chemokine', 'Protein', (164, 183))	('altered by', 'Reg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mismatch', 'Var', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('abnormal vasculature', 'Phenotype', 'HP:0002597', (237, 257))	('adhesion molecules', 'Protein', (213, 231))	('tumor', 'Disease', (81, 86))
55653	34007747	Inhibition of these cytokines enhances the antitumor effect of tumor-infiltrating lymphocytes and improves clinical outcomes .	('tumor', 'Disease', (63, 68))	('improves', 'PosReg', (98, 106))	('enhances', 'PosReg', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('clinical outcomes', 'CPA', (107, 124))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (47, 52))
55740	33692944	Molecular data were available only for a minority of patients: 11 of 37 patiens had isocitrate dehydrogenase 1 (IDH) wild-type while p53 was expressed in 9 of 11 patients.	('isocitrate dehydrogenase 1', 'Gene', '3417', (84, 110))	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (73, 74))	('a', 'Gene', '351', (39, 40))	('IDH', 'Gene', (112, 115))	('patients', 'Species', '9606', (53, 61))	('a', 'Gene', '351', (7, 8))	('a', 'Gene', '351', (22, 23))	('a', 'Gene', '351', (54, 55))	('IDH', 'Gene', '3417', (112, 115))	('a', 'Gene', '351', (20, 21))	('patients', 'Species', '9606', (162, 170))	('a', 'Gene', '351', (13, 14))	('a', 'Gene', '351', (138, 139))	('a', 'Gene', '351', (163, 164))	('a', 'Gene', '351', (91, 92))	('a', 'Gene', '351', (11, 12))	('p53', 'Var', (133, 136))	('a', 'Gene', '351', (105, 106))	('a', 'Gene', '351', (81, 82))	('isocitrate dehydrogenase 1', 'Gene', (84, 110))
55753	33692944	Two patients were enrolled in the subsequent cohort at level V (82.5 Gy, 3.3 Gy/fraction) and both showed severe toxicity.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('a', 'Gene', '351', (90, 91))	('82.5', 'Var', (64, 68))	('a', 'Gene', '351', (52, 53))	('patients', 'Species', '9606', (4, 12))	('a', 'Gene', '351', (82, 83))	('a', 'Gene', '351', (5, 6))
55873	33613747	The tumor biology is associated with the status of different molecular markers, such as isocitrate dehydrogenase (IDH), 1p/19q codeletion, and telomerase reverse transcriptase (TERT) mutation.	('tumor', 'Disease', (4, 9))	('TERT', 'Gene', '7015', (177, 181))	('IDH', 'Gene', (114, 117))	('isocitrate dehydrogenase', 'Gene', (88, 112))	('isocitrate dehydrogenase', 'Gene', '3417', (88, 112))	('IDH', 'Gene', '3417', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('1p/19q codeletion', 'Var', (120, 137))	('TERT', 'Gene', (177, 181))
55876	33613747	proposed five molecular groups according to the three biomarkers: triple-positive (mutations in both TERT and IDH plus 1p/19q codeletion), mutations in both TERT and IDH, mutation in IDH only, mutation in TERT only, and triple-negative.	('TERT', 'Gene', '7015', (101, 105))	('mutations', 'Var', (83, 92))	('IDH', 'Gene', (110, 113))	('mutation', 'Var', (171, 179))	('mutations', 'Var', (139, 148))	('TERT', 'Gene', (157, 161))	('IDH', 'Gene', (166, 169))	('IDH', 'Gene', (183, 186))	('IDH', 'Gene', '3417', (110, 113))	('TERT', 'Gene', '7015', (157, 161))	('triple-positive', 'Disease', (66, 81))	('IDH', 'Gene', '3417', (166, 169))	('IDH', 'Gene', '3417', (183, 186))	('TERT', 'Gene', (101, 105))	('TERT', 'Gene', (205, 209))	('TERT', 'Gene', '7015', (205, 209))
55877	33613747	Recent studies on gliomas using The Cancer Genome Atlas database have revealed the association of IDH mutation, 1p/19q codeletion, and TERT promoter mutation with OS.	('gliomas', 'Disease', (18, 25))	('TERT', 'Gene', '7015', (135, 139))	('Cancer', 'Disease', (36, 42))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('gliomas', 'Disease', 'MESH:D005910', (18, 25))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('gliomas', 'Phenotype', 'HP:0009733', (18, 25))	('mutation', 'Var', (102, 110))	('glioma', 'Phenotype', 'HP:0009733', (18, 24))	('association', 'Interaction', (83, 94))	('IDH', 'Gene', (98, 101))	('1p/19q codeletion', 'Var', (112, 129))	('IDH', 'Gene', '3417', (98, 101))	('TERT', 'Gene', (135, 139))
55878	33613747	Favorable prognosis has been observed in tumors with IDH mutation and/or 1p/19q codeletion but poor prognosis in those with TERT promoter mutation.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('1p/19q codeletion', 'Var', (73, 90))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('TERT', 'Gene', (124, 128))	('IDH', 'Gene', (53, 56))	('TERT', 'Gene', '7015', (124, 128))	('IDH', 'Gene', '3417', (53, 56))
55883	33613747	Grade I tumor (pilocytic astrocytoma) are clinically and pathologically distant and therefore was not included; (iv) patients were followed up >=36 months; and v) patients had information of molecular alterations, including IDH mutation and 1p/19q codeletion, and TERT promoter mutation.	('1p/19q codeletion', 'Var', (241, 258))	('patients', 'Species', '9606', (163, 171))	('IDH', 'Gene', (224, 227))	('astrocytoma', 'Phenotype', 'HP:0009592', (25, 36))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (15, 36))	('IDH', 'Gene', '3417', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TERT', 'Gene', (264, 268))	('tumor', 'Disease', (8, 13))	('TERT', 'Gene', '7015', (264, 268))	('patients', 'Species', '9606', (117, 125))	('pilocytic astrocytoma', 'Disease', (15, 36))
55886	33613747	Identification of IDH1 mutation was performed by pyrosequencing of an 88-bp-long fragment of the IDH1 gene with the mutation hotspot at codon 132.	('IDH1', 'Gene', (97, 101))	('mutation', 'Var', (23, 31))	('IDH1', 'Gene', '3417', (18, 22))	('IDH1', 'Gene', '3417', (97, 101))	('IDH1', 'Gene', (18, 22))
55887	33613747	For IDH2 mutations, pyrosequencing was performed on an 83-bp-long fragment of the IDH2 gene with the mutation hotspot at codon 172.	('IDH2', 'Gene', (82, 86))	('mutations', 'Var', (9, 18))	('IDH2', 'Gene', (4, 8))	('IDH2', 'Gene', '3418', (82, 86))	('IDH2', 'Gene', '3418', (4, 8))
55890	33613747	Based on the status of IDH mutation, 1p/19q codeletion, and TERT promoter mutation, gliomas can be classified into five molecular groups: triple-positive (mutations in both TERT and IDH plus 1p/19q codeletion), mutations in both TERT and IDH, mutation in IDH only, triple-negative, and mutation in TERT only.	('IDH', 'Gene', (255, 258))	('mutation', 'Var', (243, 251))	('gliomas', 'Disease', (84, 91))	('IDH', 'Gene', (238, 241))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('TERT', 'Gene', (60, 64))	('IDH', 'Gene', (182, 185))	('TERT', 'Gene', (173, 177))	('TERT', 'Gene', '7015', (173, 177))	('IDH', 'Gene', '3417', (255, 258))	('TERT', 'Gene', '7015', (60, 64))	('TERT', 'Gene', (298, 302))	('TERT', 'Gene', '7015', (298, 302))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('IDH', 'Gene', '3417', (238, 241))	('IDH', 'Gene', (23, 26))	('IDH', 'Gene', '3417', (182, 185))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('IDH', 'Gene', '3417', (23, 26))	('mutations', 'Var', (155, 164))	('mutations', 'Var', (211, 220))	('triple-positive', 'Disease', (138, 153))	('TERT', 'Gene', (229, 233))	('TERT', 'Gene', '7015', (229, 233))
55893	33613747	Potential predictors including age at initial diagnosis, sex, KPS on admission, tumor location, histologic type, WHO grade, extent of surgical resection of tumor, radiotherapy, chemotherapy, IDH1 mutation, IDH2 mutation, IDH mutation, 1p deletion, 19q deletion, 1p19q codeletion, TERT promoter mutation, and molecular groups.	('IDH1', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('IDH', 'Gene', (191, 194))	('19q deletion', 'Var', (248, 260))	('tumor', 'Disease', (156, 161))	('1p19q codeletion', 'Var', (262, 278))	('IDH', 'Gene', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('IDH1', 'Gene', '3417', (191, 195))	('IDH', 'Gene', (221, 224))	('IDH', 'Gene', '3417', (191, 194))	('TERT', 'Gene', (280, 284))	('TERT', 'Gene', '7015', (280, 284))	('IDH', 'Gene', '3417', (206, 209))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('1p deletion', 'Var', (235, 246))	('IDH', 'Gene', '3417', (221, 224))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutation', 'Var', (196, 204))	('IDH2', 'Gene', (206, 210))	('mutation', 'Var', (211, 219))	('IDH2', 'Gene', '3418', (206, 210))
55906	33613747	Of the eight possible combinations based on the presence or absence of the three tumor genetic markers, five could be used to classify most of the 471 (93.3%) gliomas: triple-positive (80, 17.0%), mutations in both TERT and IDH (14, 3.0%), mutation in IDH only (91, 19.3%), triple-negative (143, 30.4%), and mutation in TERT only (143, 30.4%).	('TERT', 'Gene', '7015', (320, 324))	('gliomas', 'Disease', 'MESH:D005910', (159, 166))	('gliomas', 'Phenotype', 'HP:0009733', (159, 166))	('gliomas', 'Disease', (159, 166))	('IDH', 'Gene', (224, 227))	('TERT', 'Gene', '7015', (215, 219))	('mutation', 'Var', (308, 316))	('mutations', 'Var', (197, 206))	('IDH', 'Gene', '3417', (224, 227))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutation', 'Var', (240, 248))	('IDH', 'Gene', (252, 255))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('IDH', 'Gene', '3417', (252, 255))	('TERT', 'Gene', (320, 324))	('TERT', 'Gene', (215, 219))	('tumor', 'Disease', (81, 86))
55916	33613747	Specifically, AUCs of the LR based on the Cox analysis, LASSO, and McDSL in predicting 3-year PFS probability were 0.849 (95% CI: 0.800-0.898), 0.869 (95% CI: 0.823-0.915), and 0.872 (95% CI: 0.828-0.916), respectively; AUCs of the LR based on the three selection methods in predicting 3-year OS probability were 0.870 (95% CI: 0.823-0.918), 0.901 (95% CI: 0.861-0.940), and 0.892 (95% CI: 0.851-0.933), respectively.	('Cox', 'Gene', (42, 45))	('Cox', 'Gene', '1351', (42, 45))	('0.901', 'Var', (342, 347))
55922	33613747	Among all of the known glioma-associated molecular alterations discovered to date, the status of an IDH mutation has the largest prognostic significance.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('IDH', 'Gene', (100, 103))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('IDH', 'Gene', '3417', (100, 103))	('glioma', 'Disease', (23, 29))	('mutation', 'Var', (104, 112))
55923	33613747	IDH mutations were noted in the vast majority of grade II and III gliomas, which were associated with improved survival as compared to glioblastoma (GBM).	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('IDH', 'Gene', (0, 3))	('improved', 'PosReg', (102, 110))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('grade II', 'Disease', (49, 57))	('III gliomas', 'Disease', 'MESH:D005910', (62, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))	('mutations', 'Var', (4, 13))	('glioblastoma', 'Disease', (135, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('III gliomas', 'Disease', (62, 73))
55924	33613747	Patients with an IDH mutation gliomas had a significantly longer OS as compared with those with an IDH wildtype gliomas, with a median OS of 1.7, 6.3 and 8.0 years for patients with IDH wildtype, patients with IDH mutation only (astrocytic gliomas) and patients with IDH mutation plus 1p/19q codeletion (oligodendroglial gliomas), respectively.	('IDH', 'Gene', '3417', (99, 102))	('IDH', 'Gene', '3417', (210, 213))	('oligodendroglial gliomas', 'Disease', 'MESH:D005910', (304, 328))	('gliomas', 'Disease', (321, 328))	('patients', 'Species', '9606', (253, 261))	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('patients', 'Species', '9606', (196, 204))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (229, 247))	('astrocytic gliomas', 'Disease', (229, 247))	('IDH', 'Gene', (182, 185))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))	('IDH', 'Gene', '3417', (17, 20))	('gliomas', 'Disease', 'MESH:D005910', (321, 328))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('Patients', 'Species', '9606', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (321, 327))	('gliomas', 'Disease', (240, 247))	('IDH', 'Gene', '3417', (182, 185))	('gliomas', 'Phenotype', 'HP:0009733', (321, 328))	('gliomas', 'Disease', (112, 119))	('IDH', 'Gene', (267, 270))	('IDH', 'Gene', (99, 102))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('gliomas', 'Disease', 'MESH:D005910', (240, 247))	('IDH', 'Gene', (210, 213))	('oligodendroglial gliomas', 'Disease', (304, 328))	('glioma', 'Phenotype', 'HP:0009733', (240, 246))	('mutation', 'Var', (21, 29))	('gliomas', 'Disease', (30, 37))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('patients', 'Species', '9606', (168, 176))	('IDH', 'Gene', '3417', (267, 270))	('IDH', 'Gene', (17, 20))	('gliomas', 'Phenotype', 'HP:0009733', (240, 247))
55925	33613747	Additionally, in a recent study of grade III glioma patients treated with radiotherapy and either temozolomide or nitrosourea, IDH mutation status was found to be a significant prognostic factor for PFS (hazard ratio HR] = 0.59) and OS (HR = 0.42).	('PFS', 'Disease', (199, 202))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('temozolomide', 'Chemical', 'MESH:D000077204', (98, 110))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('nitrosourea', 'Chemical', 'MESH:D009607', (114, 125))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', (45, 51))	('patients', 'Species', '9606', (52, 60))	('mutation', 'Var', (131, 139))
55927	33613747	The median OS of patients with 1p/19q codeleted tumors was 11.9 years, significantly longer than that of 8.1 years for patients with 1p/19q intact tumors.	('longer', 'PosReg', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('1p/19q codeleted', 'Var', (31, 47))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('patients', 'Species', '9606', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
55928	33613747	Regardless of treatment protocol, patients with combined 1p/19q codeletion and IDH mutation had the longest PFS at 62 months as compared with 48 months for IDH mutant alone and 20 months for IDH wildtype.	('IDH', 'Gene', (79, 82))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (191, 194))	('PFS', 'MPA', (108, 111))	('IDH', 'Gene', (156, 159))	('IDH', 'Gene', '3417', (191, 194))	('patients', 'Species', '9606', (34, 42))	('1p/19q codeletion', 'Var', (57, 74))	('IDH', 'Gene', '3417', (156, 159))
55929	33613747	TERT promoter mutations were found in approximately 80% of IDH wildtype GBM, and in the majority of IDH mutant, 1p/19q codeleted oligodendrogliomas.	('IDH', 'Gene', (100, 103))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('IDH', 'Gene', (59, 62))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (129, 147))	('IDH', 'Gene', '3417', (100, 103))	('IDH', 'Gene', '3417', (59, 62))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('oligodendrogliomas', 'Disease', (129, 147))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('1p/19q', 'Var', (112, 118))
55981	32561881	3) do not have any specific binding of [18 F]PBR111.	('PBR111', 'Chemical', '-', (45, 51))	('PBR111', 'Gene', (45, 51))	('[18 F]', 'Var', (39, 45))	('binding', 'Interaction', (28, 35))
55984	32561881	In contrast, in TSPO-/- animals bearing the diffusely infiltrating wild-type glioma, the [18 F]PBR111 retention and signal was restricted to the tumour volume without any appreciable signal in the Tspo-/- host tissue (Fig.	('tumour', 'Disease', (145, 151))	('TSPO', 'Gene', '12257', (16, 20))	('TSPO', 'Gene', (16, 20))	('Tspo', 'Gene', '12257', (197, 201))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('glioma', 'Disease', (77, 83))	('PBR111', 'Chemical', '-', (95, 101))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('[18 F]', 'Var', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('Tspo', 'Gene', (197, 201))
56038	32532977	These results collectively reveal an important association between ARS2 mRNA expression and high-grade glioma as well as poor patient survival.	('glioma', 'Disease', (103, 109))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('patient', 'Species', '9606', (126, 133))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('ARS2', 'Gene', (67, 71))	('mRNA', 'Var', (72, 76))
56046	32532977	Specific knockdown of ARS2 suppressed expression of Nestin, a marker of undifferentiated cells, with a concurrent increase in the expression of glial fibrillary acidic protein (GFAP), a marker of differentiation, in GSC 528 and X01 cells (Fig.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('expression', 'MPA', (130, 140))	('increase', 'PosReg', (114, 122))	('knockdown', 'Var', (9, 18))	('GFAP', 'Gene', (177, 181))	('glial fibrillary acidic protein', 'Gene', (144, 175))	('expression', 'MPA', (38, 48))	('glial fibrillary acidic protein', 'Gene', '2670', (144, 175))	('suppressed', 'NegReg', (27, 37))	('X01', 'CellLine', 'CVCL:C656', (228, 231))	('GFAP', 'Gene', '2670', (177, 181))	('ARS2', 'Gene', (22, 26))	('S', 'Chemical', 'MESH:D013455', (24, 25))	('S', 'Chemical', 'MESH:D013455', (217, 218))	('Nestin', 'Gene', (52, 58))	('GSC', 'Chemical', '-', (216, 219))
56048	32532977	Knockdown of ARS2 significantly decreased the sphere-forming ability of GSCs in limiting dilution assays, a widely used method for determining the self-renewal capacity of stem cells (Fig.	('Knockdown', 'Var', (0, 9))	('sphere-forming ability of GSCs', 'CPA', (46, 76))	('GSCs', 'Chemical', '-', (72, 76))	('decreased', 'NegReg', (32, 41))	('ARS2', 'Gene', (13, 17))
56049	32532977	Knockdown of ARS2 also significantly blocked proliferation of GSCs (Fig.	('proliferation of GSCs', 'CPA', (45, 66))	('Knockdown', 'Var', (0, 9))	('blocked', 'NegReg', (37, 44))	('GSCs', 'Chemical', '-', (62, 66))	('ARS2', 'Gene', (13, 17))
56053	32532977	Moreover, overall survival was significantly longer in both ARS2-knockdown xenografts than in control mice (Fig.	('mice', 'Species', '10090', (102, 106))	('overall survival', 'CPA', (10, 26))	('ARS2-knockdown', 'Var', (60, 74))	('ARS2-knockdown', 'Gene', (60, 74))	('longer', 'PosReg', (45, 51))
56055	32532977	Considering that ARS2 is a well-known transcriptional regulator involved in the maintenance of NSC stemness, we performed transcriptome profiling using RNA sequencing (RNA-Seq) analysis after deletion of ARS2.	('S', 'Chemical', 'MESH:D013455', (172, 173))	('S', 'Chemical', 'MESH:D013455', (206, 207))	('S', 'Chemical', 'MESH:D013455', (96, 97))	('NSC stemness', 'Disease', (95, 107))	('S', 'Chemical', 'MESH:D013455', (19, 20))	('deletion', 'Var', (192, 200))	('ARS2', 'Gene', (204, 208))	('NSC stemness', 'Disease', 'OMIM:617394', (95, 107))
56056	32532977	Each gene identified as being downregulated upon ARS2-knockdown was carefully examined for its significance in cancer pathogenesis.	('downregulated', 'NegReg', (30, 43))	('ARS2-knockdown', 'Var', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ARS2-knockdown', 'Gene', (49, 63))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
56058	32532977	The most promising gene downregulated upon ARS2-knockdown was MGLL, encoding MAGL (Fig.	('downregulated', 'NegReg', (24, 37))	('ARS2-knockdown', 'Var', (43, 57))	('MGLL', 'Gene', '11343', (62, 66))	('MGLL', 'Gene', (62, 66))
56065	32532977	3b, antibodies against ARS2 effectively immunoprecipitated a specific region upstream of the MGLL gene corresponding to regions 3 (-1018 to -887 bp) and 4 (-1300 to -1093 bp).	('-1018 to -887 bp', 'Var', (131, 147))	('MGLL', 'Gene', '11343', (93, 97))	('-1300 to -1093 bp', 'Var', (156, 173))	('MGLL', 'Gene', (93, 97))
56069	32532977	3h, ARS2 knockdown in X01 cells significantly decreased relative luciferase expression, indicating reduced transcriptional activity of ARS2 toward MGLL.	('ARS2', 'Gene', (4, 8))	('knockdown', 'Var', (9, 18))	('X01', 'CellLine', 'CVCL:C656', (22, 25))	('transcriptional activity', 'MPA', (107, 131))	('expression', 'MPA', (76, 86))	('MGLL', 'Gene', '11343', (147, 151))	('decreased', 'NegReg', (46, 55))	('MGLL', 'Gene', (147, 151))	('reduced', 'NegReg', (99, 106))	('luciferase', 'Enzyme', (65, 75))
56073	32532977	Conversely, deletion of MAGL in 528 and X01 cells completely abrogated sphere-forming ability (Fig.	('deletion', 'Var', (12, 20))	('MAGL', 'Gene', (24, 28))	('sphere-forming ability', 'CPA', (71, 93))	('abrogated', 'NegReg', (61, 70))	('X01', 'CellLine', 'CVCL:C656', (40, 43))
56074	32532977	Moreover, MAGL knockdown in 528 and X01 cells induced expression of the astrocytic differentiation marker, GFAP, but decreased levels of the stemness marker, Nestin (Supplementary Fig.	('expression', 'MPA', (54, 64))	('Nestin', 'MPA', (158, 164))	('knockdown', 'Var', (15, 24))	('MAGL', 'Gene', (10, 14))	('S', 'Chemical', 'MESH:D013455', (166, 167))	('GFAP', 'Gene', '2670', (107, 111))	('decreased', 'NegReg', (117, 126))	('levels of', 'MPA', (127, 136))	('X01', 'CellLine', 'CVCL:C656', (36, 39))	('GFAP', 'Gene', (107, 111))
56075	32532977	These loss- and gain-of-function analyses of MAGL demonstrated that the functional effects of modulating MAGL expression on GSC self-renewal are similar to those of modulating ARS2 expression.	('modulating', 'Var', (94, 104))	('GSC', 'Chemical', '-', (124, 127))	('loss-', 'NegReg', (6, 11))	('expression', 'MPA', (110, 120))	('GSC self-renewal', 'CPA', (124, 140))	('MAGL', 'Gene', (105, 109))	('gain-of-function', 'PosReg', (16, 32))
56076	32532977	To examine the effects of ARS2-regulated MAGL expression on the recovery of GSC self-renewal capacity, we knocked down ARS2 and then overexpressed MAGL in GSC X01 cells.	('ARS2', 'Gene', (119, 123))	('GSC', 'Chemical', '-', (155, 158))	('MAGL', 'Gene', (147, 151))	('GSC', 'Chemical', '-', (76, 79))	('X01', 'CellLine', 'CVCL:C656', (159, 162))	('knocked', 'Var', (106, 113))	('overexpressed', 'PosReg', (133, 146))
56080	32532977	Tumors were reduced in size, or were nonexistent, in MAGL-knockdown xenografts (Supplementary Fig.	('MAGL-knockdown', 'Gene', (53, 67))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('reduced', 'NegReg', (12, 19))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MAGL-knockdown', 'Var', (53, 67))
56085	32532977	To address the role of MAGL in GSCs, we first examined whether ARS2 depletion in GSCs modulates FFA levels by directly suppressing expression of MAGL, as previously reported in other cancers.	('cancers', 'Disease', (183, 190))	('ARS2', 'Gene', (63, 67))	('suppressing', 'NegReg', (119, 130))	('GSCs', 'Chemical', '-', (81, 85))	('FFA levels', 'MPA', (96, 106))	('depletion', 'Var', (68, 77))	('modulates', 'Reg', (86, 95))	('expression', 'MPA', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('GSCs', 'Chemical', '-', (31, 35))	('GSCs', 'Disease', (81, 85))	('MAGL', 'Gene', (145, 149))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
56092	32532977	Knockdown of MAGL simultaneously decreased PGE2 production and beta-catenin accumulation in GSCs (Fig.	('MAGL', 'Gene', (13, 17))	('GSCs', 'Chemical', '-', (92, 96))	('PGE2', 'Chemical', 'MESH:D015232', (43, 47))	('Knockdown', 'Var', (0, 9))	('PGE2 production', 'MPA', (43, 58))	('beta-catenin accumulation', 'MPA', (63, 88))	('decreased', 'NegReg', (33, 42))
56095	32532977	As expected, MAGL or ARS2 knockdown in 528 and X01 cells reduced beta-catenin protein levels in nuclear fraction (Fig.	('ARS2', 'Gene', (21, 25))	('knockdown', 'Var', (26, 35))	('beta-catenin protein levels in nuclear fraction', 'MPA', (65, 112))	('reduced', 'NegReg', (57, 64))	('X01', 'CellLine', 'CVCL:C656', (47, 50))
56105	32532977	In these xenograft mouse models, ARS2 or MAGL knockdown decreased staining for Iba-1, a marker of TAMs, suggesting inflammatory signaling associated with ARS2 or MAGL potentially regulates the tumorigenicity of GSCs (Supplementary Fig.	('knockdown', 'Var', (46, 55))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('regulates', 'Reg', (179, 188))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('decreased', 'NegReg', (56, 65))	('TAMs', 'Chemical', '-', (98, 102))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mouse', 'Species', '10090', (19, 24))	('tumor', 'Disease', (193, 198))	('staining', 'MPA', (66, 74))	('S', 'Chemical', 'MESH:D013455', (217, 218))	('S', 'Chemical', 'MESH:D013455', (212, 213))	('GSCs', 'Chemical', '-', (211, 215))
56108	32532977	It has previously been reported that these two subtypes of TAMs acquire opposite functions in relation to cancer: the M1-like subtype protects against cancer by suppressing angiogenesis, whereas the M2-like subtype is more likely to worsen cancer prognosis through enhanced invasion and tumor growth.	('invasion', 'CPA', (274, 282))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (151, 157))	('tumor', 'Disease', (287, 292))	('TAMs', 'Chemical', '-', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('suppressing', 'NegReg', (161, 172))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('worsen', 'NegReg', (233, 239))	('angiogenesis', 'CPA', (173, 185))	('enhanced', 'PosReg', (265, 273))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('M2-like', 'Var', (199, 206))
56122	32532977	Among the six genes, four of them (Lipocalin 2, HGF, VEGF, and IL6) were significantly upregulated by PGE2 treatment (Supplementary Fig.	('PGE2', 'Chemical', 'MESH:D015232', (102, 106))	('IL6', 'Gene', '3569', (63, 66))	('Lipocalin 2', 'Gene', (35, 46))	('PGE2', 'Gene', (102, 106))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('VEGF', 'Gene', (53, 57))	('HGF', 'Gene', (48, 51))	('HGF', 'Gene', '3082', (48, 51))	('IL6', 'Gene', (63, 66))	('Lipocalin 2', 'Gene', '3934', (35, 46))	('upregulated', 'PosReg', (87, 98))	('treatment', 'Var', (107, 116))	('VEGF', 'Gene', '7422', (53, 57))
56131	32532977	Therefore, our data support the conclusion that M1-like TAM polarization is increased by ARS2 or MAGL knockdown.	('ARS2', 'Gene', (89, 93))	('increased', 'PosReg', (76, 85))	('TAM', 'Gene', (56, 59))	('MAGL', 'Gene', (97, 101))	('knockdown', 'Var', (102, 111))	('TAM', 'Gene', '8205', (56, 59))
56132	32532977	Importantly, expression of the stemness marker Nestin was decreased and expression of the differentiation marker GFAP was increased in tumor tissues formed from ARS2- or MAGL-knockdown GSCs (Fig.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GFAP', 'Gene', (113, 117))	('Nestin', 'Protein', (47, 53))	('expression', 'MPA', (13, 23))	('ARS2-', 'Gene', (161, 166))	('decreased', 'NegReg', (58, 67))	('tumor', 'Disease', (135, 140))	('expression', 'MPA', (72, 82))	('MAGL-knockdown', 'Var', (170, 184))	('GSCs', 'Chemical', '-', (185, 189))	('GFAP', 'Gene', '2670', (113, 117))	('increased', 'PosReg', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
56136	32532977	JZL184 at a concentration as low as 1 muM eliminated detectable MAGL hydrolase activity in the GSC cell lines, 528 and X01 (Supplementary Fig.	('activity', 'MPA', (79, 87))	('JZL184', 'Var', (0, 6))	('muM', 'Gene', '56925', (38, 41))	('S', 'Chemical', 'MESH:D013455', (96, 97))	('S', 'Chemical', 'MESH:D013455', (124, 125))	('eliminated', 'NegReg', (42, 52))	('muM', 'Gene', (38, 41))	('MAGL hydrolase', 'Enzyme', (64, 78))	('X01', 'CellLine', 'CVCL:C656', (119, 122))	('GSC', 'Chemical', '-', (95, 98))	('JZL184', 'Chemical', 'MESH:C534333', (0, 6))
56139	32532977	Treatment with JZL184 decreased tumor mass; immunohistochemical staining further showed that JZL184 decreased MAGL levels and the number of Iba-1-expressing cells (Fig.	('decreased MAGL', 'Phenotype', 'HP:0002850', (100, 114))	('Iba-1-expressing', 'Gene', (140, 156))	('JZL184', 'Chemical', 'MESH:C534333', (93, 99))	('MAGL levels', 'MPA', (110, 121))	('JZL184', 'Var', (93, 99))	('JZL184', 'Chemical', 'MESH:C534333', (15, 21))	('decreased', 'NegReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('decreased tumor', 'Disease', (22, 37))	('decreased tumor', 'Disease', 'MESH:D002303', (22, 37))
56140	32532977	Notably, administration of JZL184 was sufficient to suppress MAGL expression in GSCs and infiltration of TAMs (Fig.	('JZL184', 'Var', (27, 33))	('suppress', 'NegReg', (52, 60))	('MAGL', 'Protein', (61, 65))	('JZL184', 'Chemical', 'MESH:C534333', (27, 33))	('infiltration', 'CPA', (89, 101))	('GSCs', 'Chemical', '-', (80, 84))	('TAMs', 'Chemical', '-', (105, 109))
56142	32532977	M1-like TAM polarization, represented by the marker CD86, was increased in X01 cells by treatment with JZL184, whereas M2-like TAMs, marked by CD206 and ARG1 expression, exhibited an opposite response to JZL184 administration (Fig.	('increased', 'PosReg', (62, 71))	('TAMs', 'Chemical', '-', (127, 131))	('JZL184', 'Var', (103, 109))	('M1-like', 'MPA', (0, 7))	('JZL184', 'Chemical', 'MESH:C534333', (204, 210))	('TAM', 'Gene', '8205', (8, 11))	('TAM', 'Gene', (8, 11))	('TAM', 'Gene', '8205', (127, 130))	('ARG1 expression', 'MPA', (153, 168))	('X01', 'CellLine', 'CVCL:C656', (75, 78))	('TAM', 'Gene', (127, 130))	('JZL184', 'Chemical', 'MESH:C534333', (103, 109))
56145	32532977	These experiments revealed that survival was significantly longer for JZL184-treated xenograft mice compared with vehicle-treated controls (Fig.	('JZL184-treated', 'Var', (70, 84))	('mice', 'Species', '10090', (95, 99))	('longer', 'PosReg', (59, 65))	('survival', 'CPA', (32, 40))	('JZL184', 'Chemical', 'MESH:C534333', (70, 76))
56149	32532977	These beneficial effects of JZL184 or celecoxib treatment indicate that pharmacological inhibition of MAGL or COX2 to block PGE2 production suppresses the self-renewal and tumorigenic capacity of GSCs and promotes M1-like polarization of TAMs.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('celecoxib', 'Chemical', 'MESH:D000068579', (38, 47))	('tumor', 'Disease', (172, 177))	('TAMs', 'Chemical', '-', (238, 242))	('GSCs', 'Chemical', '-', (196, 200))	('suppresses', 'NegReg', (140, 150))	('COX2', 'Gene', '4513', (110, 114))	('PGE2', 'Chemical', 'MESH:D015232', (124, 128))	('self-renewal', 'CPA', (155, 167))	('COX2', 'Gene', (110, 114))	('JZL184', 'Chemical', 'MESH:C534333', (28, 34))	('PGE2', 'Gene', (124, 128))	('promotes', 'PosReg', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('inhibition', 'Var', (88, 98))	('M1-like polarization of TAMs', 'CPA', (214, 242))
56160	32532977	These results suggest that pharmacological inhibition of MAGL blocks MES subtype change which is triggered by infiltrating M2-like macrophage.	('MES', 'Disease', (69, 72))	('MES', 'Chemical', '-', (69, 72))	('blocks', 'NegReg', (62, 68))	('pharmacological inhibition', 'Var', (27, 53))	('MAGL', 'Gene', (57, 61))
56166	32532977	So, we designed combination treatment of JZL184 and anti-PD-1 monoclonal antibody in syngeneic mouse model, which showed synergistic effect to improve the median survival (Fig.	('JZL184', 'Var', (41, 47))	('median survival', 'CPA', (155, 170))	('improve', 'PosReg', (143, 150))	('JZL184', 'Chemical', 'MESH:C534333', (41, 47))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('mouse', 'Species', '10090', (95, 100))
56171	32532977	Moreover, we provide the first demonstration that pharmacological inhibition of MAGL effectively suppresses GSC self-renewal and tumorigenicity:the major therapeutic challenges in GBM.	('pharmacological', 'Var', (50, 65))	('suppresses', 'NegReg', (97, 107))	('GSC', 'Chemical', '-', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MAGL', 'Gene', (80, 84))	('tumor', 'Disease', (129, 134))	('GSC self-renewal', 'CPA', (108, 124))
56192	32532977	Although this classification scheme is not absolute, each subtype generally exhibits a phenotype opposite that of the other: the M2-like subtype is correlated with high-risk glioma patients and tumor invasion, whereas the M1-like subtype is associated with suppression of angiogenesis and tumor growth:characteristics that may offer promising therapeutic advantages.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('correlated', 'Reg', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (289, 294))	('glioma', 'Disease', (174, 180))	('M2-like', 'Var', (129, 136))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Disease', (194, 199))	('angiogenesis', 'CPA', (272, 284))	('suppression', 'CPA', (257, 268))
56193	32532977	In the current study, we utilized an immunofluorescence approach to visualize CD86, a marker of M1-like TAM polarization, and CD206 and ARG1, markers of M2-like polarization.	('CD86', 'Gene', (78, 82))	('TAM', 'Gene', (104, 107))	('ARG1', 'Var', (136, 140))	('TAM', 'Gene', '8205', (104, 107))	('CD206', 'Var', (126, 131))
56194	32532977	Overall, knockdown of ARS2 or MAGL expression decreased neuroinflammation, but different trends in ARS2 and MAGL expression were observed in relation to the phenotypes of TAMs: whereas ARS2 and MAGL expression in GSCs were both correlated with upregulation of the M2-like phenotype, knockdown of either factor led to an increase in the M1-like polarization.	('increase', 'PosReg', (320, 328))	('ARS2', 'Gene', (185, 189))	('M1-like polarization', 'CPA', (336, 356))	('knockdown', 'Var', (9, 18))	('TAMs', 'Chemical', '-', (171, 175))	('knockdown', 'Var', (283, 292))	('GSCs', 'Chemical', '-', (213, 217))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('decreased', 'NegReg', (46, 55))	('MAGL', 'Gene', (194, 198))	('upregulation', 'PosReg', (244, 256))	('M2-like phenotype', 'MPA', (264, 281))
56197	32532977	Already known for its high selectivity for MAGL, JZL184 treatment clearly suppressed MAGL expression both in vitro and in vivo, in association with a significant reduction in the self-renewal capacity of GSCs and suppression of neuroinflammation.	('self-renewal capacity of GSCs', 'CPA', (179, 208))	('JZL184', 'Chemical', 'MESH:C534333', (49, 55))	('reduction', 'NegReg', (162, 171))	('MAGL', 'Gene', (85, 89))	('JZL184', 'Var', (49, 55))	('suppressed', 'NegReg', (74, 84))	('expression', 'MPA', (90, 100))	('suppression of neuroinflammation', 'Disease', 'MESH:D011596', (213, 245))	('GSCs', 'Chemical', '-', (204, 208))	('suppression of neuroinflammation', 'Disease', (213, 245))
56198	32532977	It should be noted that previous studies in mice have shown that treatment with JZL184 is accompanied by side effects related to cannabinoid receptor 1-dependent signaling, including analgesia, hypothermia, and/or gastrointestinal bleeding.	('hypothermia', 'Disease', 'MESH:D007035', (194, 205))	('JZL184', 'Chemical', 'MESH:C534333', (80, 86))	('gastrointestinal bleeding', 'Disease', (214, 239))	('JZL184', 'Var', (80, 86))	('cannabinoid receptor 1', 'Gene', '12801', (129, 151))	('hypothermia', 'Disease', (194, 205))	('cannabinoid receptor 1', 'Gene', (129, 151))	('analgesia', 'Disease', (183, 192))	('hypothermia', 'Phenotype', 'HP:0002045', (194, 205))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (214, 239))	('mice', 'Species', '10090', (44, 48))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (214, 239))
56201	32532977	In conclusion, we identified ARS2 as a new and important transcription factor that promotes the stem cell identity of GSCs through MAGL-mediated signaling and further showed that blockade of MAGL provides a promising therapeutic avenue for treating GBM.	('blockade', 'Var', (179, 187))	('promotes', 'PosReg', (83, 91))	('MAGL-mediated signaling', 'MPA', (131, 154))	('stem cell identity', 'CPA', (96, 114))	('MAGL', 'Gene', (191, 195))	('GBM', 'Disease', (249, 252))	('ARS2', 'Gene', (29, 33))	('GSCs', 'Chemical', '-', (118, 122))
56239	32532977	After 24 h, cells were treated with JZL184 (1 muM and 2 muM) or vehicle (DMSO) for 24 h and harvested for MAGL hydrolase activity measurements.	('DMSO', 'Chemical', 'MESH:D004121', (73, 77))	('JZL184', 'Chemical', 'MESH:C534333', (36, 42))	('muM', 'Gene', '56925', (56, 59))	('JZL184', 'Var', (36, 42))	('muM', 'Gene', '56925', (46, 49))	('muM', 'Gene', (56, 59))	('muM', 'Gene', (46, 49))
56247	32532977	After permeabilization, GSCs were immunostained for the cancer stem cell markers, Nestin (BD Biosciences, 611658, 1:500) and GFAP (MP Biomedicals, 691102, 1:500), as ARS2 (Genetex, GTX119872, 1:500), PGE2 (Abcam, ab2318, 1:100), and beta-Catenin(D10A8, Cell Signaling Technology, #8480, 1:500), CD86 (EP1158Y, Abcam, ab53004, 1:500), CD206 (Abcam, ab64693, 1:500), ARG1 (E-2, Santa Cruz Biotech, sc-271430, 1:500) by incubating overnight at 4  C in a humidified chamber with primary antibody, diluted for the working concentration with antibody diluent buffer (IHC World).	('E-2', 'Gene', (371, 374))	('GFAP', 'Gene', '2670', (125, 129))	('cancer', 'Disease', (56, 62))	('beta-Catenin', 'Gene', (233, 245))	('P', 'Chemical', 'MESH:D010758', (132, 133))	('S', 'Chemical', 'MESH:D013455', (258, 259))	('S', 'Chemical', 'MESH:D013455', (376, 377))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('PGE2', 'Chemical', 'MESH:D015232', (200, 204))	('P', 'Chemical', 'MESH:D010758', (200, 201))	('CD206', 'Var', (334, 339))	('P', 'Chemical', 'MESH:D010758', (302, 303))	('P', 'Chemical', 'MESH:D010758', (128, 129))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('S', 'Chemical', 'MESH:D013455', (168, 169))	('E-2', 'Gene', '26765', (371, 374))	('S', 'Chemical', 'MESH:D013455', (25, 26))	('ARG1', 'Var', (365, 369))	('GSCs', 'Chemical', '-', (24, 28))	('GFAP', 'Gene', (125, 129))	('beta-Catenin', 'Gene', '1499', (233, 245))
56263	32532977	On day 5, naive BMDMs were stimulated with LPS (10 ng/mL; Sigma-Aldrich) or IL-4 (10 ng/mL; Selleckem) to generate the BMDM-M1 or BMDM-M2 macrophages, respectively, for 24 h. For surface marker analysis, live cells were re-suspended in 0.1% BSA 1xPBS and stained with anti-mouse F4/80 (PE, 1:100, Invitrogen), CD11b (PerCP-Cyanine5.5, 1:100 Invitrogen), and CD86 (APC, 1:100, BioLegend) at 4  C for 20 min.	('IL-4', 'Gene', '3565', (76, 80))	('APC', 'Gene', '11789', (364, 367))	('S', 'Chemical', 'MESH:D013455', (92, 93))	('CD11b', 'Gene', '16409', (310, 315))	('IL-4', 'Gene', (76, 80))	('P', 'Chemical', 'MESH:D010758', (321, 322))	('P', 'Chemical', 'MESH:D010758', (44, 45))	('S', 'Chemical', 'MESH:D013455', (45, 46))	('PBS', 'Chemical', 'MESH:D007854', (247, 250))	('S', 'Chemical', 'MESH:D013455', (249, 250))	('CD86', 'Var', (358, 362))	('S', 'Chemical', 'MESH:D013455', (242, 243))	('CD11b', 'Gene', (310, 315))	('S', 'Chemical', 'MESH:D013455', (58, 59))	('P', 'Chemical', 'MESH:D010758', (247, 248))	('F4/80', 'Gene', '13733', (279, 284))	('APC', 'Gene', (364, 367))	('P', 'Chemical', 'MESH:D010758', (286, 287))	('P', 'Chemical', 'MESH:D010758', (317, 318))	('P', 'Chemical', 'MESH:D010758', (365, 366))	('mouse', 'Species', '10090', (273, 278))	('LPS', 'Chemical', 'MESH:D008070', (43, 46))	('F4/80', 'Gene', (279, 284))
56303	32532977	J.Y., E.C., S.S.K., Y.T.O., J.H.H., S.H.P., J.H.K., W.L., and Y.Y.	('P', 'Chemical', 'MESH:D010758', (40, 41))	('J.H.K.', 'Var', (44, 50))	('S.H.P.', 'Var', (36, 42))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('S.S.K.', 'Var', (12, 18))	('S', 'Chemical', 'MESH:D013455', (12, 13))	('J.H.H.', 'Var', (28, 34))	('J.H.H', 'CellLine', 'CVCL:Y658', (28, 33))	('S', 'Chemical', 'MESH:D013455', (14, 15))
56306	32532977	H.K., J.L., D.H.N., K.S.C., and B.Y.	('S', 'Chemical', 'MESH:D013455', (22, 23))	('D.H.N.', 'Var', (12, 18))	('K.S.C.', 'Var', (20, 26))
56308	32532977	J.Y., E.C., S.S.K., Y.T.O., A.I., J.H.K., and J.B.P.	('J.H.K.', 'Var', (34, 40))	('S.S.K.', 'Var', (12, 18))	('S', 'Chemical', 'MESH:D013455', (12, 13))	('A.I.', 'Var', (28, 32))	('S', 'Chemical', 'MESH:D013455', (14, 15))	('P', 'Chemical', 'MESH:D010758', (50, 51))
56310	32532977	RNA sequencing data have been uploaded in European Genome-phenome Archive (EGA) with EGA-box-1261 accession code and NCBI Gene Expression Omnibus (GEO) with GSE150630 and GSE150631.	('GSE150630', 'Var', (157, 166))	('GSE150631', 'Var', (171, 180))	('S', 'Chemical', 'MESH:D013455', (158, 159))	('S', 'Chemical', 'MESH:D013455', (172, 173))
56341	32474411	Lui et al reported improved survival in a subset of B16F10 melanoma-bearing mice with anti-PD-1 (programmed death-1) immunotherapy.	('B16F10', 'CellLine', 'CVCL:0159', (52, 58))	('survival', 'CPA', (28, 36))	('mice', 'Species', '10090', (76, 80))	('anti-PD-1', 'Var', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('improved', 'PosReg', (19, 27))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
56345	32474411	Pre-treatment biopsies did not show any immune cell population differences between responders and non-responders, but early on-treatment biopsies showed higher CD8+ cell populations in responders to anti-CTLA-4.	('CD8', 'Gene', '925', (160, 163))	('higher', 'PosReg', (153, 159))	('anti-CTLA-4', 'Var', (199, 210))	('CD8', 'Gene', (160, 163))
56351	32474411	They discovered that objective response was achieved in 28.4% of patients with PD-L1 expression >5%, in 23.8% of patients with PD-L1 expression >1% and in only 16.1% in patients with PD-L1 expression <1%.	('>5%', 'Var', (96, 99))	('PD-L1', 'Gene', (183, 188))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (113, 121))	('PD-L1', 'Gene', '29126', (183, 188))	('PD-L1', 'Gene', (79, 84))	('PD-L1', 'Gene', (127, 132))	('patients', 'Species', '9606', (65, 73))	('expression >5%', 'Var', (85, 99))	('PD-L1', 'Gene', '29126', (79, 84))	('PD-L1', 'Gene', '29126', (127, 132))
56356	32474411	When analyzing blood and tumor tissue from 45 patients undergoing checkpoint blockade, they found that combination therapy with antibodies targeting PD-1 and CTLA-4 led to an increase in T cell genes differentially expressed and a robust upregulation of IFN-gamma.	('T cell genes', 'Gene', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('patients', 'Species', '9606', (46, 54))	('IFN-gamma', 'Protein', (254, 263))	('upregulation', 'PosReg', (238, 250))	('tumor', 'Disease', (25, 30))	('increase in T cell', 'Phenotype', 'HP:0100828', (175, 193))	('increase', 'PosReg', (175, 183))	('antibodies', 'Var', (128, 138))	('CTLA-4', 'Gene', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('combination', 'Interaction', (103, 114))	('PD-1', 'Gene', (149, 153))
56361	32474411	High mutational burden has been associated with greater therapeutic response to immune therapy in non-CNS malignancies, particularly NSCLC and melanoma, among others.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('High mutational burden', 'Var', (0, 22))	('malignancies', 'Disease', (106, 118))	('greater', 'PosReg', (48, 55))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('NSCLC', 'Disease', (133, 138))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
56362	32474411	Mutational burden has been particularly supported as a predictive biomarker of clinical benefit for patients with NSCLC on immune therapy, despite it not being prognostic of survival for patients not on immune therapy.	('patients', 'Species', '9606', (187, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (114, 119))	('patients', 'Species', '9606', (100, 108))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('Mutational burden', 'Var', (0, 17))
56376	32474411	More importantly, however, a subgroup analysis of 27 patients with brain metastases showed that NLR <4.7 and dNLR <3.8 were associated with extended OS and progression-free survival (PFS).	('metastases', 'Disease', (73, 83))	('OS', 'Gene', '17451', (149, 151))	('patients', 'Species', '9606', (53, 61))	('NLR', 'Gene', (96, 99))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('progression-free survival', 'CPA', (156, 181))	('dNLR', 'Var', (109, 113))
56378	32474411	This study showed a strong positive correlation between median OS and CD3+, CD8+ and CD45RO+ TIL density.	('CD45', 'Gene', '5788', (85, 89))	('OS', 'Gene', '17451', (63, 65))	('CD45', 'Gene', (85, 89))	('CD8', 'Gene', (76, 79))	('CD8', 'Gene', '925', (76, 79))	('CD3+', 'Var', (70, 74))
56384	32474411	Similarly, Fecci et al demonstrated that CTLA-4 blockade enhanced CD4+ T cell proliferative capacity and mitigated Treg-meditated suppression of these cells in murine models.	('CTLA-4', 'Gene', (41, 47))	('murine', 'Species', '10090', (160, 166))	('Treg', 'Chemical', '-', (115, 119))	('blockade', 'Var', (48, 56))	('mitigated', 'NegReg', (105, 114))	('enhanced', 'PosReg', (57, 65))	('CD4+ T cell proliferative capacity', 'CPA', (66, 100))
56385	32474411	Conversely, temozolomide increases the proportion of exhausted T cells in mice with intracranially implanted gliomas, and this reduces their response to checkpoint inhibition.	('reduces', 'NegReg', (127, 134))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('increases the proportion of exhausted T cells', 'Phenotype', 'HP:0031514', (25, 70))	('increases', 'PosReg', (25, 34))	('response to checkpoint inhibition', 'MPA', (141, 174))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('temozolomide', 'Chemical', 'MESH:D000077204', (12, 24))	('mice', 'Species', '10090', (74, 78))	('temozolomide', 'Var', (12, 24))
56408	32474411	This ratio was also increased by VXM01 treatment.	('increased', 'PosReg', (20, 29))	('VXM01', 'Chemical', '-', (33, 38))	('VXM01 treatment', 'Var', (33, 48))
56417	32474411	For example, Wu et al found that GL261-Luc+-implanted mice treated with combination anti-PD-1 and anti-CXCR4 immunotherapy showed decreased production of pro-inflammatory cytokines including tumor necrosis factor-alpha and IFN-gamma compared with controls.	('tumor necrosis factor-alpha', 'Gene', '21926', (191, 218))	('production', 'MPA', (140, 150))	('CXCR4', 'Gene', (103, 108))	('decreased production of pro-inflammatory cytokines', 'Phenotype', 'HP:0012648', (130, 180))	('GL261', 'Chemical', '-', (33, 38))	('CXCR4', 'Gene', '12767', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor necrosis factor-alpha', 'Gene', (191, 218))	('mice', 'Species', '10090', (54, 58))	('anti-PD-1', 'Var', (84, 93))	('decreased', 'NegReg', (130, 139))
56428	32474411	A phase I clinical trial evaluating the immune response to a multiepitope-pulsed autologous dendritic cell vaccine in newly diagnosed patients with GBM showed that the expression of MAGE1 and AIM-2 on glioma cells was associated with significantly increased PFS.	('PFS', 'Disease', (258, 261))	('increased', 'PosReg', (248, 257))	('glioma', 'Disease', (201, 207))	('MAGE1', 'Gene', '4100', (182, 187))	('patients', 'Species', '9606', (134, 142))	('AIM-2', 'Gene', (192, 197))	('AIM-2', 'Gene', '9447', (192, 197))	('glioma', 'Phenotype', 'HP:0009733', (201, 207))	('MAGE1', 'Gene', (182, 187))	('expression', 'Var', (168, 178))	('glioma', 'Disease', 'MESH:D005910', (201, 207))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))
56440	32474411	Genetic and epigenetic aberrations are frequent in malignancy, including GBM.	('epigenetic aberrations', 'Var', (12, 34))	('malignancy', 'Disease', 'MESH:D009369', (51, 61))	('GBM', 'Disease', (73, 76))	('frequent', 'Reg', (39, 47))	('Genetic', 'Var', (0, 7))	('malignancy', 'Disease', (51, 61))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))
56441	32474411	O6-methylguanine-DNA methyltransferase (MGMT) methylation is a predictive biomarker for response to standard chemoradiation.	('O6-methylguanine-DNA methyltransferase', 'Gene', (0, 38))	('methylation', 'Var', (46, 57))	('MGMT', 'Gene', '4255', (40, 44))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 38))	('MGMT', 'Gene', (40, 44))
56446	32474411	Mutational status in the tumor suppressor gene, phosphatase and tensin homolog (PTEN), may also be a predictive biomarker.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('tumor', 'Disease', (25, 30))	('phosphatase and tensin homolog', 'Gene', '5728', (48, 78))	('Mutational status', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
56448	32474411	They discovered that the non-responders had PTEN mutations associated with immunosuppression, while responders had enriched MAPK pathways.	('PTEN', 'Gene', '5728', (44, 48))	('PTEN', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))	('associated', 'Reg', (59, 69))
56449	32474411	Isocitrate dehydrogenase (IDH) mutational status has been demonstrated as a prognostic factor in primary GBM, but this may not be a predictive marker for immune therapy.	('mutational', 'Var', (31, 41))	('Isocitrate dehydrogenase', 'Gene', (0, 24))	('primary GBM', 'Disease', (97, 108))	('IDH', 'Gene', (26, 29))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))	('IDH', 'Gene', '3417', (26, 29))	('Isocitrate dehydrogenase', 'Gene', '3417', (0, 24))
56451	32474411	In a retrospective analysis of their patient population, they did not find a survival advantage for patients who harbored the IDH1 mutation.	('IDH1', 'Gene', '3417', (126, 130))	('patient', 'Species', '9606', (37, 44))	('patient', 'Species', '9606', (100, 107))	('patients', 'Species', '9606', (100, 108))	('IDH1', 'Gene', (126, 130))	('mutation', 'Var', (131, 139))
56468	32474411	They noted that the use of neoadjuvant anti-PD-1 correlated with an upregulation of IFN-gamma-related gene expression, while downregulating cell cycle-related genes in the tumor when compared with the adjuvant anti-PD-1 group.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('downregulating', 'NegReg', (125, 139))	('tumor', 'Disease', (172, 177))	('expression', 'MPA', (107, 117))	('IFN-gamma-related gene', 'Gene', (84, 106))	('upregulation', 'PosReg', (68, 80))	('cell cycle-related genes', 'Gene', (140, 164))	('anti-PD-1', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
56487	32474411	Another study of 200 patients with breast, lung, colorectal or ovarian cancer showed a high concordance of mutations in ctDNA and tumor tissue.	('mutations', 'Var', (107, 116))	('breast', 'Disease', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ctDNA', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal or ovarian cancer', 'Disease', (49, 77))	('colorectal or ovarian cancer', 'Disease', 'MESH:D015179', (49, 77))	('lung', 'Disease', (43, 47))	('tumor', 'Disease', (130, 135))
56488	32474411	Additionally, an analysis of the colorectal patient cohort revealed that high levels of ctDNA was associated with lower OS and disease recurrence.	('patient', 'Species', '9606', (44, 51))	('disease recurrence', 'CPA', (127, 145))	('ctDNA', 'Gene', (88, 93))	('high levels', 'Var', (73, 84))	('OS', 'Gene', '17451', (120, 122))
56512	31534499	In addition, miR-26a decreased AP-2alpha expression by binding to the 3' untranslated region (UTR) of AP-2alpha and reversed the tumor suppressive role of AP-2alpha in glioma, which was rescued by a miR-26a inhibitor.	('AP-2alpha', 'Gene', (102, 111))	('glioma', 'Disease', 'MESH:D005910', (168, 174))	('expression', 'MPA', (41, 51))	('decreased', 'NegReg', (21, 30))	('glioma', 'Phenotype', 'HP:0009733', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('AP-2alpha', 'Gene', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('binding', 'Interaction', (55, 62))	('glioma', 'Disease', (168, 174))	('tumor', 'Disease', (129, 134))	('miR-26a', 'Var', (13, 20))
56526	31534499	Some data showed that a high proportion of AP-2alpha nucleoplasm localization was related to increased tumor malignancy and poor survival in certain tumor subtypes.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('increased tumor malignancy', 'Disease', (93, 119))	('increased tumor malignancy', 'Disease', 'MESH:D018198', (93, 119))	('AP-2alpha nucleoplasm', 'Var', (43, 64))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('poor', 'NegReg', (124, 128))
56529	31534499	Thus, AP-2alpha acts as a bifunctional transcription factor in the development and progression of carcinogenesis by influencing multiple signaling pathways, including VEGF, PI3K/AKT, Wnt/beta-catenin, Apaf1/caspase 9, HIF and p53, to modulate angiogenesis, cell proliferation, invasion and the microenvironment.	('Apaf1', 'Gene', '317', (201, 206))	('cell proliferation', 'CPA', (257, 275))	('modulate', 'Reg', (234, 242))	('influencing', 'Reg', (116, 127))	('carcinogenesis', 'Disease', (98, 112))	('HIF', 'Disease', (218, 221))	('Apaf1', 'Gene', (201, 206))	('caspase 9', 'Gene', (207, 216))	('AKT', 'Gene', (178, 181))	('AP-2alpha', 'Var', (6, 15))	('VEGF', 'Gene', '7422', (167, 171))	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('beta-catenin', 'Gene', (187, 199))	('beta-catenin', 'Gene', '1499', (187, 199))	('VEGF', 'Gene', (167, 171))	('p53', 'Gene', '7157', (226, 229))	('HIF', 'Disease', 'None', (218, 221))	('caspase 9', 'Gene', '842', (207, 216))	('angiogenesis', 'CPA', (243, 255))	('invasion', 'CPA', (277, 285))	('AKT', 'Gene', '207', (178, 181))	('p53', 'Gene', (226, 229))
56531	31534499	AP-2alpha expression sensitized cancer cells to chemotherapy drugs and enhanced tumor killing, while AP-2alpha deletion led to drug resistance, suggesting the significance of AP-2alpha in tumor recurrence and clinical therapies.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('enhanced', 'PosReg', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('drug resistance', 'Phenotype', 'HP:0020174', (127, 142))	('sensitized', 'Reg', (21, 31))	('AP-2alpha', 'Gene', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (32, 38))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('drug resistance', 'MPA', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('AP-2alpha', 'Gene', (101, 110))	('led to', 'Reg', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('deletion', 'Var', (111, 119))
56534	31534499	Moreover, the tumor suppressive effect of AP-2alpha was exerted through inhibiting the transcriptional activity of the Nanog gene and the IL6/STAT3 signaling pathway to attenuate the stemness and TMZ resistance of glioma cells.	('Nanog gene', 'Gene', (119, 129))	('AP-2alpha', 'Var', (42, 51))	('glioma cells', 'Disease', 'MESH:D005910', (214, 226))	('tumor', 'Disease', (14, 19))	('TMZ', 'Chemical', 'MESH:D000077204', (196, 199))	('inhibiting', 'NegReg', (72, 82))	('transcriptional activity', 'MPA', (87, 111))	('glioma cells', 'Disease', (214, 226))	('attenuate', 'NegReg', (169, 178))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('stemness', 'Disease', 'MESH:D020295', (183, 191))	('IL6/STAT3 signaling pathway', 'Pathway', (138, 165))	('stemness', 'Disease', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
56541	31534499	Antibodies used are listed as following, mouse monoclonal antibodies against AP-2alpha (sc-12726), cyclin D1 (CCND1) (sc-4074), c-Myc (sc-4084), beta-actin (sc-58673) and GAPDH (sc-47724) were from Santa Cruz Biotechnology (Santa Cruz, CA).	('sc-47724', 'Var', (178, 186))	('CCND1', 'Gene', (110, 115))	('mouse', 'Species', '10090', (41, 46))	('c-Myc', 'Gene', '4609', (128, 133))	('AP-2alpha', 'Gene', (77, 86))	('sc-4074', 'Var', (118, 125))	('sc-58673', 'Var', (157, 165))	('cyclin D1', 'Gene', '595', (99, 108))	('CCND1', 'Gene', '595', (110, 115))	('sc-4084', 'Var', (135, 142))	('c-Myc', 'Gene', (128, 133))	('cyclin D1', 'Gene', (99, 108))	('GAPDH', 'Gene', '2597', (171, 176))	('beta-actin', 'Gene', '728378', (145, 155))	('GAPDH', 'Gene', (171, 176))	('beta-actin', 'Gene', (145, 155))
56542	31534499	Rabbit polyclonal antibodies against STAT3 (12640) and phosphorylated STAT3 (Y705) (9145), Bcl-2 (4223), Pro-caspase3 (14220) were from Cell Signaling Technology (MA, USA).	('12640', 'Var', (44, 49))	('Pro-caspase3', 'Gene', (105, 117))	('Pro-caspase3', 'Gene', '836', (105, 117))	('Bcl-2', 'Gene', '596', (91, 96))	('14220', 'Var', (119, 124))	('Bcl-2', 'Gene', (91, 96))	('Y705) (9145', 'Var', (77, 88))	('Rabbit', 'Species', '9986', (0, 6))
56543	31534499	Rabbit polyclonal antibodies against JAK2 (A7694), phosphorylated JAK2 (Y1007/1008) (AP0531) and IL-6 (A2447) were from AbClonal Technology (MA, USA).	('A7694', 'Var', (43, 48))	('JAK2', 'Gene', (66, 70))	('JAK2', 'Gene', (37, 41))	('IL-6', 'Gene', '3569', (97, 101))	('JAK2', 'Gene', '3717', (66, 70))	('Y1007/1008', 'Var', (72, 82))	('Rabbit', 'Species', '9986', (0, 6))	('IL-6', 'Gene', (97, 101))	('JAK2', 'Gene', '3717', (37, 41))
56544	31534499	Rabbit polyclonal antibodies against Nanog (D262945), Sox2 (D164316) and GFAP (D162817) were from Sangon Biotech (Shanghai, China).	('GFAP', 'Gene', (73, 77))	('Sox2', 'Gene', '6657', (54, 58))	('GFAP', 'Gene', '2670', (73, 77))	('D262945', 'Var', (44, 51))	('D162817', 'Var', (79, 86))	('Nanog', 'Gene', (37, 42))	('Sox2', 'Gene', (54, 58))	('D164316', 'Var', (60, 67))	('Rabbit', 'Species', '9986', (0, 6))
56553	31534499	The primary antibodies used were mouse monoclonal antibodies against AP-2alpha (sc-12726) (Santa Cruz, CA), rabbit polyclonal antibodies against Nanog (AF5388), CD133 (BA3141) and Nestin (BA1289) (Boster Biological Technology) while the secondary antibodies were Alexa Fluor 488 phalloidin (A12379) and 594 dye (A12381) (Invitrogen), the nucleus were visualized by Hoechst 33258 staining (14530) (Sigma).	('Nanog', 'Var', (145, 150))	('mouse', 'Species', '10090', (33, 38))	('Nestin', 'Gene', (180, 186))	('rabbit', 'Species', '9986', (108, 114))	('Alexa Fluor 488', 'Chemical', '-', (263, 278))	('A12379', 'Var', (291, 297))	('CD133', 'Gene', (161, 166))	('CD133', 'Gene', '8842', (161, 166))	('A12381', 'Var', (312, 318))	('Nestin', 'Gene', '10763', (180, 186))
56567	31534499	Suspensions of single-cells were seeded into 6-well plates at a density of 5,000 cells/mL in stem cell-conditioned medium containing DMEM/F12 supplemented with 100 IU/mL penicillin G, 100 mug/mL streptomycin, 10 ng/mL EGF (Peprotech Inc., Rocky Hill, NJ, USA), 10 ng/mL bFGF (Peprotech Inc., Rocky Hill, NJ, USA), and 1xB27 (Invitrogen).	('streptomycin', 'Chemical', 'MESH:D013307', (195, 207))	('EGF', 'Gene', (218, 221))	('F12', 'Gene', (138, 141))	('penicillin G', 'Chemical', 'MESH:D010400', (170, 182))	('EGF', 'Gene', '1950', (218, 221))	('1xB27', 'Var', (318, 323))	('bFGF', 'Gene', '2247', (270, 274))	('F12', 'Gene', '2161', (138, 141))	('DMEM', 'Chemical', '-', (133, 137))	('bFGF', 'Gene', (270, 274))
56606	31534499	To further investigate the role of AP-2alpha in human glioma cells, AP-2alpha was cloned into the lentiviral vector pGC-FU-3Flag-IRES-Puromycin as described previously, and stable glioma cell lines overexpressing AP-2alpha (pFLAG-AP-2alpha) or a negative control (pFLAG-NC) were screened and established.	('Puromycin', 'Chemical', 'MESH:D011691', (134, 143))	('glioma cell', 'Disease', 'MESH:D005910', (180, 191))	('human', 'Species', '9606', (48, 53))	('glioma cell', 'Disease', (180, 191))	('glioma cells', 'Disease', (54, 66))	('AP-2alpha', 'Var', (213, 222))	('glioma cell', 'Disease', 'MESH:D005910', (54, 65))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('glioma cells', 'Disease', 'MESH:D005910', (54, 66))
56610	31534499	Glioma cells overexpressing AP-2alpha exhibited a decreased growth compared with that of negative control cells (Figure 2C and Figure S1D).	('AP-2alpha', 'Var', (28, 37))	('growth', 'MPA', (60, 66))	('decreased growth', 'Phenotype', 'HP:0001510', (50, 66))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('decreased', 'NegReg', (50, 59))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))
56622	31534499	Strikingly, AP-2alpha (18.53 +- 17.9 mm3) reduced the intracranial tumor volume by about 75% compared with that in the NC group (73.79 +- 32.3 mm3) (P=0.04) (Figure 2L).	('reduced', 'NegReg', (42, 49))	('intracranial tumor', 'Disease', 'MESH:D001932', (54, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('AP-2alpha', 'Var', (12, 21))	('intracranial tumor', 'Disease', (54, 72))
56623	31534499	AP-2alpha prolonged the survival of intracranial xenograft mice, as shown by Kaplan-Meier analysis (Figure 2M).	('prolonged', 'PosReg', (10, 19))	('AP-2alpha', 'Var', (0, 9))	('mice', 'Species', '10090', (59, 63))	('survival', 'CPA', (24, 32))
56629	31534499	Among the control GSCs, 454 +- 49 U251 cells and 598 +- 21 U87 cells formed spheres, whereas the number of sphere-forming cells was significantly decreased (U251 109 +- 9, U87 194 +- 6, P <0.01) in the AP-2alpha-overexpressing GSC group (Figure 3C).	('U251', 'CellLine', 'CVCL:0021', (34, 38))	('U251', 'CellLine', 'CVCL:0021', (157, 161))	('U87 194 +- 6', 'Var', (172, 184))	('U87', 'CellLine', 'CVCL:0022', (172, 175))	('U87', 'CellLine', 'CVCL:0022', (59, 62))	('decreased', 'NegReg', (146, 155))
56636	31534499	However, AP-2alpha was found to generate a small number of secondary tumor spheres, while control gliosphere cells formed many spheres (Figure 3F and S2B).	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('AP-2alpha', 'Var', (9, 18))
56646	31534499	The limiting dilutions and cell counting assays showed that AP-2alpha inhibited the tumor self-renewal and proliferative capacity of CD133+ glioma cells (Figure S3E-G).	('glioma cells', 'Disease', 'MESH:D005910', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CD133', 'Gene', (133, 138))	('tumor', 'Disease', (84, 89))	('CD133', 'Gene', '8842', (133, 138))	('proliferative capacity', 'CPA', (107, 129))	('inhibited', 'NegReg', (70, 79))	('glioma cells', 'Disease', (140, 152))	('AP-2alpha', 'Var', (60, 69))
56648	31534499	We found that AP-2alpha (10.96 +- 10.46 mm3) reduced the intracranial tumor volume by over 87% compared with that of tumors generated from NC stem cells (84.56 +- 26.78 mm3) (P=0.04) (Figure 3G-H).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('reduced', 'NegReg', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('intracranial tumor', 'Disease', (57, 75))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('10.96', 'Var', (25, 30))	('intracranial tumor', 'Disease', 'MESH:D001932', (57, 75))
56649	31534499	Intriguingly, AP-2alpha prolonged the survival of intracranial xenograft mice, as shown by the Kaplan-Meier anlysis (Figure 3I).	('prolonged', 'PosReg', (24, 33))	('mice', 'Species', '10090', (73, 77))	('AP-2alpha', 'Var', (14, 23))	('survival', 'CPA', (38, 46))
56651	31534499	In contrast, AP-2alpha increased the median survival by 35% to 42.5 days (P=0.0033), indicating that AP-2alpha overexpression generated slower growing tumors that exhibited a longer tumor latency (12 days) than control stem cells.	('slower', 'NegReg', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('AP-2alpha', 'Var', (101, 110))	('longer tumor', 'Disease', (175, 187))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('longer tumor', 'Disease', 'MESH:D009369', (175, 187))	('overexpression', 'PosReg', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
56655	31534499	The IC50 value of U251 cells treated with TMZ was 452 microM, but this value was lowered to 167.2 microM in AP-2alpha-overexpressing U251 cells (P<0.01).	('IC50', 'MPA', (4, 8))	('U251', 'CellLine', 'CVCL:0021', (18, 22))	('TMZ', 'Var', (42, 45))	('U251', 'CellLine', 'CVCL:0021', (133, 137))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))
56657	31534499	Moreover, the combination of TMZ and AP-2alpha significantly attenuated the tumor sphere formation ability of U251 GSCs (Figure 4B).	('U251', 'CellLine', 'CVCL:0021', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('TMZ', 'Chemical', 'MESH:D000077204', (29, 32))	('AP-2alpha', 'Var', (37, 46))	('attenuated', 'NegReg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
56659	31534499	The combination of TMZ and AP-2alpha exhibited an even stronger inhibitory effect on the proliferation (p<0.01) of both glioma cells and GSCs compared to that generated by the controls (Figure 4C).	('proliferation', 'CPA', (89, 102))	('inhibitory effect', 'NegReg', (64, 81))	('glioma cells', 'Disease', 'MESH:D005910', (120, 132))	('TMZ', 'Var', (19, 22))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('TMZ', 'Chemical', 'MESH:D000077204', (19, 22))	('AP-2alpha', 'Gene', (27, 36))	('glioma cells', 'Disease', (120, 132))
56664	31534499	Both TMZ and AP-2alpha synergistically inhibited the growth and induced the apoptosis of glioma cells, accompanied by decreased levels of Bcl-2, Pro Caspase-3 and the stem cell markers Nanog and Sox2 in a dose-dependent manner (Figure 4F).	('Sox2', 'Gene', (195, 199))	('TMZ', 'Var', (5, 8))	('Bcl-2', 'Gene', (138, 143))	('inhibited', 'NegReg', (39, 48))	('Bcl-2', 'Gene', '596', (138, 143))	('glioma cells', 'Disease', 'MESH:D005910', (89, 101))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('induced', 'Reg', (64, 71))	('TMZ', 'Chemical', 'MESH:D000077204', (5, 8))	('Caspase-3', 'Gene', (149, 158))	('Sox2', 'Gene', '6657', (195, 199))	('growth', 'CPA', (53, 59))	('decreased', 'NegReg', (118, 127))	('Caspase-3', 'Gene', '836', (149, 158))	('apoptosis', 'CPA', (76, 85))	('AP-2alpha', 'Var', (13, 22))	('glioma cells', 'Disease', (89, 101))
56669	31534499	Moreover, Western blot analysis demonstrated that AP-2alpha decreased the expression of Nanog, Sox2 and CD133, and increased the levels of GFAP in both U251 cells and subcutaneous mouse tumor tissues originating from U87 cells (Figure 5B).	('expression', 'MPA', (74, 84))	('GFAP', 'Gene', (139, 143))	('decreased', 'NegReg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('CD133', 'Gene', (104, 109))	('increased', 'PosReg', (115, 124))	('CD133', 'Gene', '8842', (104, 109))	('U87', 'CellLine', 'CVCL:0022', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('AP-2alpha', 'Var', (50, 59))	('tumor', 'Disease', (186, 191))	('Nanog', 'Gene', (88, 93))	('U251', 'CellLine', 'CVCL:0021', (152, 156))	('mouse', 'Species', '10090', (180, 185))	('GFAP', 'Gene', '2670', (139, 143))	('levels', 'MPA', (129, 135))	('Sox2', 'Gene', '6657', (95, 99))	('Sox2', 'Gene', (95, 99))
56671	31534499	We next generated three Nanog promoter-luciferase reporters bearing mutated AP-2 binding sites.	('AP-2', 'Gene', '7020', (76, 80))	('mutated', 'Var', (68, 75))	('AP-2', 'Gene', (76, 80))
56672	31534499	Double mutation of the AP-2 binding sites (-560 GCCACGGCC and -516 GCGCCCGGC) greatly reduced the inhibition of AP-2alpha-mediated Nanog reporters by 41%, while single mutation had no effect (Figure 5D).	('reduced', 'NegReg', (86, 93))	('-560 GCCACGGCC', 'Var', (43, 57))	('AP-2', 'Gene', '7020', (112, 116))	('AP-2', 'Gene', '7020', (23, 27))	('inhibition', 'MPA', (98, 108))	('AP-2', 'Gene', (112, 116))	('AP-2', 'Gene', (23, 27))
56675	31534499	We next found that AP-2alpha and Nanog colocalized in the nuclei of U251 cells and that AP-2alpha decreased the fluorescence intensity of Nanog, indicating that AP-2alpha can downregulate Nanog protein levels (Figure 5F).	('downregulate', 'NegReg', (175, 187))	('Nanog protein levels', 'MPA', (188, 208))	('AP-2alpha', 'Var', (88, 97))	('decreased', 'NegReg', (98, 107))	('U251', 'CellLine', 'CVCL:0021', (68, 72))	('fluorescence intensity', 'MPA', (112, 134))
56688	31534499	The expression of p-STAT3 was negatively correlated with AP-2alpha expression in glioma samples (Figure 6E), in which p-STAT3 expression was observed together with low AP-2alpha expression (Fisher's exact test, P<0.001; Table S7).	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('expression', 'MPA', (4, 14))	('glioma', 'Disease', (81, 87))	('negatively', 'NegReg', (30, 40))	('p-STAT3', 'Var', (118, 125))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
56693	31534499	However, Western blot showed that only miR-26a significantly decreased AP-2alpha protein expression (Figure 7C), while the miR-26a inhibitor was able to rescue this suppression in U251 cells (Figure 7D).	('decreased', 'NegReg', (61, 70))	('miR-26a', 'Var', (39, 46))	('AP-2alpha protein', 'Protein', (71, 88))	('U251', 'CellLine', 'CVCL:0021', (180, 184))
56695	31534499	Moreover, miR-26a was negatively associated with the overall survival of glioma patients based on data from The Cancer Genome Atlas (TCGA) (Figure 7G).	('miR-26a', 'Var', (10, 17))	('Cancer Genome Atlas', 'Disease', (112, 131))	('glioma', 'Disease', (73, 79))	('patients', 'Species', '9606', (80, 88))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (112, 131))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('negatively', 'NegReg', (22, 32))	('associated', 'Reg', (33, 43))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))
56703	31534499	Collectively, these results suggested that AP-2alpha is a direct target of miR-26a, and the miR-26a inhibitor can upregulate AP-2alpha expression and function as a tumor suppressor in glioma cells.	('upregulate', 'PosReg', (114, 124))	('tumor', 'Disease', (164, 169))	('glioma cells', 'Disease', (184, 196))	('miR-26a inhibitor', 'Var', (92, 109))	('expression', 'MPA', (135, 145))	('inhibitor', 'Var', (100, 109))	('glioma cells', 'Disease', 'MESH:D005910', (184, 196))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('AP-2alpha', 'Protein', (125, 134))
56726	31534499	The alkylating agent TMZ methylates the nucleotide units of DNA and causes the formation of an abnormal O6-MG/T match, which activates the DNA mismatch repair (MMR) system and results in unrepairable DNA damage followed by glioma cell cycle arrest and apoptosis.	('activates', 'PosReg', (125, 134))	('glioma cell cycle arrest', 'Disease', (223, 247))	('apoptosis', 'CPA', (252, 261))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (230, 247))	('unrepairable DNA damage', 'MPA', (187, 210))	('glioma cell cycle arrest', 'Disease', 'MESH:D005910', (223, 247))	('O6-MG/T match', 'Var', (104, 117))	('TMZ', 'Chemical', 'MESH:D000077204', (21, 24))	('results in', 'Reg', (176, 186))
56728	31534499	AP-2alpha inhibits cell growth by inducing cell cycle arrest and apoptosis and increases the chemosensitivity of hepatocellular carcinoma cells to cisplatin.	('inducing', 'PosReg', (34, 42))	('inhibits', 'NegReg', (10, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('increases', 'PosReg', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cell growth', 'CPA', (19, 30))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('apoptosis', 'CPA', (65, 74))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('hepatocellular carcinoma', 'Disease', (113, 137))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (113, 137))	('AP-2alpha', 'Var', (0, 9))	('arrest', 'Disease', (54, 60))	('chemosensitivity', 'MPA', (93, 109))
56730	31534499	AP-2alpha also inhibits the DNA repair protein MGMT, which renders cells resistant to the cytotoxic actions of methylating and chloroethylating agents, such as TMZ.	('DNA repair protein', 'Protein', (28, 46))	('TMZ', 'Chemical', 'MESH:D000077204', (160, 163))	('MGMT', 'Gene', (47, 51))	('inhibits', 'NegReg', (15, 23))	('MGMT', 'Gene', '4255', (47, 51))	('AP-2alpha', 'Var', (0, 9))
56739	31534499	AP-2alpha was found to suppress classically activated (M1) macrophages producing the cytokine IL-6 and Jak2/STAT3 activation and subsequently decrease PD-L1 expression in glioma cells.	('Jak2', 'Gene', '3717', (103, 107))	('decrease PD', 'Phenotype', 'HP:0032198', (142, 153))	('PD-L1', 'Gene', '29126', (151, 156))	('IL-6', 'Gene', (94, 98))	('glioma cells', 'Disease', 'MESH:D005910', (171, 183))	('expression', 'MPA', (157, 167))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('IL-6', 'Gene', '3569', (94, 98))	('PD-L1', 'Gene', (151, 156))	('suppress', 'NegReg', (23, 31))	('decrease', 'NegReg', (142, 150))	('Jak2', 'Gene', (103, 107))	('classically activated', 'CPA', (32, 53))	('AP-2alpha', 'Var', (0, 9))	('glioma cells', 'Disease', (171, 183))
56742	31534499	AP-2alpha inhibits the stemness of GSCs, synergistically decreases TMZ resistance, improves anticancer chemotherapies and leads to the avoidance of immune evasion (Figure 8G).	('inhibits', 'NegReg', (10, 18))	('stemness', 'Disease', (23, 31))	('immune evasion', 'MPA', (148, 162))	('stemness', 'Disease', 'MESH:D020295', (23, 31))	('leads to', 'Reg', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TMZ', 'Chemical', 'MESH:D000077204', (67, 70))	('improves', 'PosReg', (83, 91))	('TMZ resistance', 'MPA', (67, 81))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('decreases', 'NegReg', (57, 66))	('AP-2alpha', 'Var', (0, 9))	('cancer', 'Disease', (96, 102))
56749	31534499	The miR-26a inhibitor generated tumors that grew slower and had a longer tumor latency (10 days) than those generated by control.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('miR-26a', 'Gene', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('grew', 'CPA', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('longer tumor', 'Disease', 'MESH:D009369', (66, 78))	('slower', 'NegReg', (49, 55))	('inhibitor', 'Var', (12, 21))	('tumors', 'Disease', (32, 38))	('longer tumor', 'Disease', (66, 78))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
56751	31534499	AP-2alpha functions as a novel tumor suppressor to inhibit the stemness of glioma cancer cells by inhibiting the Nanog/Sox2/CD133 regulatory axis and decreasing the resistance of glioma cells to TMZ by blocking the IL6/Jak2/STAT3 signaling pathway.	('blocking', 'NegReg', (202, 210))	('glioma cells', 'Disease', 'MESH:D005910', (179, 191))	('AP-2alpha', 'Var', (0, 9))	('resistance', 'MPA', (165, 175))	('inhibiting', 'NegReg', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Sox2', 'Gene', '6657', (119, 123))	('Jak2', 'Gene', (219, 223))	('Jak2', 'Gene', '3717', (219, 223))	('stemness of glioma cancer', 'Disease', 'MESH:D005910', (63, 88))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('stemness of glioma cancer', 'Disease', (63, 88))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('inhibit', 'NegReg', (51, 58))	('TMZ', 'Chemical', 'MESH:D000077204', (195, 198))	('glioma cells', 'Disease', (179, 191))	('CD133', 'Gene', (124, 129))	('CD133', 'Gene', '8842', (124, 129))	('tumor', 'Disease', (31, 36))	('decreasing', 'NegReg', (150, 160))	('Sox2', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
56752	31534499	Additionally, AP-2alpha expression is downregulated by oncogenic miR-26a, and inhibiting miR-26a represents as a novel factor for synergistic therapy with TMZ.	('TMZ', 'Chemical', 'MESH:D000077204', (155, 158))	('expression', 'MPA', (24, 34))	('miR-26a', 'Gene', (65, 72))	('AP-2alpha', 'Protein', (14, 23))	('downregulated', 'NegReg', (38, 51))	('oncogenic', 'Var', (55, 64))	('inhibiting', 'Var', (78, 88))
56831	29164063	They looked at the expression of Dm-dNK human in colorectal cancer cells (HCT-116 and SW620) using RT-PCR.	('Dm-dNK', 'Var', (33, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('colorectal cancer', 'Disease', (49, 66))	('SW620', 'CellLine', 'CVCL:0547', (86, 91))	('HCT-116', 'CellLine', 'CVCL:0291', (74, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('looked', 'Reg', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (40, 45))
56836	29164063	Furthermore, they were able to demonstrate that the virus inhibited the growth of xenograft tumor in vivo.	('xenograft tumor', 'Disease', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inhibited', 'NegReg', (58, 67))	('xenograft tumor', 'Disease', 'MESH:D009369', (82, 97))	('rat', 'Species', '10116', (38, 41))	('virus', 'Var', (52, 57))
56847	29164063	They found that human squamous cell carcinoma cell lines infected with rVSV-IL12 had a high level of IL12 expression at 48 h postinfection.	('squamous cell carcinoma cell lines infected', 'Disease', 'MESH:D002294', (22, 65))	('rVSV-IL12', 'Var', (71, 80))	('VSV', 'Species', '11276', (72, 75))	('expression', 'MPA', (106, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma cell lines infected', 'Disease', (22, 65))	('IL12', 'Gene', (101, 105))	('human', 'Species', '9606', (16, 21))
56849	29164063	The mice treated with rVSV-IL12 had a much greater reduction of the tumor compared with the mice treated with rVSV-F.	('tumor', 'Disease', (68, 73))	('reduction', 'NegReg', (51, 60))	('VSV', 'Species', '11276', (111, 114))	('mice', 'Species', '10090', (4, 8))	('rVSV-IL12', 'Var', (22, 31))	('rVSV-F', 'Chemical', '-', (110, 116))	('VSV', 'Species', '11276', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (92, 96))
56903	28870216	Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM).	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('patients', 'Species', '9606', (204, 212))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (46, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma', 'Disease', (218, 230))	('glioblastoma', 'Disease', 'MESH:D005909', (218, 230))	('increases', 'PosReg', (46, 55))	('impairing', 'NegReg', (92, 101))	('radiosensitivity', 'MPA', (56, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (218, 230))	('treatment failure', 'Disease', 'MESH:D016609', (183, 200))	('treatment failure', 'Disease', (183, 200))	('Trifluoperazine', 'Chemical', 'MESH:D014268', (0, 15))	('glioblastoma', 'Disease', (76, 88))	('Trifluoperazine', 'Var', (0, 15))
56922	28870216	Several studies have shown that inhibiting autophagy could increase the radiosensitivity of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('increase the radiosensitivity of tumor', 'Phenotype', 'HP:0010997', (59, 97))	('inhibiting', 'Var', (32, 42))	('autophagy', 'CPA', (43, 52))	('tumor', 'Disease', (92, 97))	('increase', 'PosReg', (59, 67))
56929	28870216	Here, we examined the responses of GBM cells to TFP in vitro and in vivo and show that TFP inhibits autophagy by interfering with lysosome acidification.	('lysosome acidification', 'MPA', (130, 152))	('autophagy', 'CPA', (100, 109))	('TFP', 'Chemical', 'MESH:D014268', (87, 90))	('TFP', 'Chemical', 'MESH:D014268', (48, 51))	('TFP', 'Var', (87, 90))	('inhibits', 'NegReg', (91, 99))	('interfering', 'NegReg', (113, 124))
56934	28870216	The P3 tumor has the following molecular characteristics (+ [Chr 7, Chr19, 20q], -[1q42-q43, Chr9, Chr10, 20p] --[PIK3R1, CDKN2A/B].	('Chr9', 'Var', (93, 97))	('+ [Chr 7', 'Var', (58, 66))	('tumor', 'Disease', (7, 12))	('CDKN2A', 'Gene', (122, 128))	('PIK3R1', 'Gene', '5295', (114, 120))	('CDKN2A', 'Gene', '1029', (122, 128))	('PIK3R1', 'Gene', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
57000	28870216	Confocal microscopy showed an increase in fluorescence puncta in TFP treated cells after 24 h (Fig.	('fluorescence puncta', 'MPA', (42, 61))	('TFP', 'Chemical', 'MESH:D014268', (65, 68))	('increase', 'PosReg', (30, 38))	('TFP', 'Var', (65, 68))
57002	28870216	The levels of SQSTM/p62, one of the most important long-lived proteins critical for autophagy, accumulated in a dose-dependent manner in response to TFP (Fig.	('p62', 'Gene', '8878', (20, 23))	('p62', 'Gene', (20, 23))	('TFP', 'Var', (149, 152))	('TFP', 'Chemical', 'MESH:D014268', (149, 152))	('accumulated', 'PosReg', (95, 106))
57022	28870216	We found that after TFP treatment, the HR efficiency decreased significantly (P < 0.05) compared to the control group (Fig.	('TFP', 'Chemical', 'MESH:D014268', (20, 23))	('HR efficiency decreased', 'Disease', 'MESH:D007022', (39, 62))	('treatment', 'Var', (24, 33))	('HR efficiency decreased', 'Disease', (39, 62))
57023	28870216	TFP might therefore lead to an increase in DSBs and radiosensitivity by inhibiting the expression of central DNA repair proteins.	('TFP', 'Var', (0, 3))	('TFP', 'Chemical', 'MESH:D014268', (0, 3))	('radiosensitivity', 'CPA', (52, 68))	('DSBs', 'Disease', (43, 47))	('inhibiting', 'NegReg', (72, 82))	('expression', 'MPA', (87, 97))	('DSBs', 'Chemical', '-', (43, 47))	('central DNA repair proteins', 'Protein', (101, 128))	('increase', 'PosReg', (31, 39))
57032	28870216	Finally, HR efficiency also decreased significantly after knocking down cathepsin L (Fig.	('cathepsin L', 'Gene', (72, 83))	('knocking down', 'Var', (58, 71))	('cathepsin L', 'Gene', '1514', (72, 83))	('decreased', 'NegReg', (28, 37))	('HR efficiency', 'Disease', 'MESH:D001919', (9, 22))	('HR efficiency', 'Disease', (9, 22))
57041	28870216	In summary, our data demonstrates that TFP sufficiently penetrates the BBB and increases radiosensitivity in vivo.	('TFP', 'Var', (39, 42))	('TFP', 'Chemical', 'MESH:D014268', (39, 42))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (79, 105))	('increases', 'PosReg', (79, 88))	('radiosensitivity', 'CPA', (89, 105))
57046	28870216	Mechanistically we show that TFP interrupts autophagy flux by inhibiting the acidification of lysosomes.	('acidification of lysosomes', 'MPA', (77, 103))	('autophagy flux', 'CPA', (44, 58))	('inhibiting', 'NegReg', (62, 72))	('interrupts', 'NegReg', (33, 43))	('TFP', 'Var', (29, 32))	('TFP', 'Chemical', 'MESH:D014268', (29, 32))
57052	28870216	In the present work, we show that TFP decreases the expression of the HR proteins Rad51, BRCA1 and BRCA2, followed by increased DNA damage.	('decreases', 'NegReg', (38, 47))	('DNA damage', 'MPA', (128, 138))	('TFP', 'Var', (34, 37))	('TFP', 'Chemical', 'MESH:D014268', (34, 37))	('BRCA1', 'Gene', (89, 94))	('expression', 'MPA', (52, 62))	('increased', 'PosReg', (118, 127))	('BRCA2', 'Gene', (99, 104))	('Rad51', 'Gene', (82, 87))	('Rad51', 'Gene', '5888', (82, 87))	('BRCA1', 'Gene', '672', (89, 94))	('BRCA2', 'Gene', '675', (99, 104))
57054	28870216	In our study, we find that TFP impairs lysosome acidification.	('TFP', 'Var', (27, 30))	('impairs', 'NegReg', (31, 38))	('TFP', 'Chemical', 'MESH:D014268', (27, 30))	('lysosome acidification', 'MPA', (39, 61))
57056	28870216	We show here that the activity as well as protein levels of cathepsin L decreases significantly after TFP treatment.	('TFP', 'Var', (102, 105))	('TFP', 'Chemical', 'MESH:D014268', (102, 105))	('decreases', 'NegReg', (72, 81))	('treatment', 'Var', (106, 115))	('cathepsin L', 'Gene', (60, 71))	('cathepsin L', 'Gene', '1514', (60, 71))	('activity', 'MPA', (22, 30))	('protein levels', 'MPA', (42, 56))
57057	28870216	Moreover, western blot analysis shows that cathepsin L silencing increases P62 and gamma-H2AX, whereas Rad51 is decreased.	('Rad51', 'Gene', (103, 108))	('Rad51', 'Gene', '5888', (103, 108))	('increases', 'PosReg', (65, 74))	('silencing', 'Var', (55, 64))	('P62', 'Gene', (75, 78))	('P62', 'Gene', '8878', (75, 78))	('cathepsin L', 'Gene', (43, 54))	('gamma-H2A', 'Chemical', '-', (83, 92))	('H2AX', 'Gene', '3014', (89, 93))	('cathepsin L', 'Gene', '1514', (43, 54))	('H2AX', 'Gene', (89, 93))
57058	28870216	Also, knock-down of cathepsin L led to a decreased HR efficiency.	('cathepsin L', 'Gene', '1514', (20, 31))	('decreased HR efficiency', 'Disease', (41, 64))	('decreased HR efficiency', 'Disease', 'MESH:D007022', (41, 64))	('knock-down', 'Var', (6, 16))	('cathepsin L', 'Gene', (20, 31))
57088	26646075	The DNA repair enzyme O6-methylguanine methyltransferase (MGMT) repairs O6- methylguanine adducts.	('MGMT', 'Gene', '4255', (58, 62))	('MGMT', 'Gene', (58, 62))	('O6-', 'Var', (72, 75))	('O6-methylguanine methyltransferase', 'Gene', (22, 56))	('O6-methylguanine methyltransferase', 'Gene', '4255', (22, 56))	('O6- methylguanine', 'Chemical', 'MESH:C008449', (72, 89))
57089	26646075	Hypermethylation of the MGMT gene promoter leads to silencing of MGMT expression.	('silencing', 'NegReg', (52, 61))	('MGMT', 'Gene', (65, 69))	('MGMT', 'Gene', '4255', (24, 28))	('MGMT', 'Gene', '4255', (65, 69))	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (70, 80))	('MGMT', 'Gene', (24, 28))
57110	26646075	Initial efforts in genome-wide sequencing and mutational analysis found genes previously associated with GB and other cancers, such as PTEN, EGFR, P53, and PIK3CA, mutated in GBs.	('associated', 'Reg', (89, 99))	('cancers', 'Disease', (118, 125))	('EGFR', 'Gene', '1950', (141, 145))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('PIK3CA', 'Gene', '5290', (156, 162))	('GB', 'Phenotype', 'HP:0012174', (175, 177))	('PTEN', 'Gene', (135, 139))	('P53', 'Gene', (147, 150))	('PTEN', 'Gene', '5728', (135, 139))	('EGFR', 'Gene', (141, 145))	('P53', 'Gene', '7157', (147, 150))	('mutated', 'Var', (164, 171))	('GB', 'Phenotype', 'HP:0012174', (105, 107))	('PIK3CA', 'Gene', (156, 162))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
57111	26646075	However, there were some surprising findings, particularly the discovery of isocitrate dehydrogenase 1 (IDH1) mutations in 10 of 105 GBs.	('isocitrate dehydrogenase 1', 'Gene', (76, 102))	('GB', 'Phenotype', 'HP:0012174', (133, 135))	('mutations', 'Var', (110, 119))	('IDH1', 'Gene', (104, 108))	('isocitrate dehydrogenase 1', 'Gene', '3417', (76, 102))
57112	26646075	In a larger study of primary brain tumors, IDH1 mutations were found in the majority of World Health Organization (WHO) grade II and III infiltrating astrocytic and oligodendroglial tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('brain tumors', 'Disease', 'MESH:D001932', (29, 41))	('brain tumors', 'Phenotype', 'HP:0030692', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('brain tumors', 'Disease', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('IDH1', 'Gene', (43, 47))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (165, 188))	('oligodendroglial tumors', 'Disease', (165, 188))	('found', 'Reg', (63, 68))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
57113	26646075	Mutant IDH1 protein results in neomorphic enzymatic activity and over-expression of an abnormal cellular metabolite, 2-hydroxyglutarate (2-HG).	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (117, 135))	('over-expression', 'PosReg', (65, 80))	('neomorphic enzymatic activity', 'MPA', (31, 60))	('protein', 'Protein', (12, 19))	('results in', 'Reg', (20, 30))	('2-hydroxyglutarate', 'MPA', (117, 135))	('Mutant', 'Var', (0, 6))	('IDH1', 'Gene', (7, 11))	('2-HG', 'Chemical', 'MESH:C019417', (137, 141))
57115	26646075	Most importantly, IDH1 mutant GBs have an improved prognosis compared to IDH1 wild-type tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('improved', 'PosReg', (42, 50))	('prognosis', 'MPA', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('GB', 'Phenotype', 'HP:0012174', (30, 32))	('IDH1', 'Gene', (18, 22))	('mutant', 'Var', (23, 29))
57116	26646075	IDH1 mutations are present in only 5-10 % of GBs overall, and the average OS for IDH1 mutant GBs is 3 years or longer compared to just over 14-16 months for wild-type tumors.	('mutant', 'Var', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('GB', 'Phenotype', 'HP:0012174', (45, 47))	('GB', 'Phenotype', 'HP:0012174', (93, 95))	('IDH1', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
57119	26646075	The majority of IDH1 mutant high-grade gliomas also have MGMT promoter methylation, and IDH1 mutation is a stronger prognostic biomarker than MGMT promoter methylation.	('MGMT', 'Gene', '4255', (142, 146))	('mutant', 'Var', (21, 27))	('MGMT', 'Gene', (142, 146))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('IDH1', 'Gene', (16, 20))	('gliomas', 'Disease', (39, 46))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('MGMT', 'Gene', '4255', (57, 61))	('MGMT', 'Gene', (57, 61))
57120	26646075	Combined analysis of IDH mutation and MGMT promoter methylation may improve prognostication over analysis of either biomarker alone, although the prognostic significance of MGMT promoter methylation may be more significant in IDH1 wild-type tumors.	('IDH', 'Gene', (21, 24))	('MGMT', 'Gene', '4255', (38, 42))	('IDH', 'Gene', '3417', (226, 229))	('improve', 'PosReg', (68, 75))	('MGMT', 'Gene', (38, 42))	('IDH', 'Gene', '3417', (21, 24))	('mutation', 'Var', (25, 33))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('MGMT', 'Gene', '4255', (173, 177))	('MGMT', 'Gene', (173, 177))	('prognostication', 'MPA', (76, 91))	('IDH', 'Gene', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
57124	26646075	Nearly all the G-CIMP tumors have IDH1 mutations and a proneural pattern of gene expression, and have an improved prognosis.	('proneural pattern of gene expression', 'MPA', (55, 91))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (39, 48))	('CIMP', 'Chemical', '-', (17, 21))	('IDH1', 'Gene', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
57125	26646075	This distinct subgroup of GBs, with a G-CIMP phenotype and IDH1 mutation, represent only 5-10 % of GBs in total.	('CIMP', 'Chemical', '-', (40, 44))	('mutation', 'Var', (64, 72))	('GB', 'Phenotype', 'HP:0012174', (26, 28))	('IDH1', 'Gene', (59, 63))	('GB', 'Phenotype', 'HP:0012174', (99, 101))
57126	26646075	By contrast, GBs with a mesenchymal gene expression pattern have inferior survival outcomes with an average OS of 12 months or less and make up a much larger proportion, approximately 30 %, of GB patients.	('GB', 'Phenotype', 'HP:0012174', (13, 15))	('mesenchymal gene expression', 'Var', (24, 51))	('patients', 'Species', '9606', (196, 204))	('survival', 'MPA', (74, 82))	('inferior', 'NegReg', (65, 73))	('GB', 'Phenotype', 'HP:0012174', (193, 195))
57127	26646075	Studies using a genome-wide approach have identified additional mutations that may be important in understanding tumor biology, refining prognostic groups, and which may eventually guide use of targeted therapeutics.	('tumor', 'Disease', (113, 118))	('guide', 'Reg', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutations', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
57128	26646075	Multiple studies have reported oncogene and tumor suppressor genes frequently mutated in other cancers, including PTEN, TP53, PIK3CA, PIK3R1, NF1, RB1, as well as amplification of the PDGFR1A and EGFR receptor tyrosine kinases.	('NF1', 'Gene', '4763', (142, 145))	('EGFR', 'Gene', '1950', (196, 200))	('mutated', 'Var', (78, 85))	('PDGFR1A', 'Gene', (184, 191))	('NF1', 'Gene', (142, 145))	('PIK3R1', 'Gene', '5295', (134, 140))	('tumor', 'Disease', (44, 49))	('TP53', 'Gene', '7157', (120, 124))	('amplification', 'Var', (163, 176))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PIK3CA', 'Gene', '5290', (126, 132))	('RB1', 'Gene', (147, 150))	('PTEN', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TP53', 'Gene', (120, 124))	('EGFR', 'Gene', (196, 200))	('PIK3R1', 'Gene', (134, 140))	('PIK3CA', 'Gene', (126, 132))	('RB1', 'Gene', '5925', (147, 150))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('PTEN', 'Gene', '5728', (114, 118))	('oncogene', 'Gene', (31, 39))
57130	26646075	The majority of secondary glioblastomas have IDH1 and TP53 mutations, and serve to mark their evolution from WHO grade II and III lower grade gliomas which share these mutations.	('gliomas', 'Phenotype', 'HP:0009733', (142, 149))	('gliomas', 'Disease', (142, 149))	('glioblastomas', 'Phenotype', 'HP:0012174', (26, 39))	('gliomas', 'Disease', 'MESH:D005910', (142, 149))	('glioblastomas', 'Disease', 'MESH:D005909', (26, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('TP53', 'Gene', '7157', (54, 58))	('glioblastomas', 'Disease', (26, 39))	('mutations', 'Var', (59, 68))	('IDH1', 'Gene', (45, 49))	('TP53', 'Gene', (54, 58))
57131	26646075	Recently, it was discovered that most IDH1 mutant glioblastomas also have ATRX mutations.	('glioblastomas', 'Disease', 'MESH:D005909', (50, 63))	('ATRX', 'Gene', (74, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('glioblastomas', 'Disease', (50, 63))	('ATRX', 'Gene', '546', (74, 78))	('mutant', 'Var', (43, 49))	('IDH1', 'Gene', (38, 42))	('glioblastomas', 'Phenotype', 'HP:0012174', (50, 63))	('mutations', 'Var', (79, 88))
57132	26646075	IDH1 and ATRX mutations are mutually exclusive from the genetic events that typically occur in primary (or de novo) GBs, such as EGFR gene amplification and loss of PTEN function.	('ATRX', 'Gene', '546', (9, 13))	('amplification', 'Var', (139, 152))	('PTEN', 'Gene', (165, 169))	('EGFR', 'Gene', '1950', (129, 133))	('loss', 'NegReg', (157, 161))	('IDH1', 'Gene', (0, 4))	('GB', 'Phenotype', 'HP:0012174', (116, 118))	('EGFR', 'Gene', (129, 133))	('ATRX', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('PTEN', 'Gene', '5728', (165, 169))
57135	26646075	These mutations include point mutations in the BRAF gene, BRAF V600E and V600K.	('V600E', 'Var', (63, 68))	('BRAF', 'Gene', (47, 51))	('V600K', 'Var', (73, 78))	('BRAF', 'Gene', '673', (47, 51))	('point mutations', 'Var', (24, 39))	('V600K', 'Mutation', 'rs121913227', (73, 78))	('BRAF', 'Gene', '673', (58, 62))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('BRAF', 'Gene', (58, 62))
57136	26646075	BRAF V600E mutations are present in a small minority, fewer than 2 % of GBs, but identification may be important as vemurafenib or dabrafenib, approved for use in metastatic melanoma, may be potential treatments.	('vemurafenib', 'Chemical', 'MESH:D000077484', (116, 127))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('GB', 'Phenotype', 'HP:0012174', (72, 74))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('BRAF', 'Gene', (0, 4))	('dabrafenib', 'Chemical', 'MESH:C561627', (131, 141))
57138	26646075	Unique gene fusions have been discovered in many cancers to date, and GB is no exception as the recently described FGFR-TACC gene fusion produces a fusion protein with oncogenic activity.	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('fusion', 'Protein', (148, 154))	('GB', 'Phenotype', 'HP:0012174', (70, 72))	('gene fusion', 'Var', (125, 136))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('FGFR-TACC', 'Gene', (115, 124))	('cancers', 'Disease', (49, 56))	('oncogenic activity', 'CPA', (168, 186))
57142	26646075	Likewise, designing clinical trials targeting a particular oncogene or tumor suppressor gene mutation enriched in a specific subset of newly diagnosed GB patients, for example NF1 mutations in mesenchymal GBs, may allow for more efficient trial designs with a higher likelihood of success.	('NF1', 'Gene', '4763', (176, 179))	('NF1', 'Gene', (176, 179))	('mutations', 'Var', (180, 189))	('GB', 'Phenotype', 'HP:0012174', (151, 153))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('patients', 'Species', '9606', (154, 162))	('GB', 'Phenotype', 'HP:0012174', (205, 207))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mesenchymal GBs', 'Gene', (193, 208))	('tumor', 'Disease', (71, 76))
57145	26646075	One large retrospective study demonstrated that IDH1 wild-type anaplastic astrocytomas had inferior survival outcomes to IDH1 mutant GBs.	('GB', 'Phenotype', 'HP:0012174', (133, 135))	('IDH1', 'Gene', (121, 125))	('astrocytomas', 'Disease', (74, 86))	('astrocytomas', 'Disease', 'MESH:D001254', (74, 86))	('IDH1', 'Gene', (48, 52))	('mutant', 'Var', (126, 132))
57148	26646075	GBs can be molecularly stratified at diagnosis into subgroups using IDH1 mutation status, MGMT promoter methylation, and gene expression signature (Fig.	('MGMT', 'Gene', (90, 94))	('GB', 'Phenotype', 'HP:0012174', (0, 2))	('MGMT', 'Gene', '4255', (90, 94))	('IDH1', 'Gene', (68, 72))	('mutation', 'Var', (73, 81))
57150	26646075	Testing for IDH1 mutation by immunohistochemistry, IDH1 and 2 mutation testing by polymerase chain reaction, and commercial testing of MGMT promoter methylation are widely available.	('IDH1', 'Gene', (12, 16))	('MGMT', 'Gene', (135, 139))	('mutation', 'Var', (17, 25))	('MGMT', 'Gene', '4255', (135, 139))	('IDH1 and 2', 'Gene', '3417;3418', (51, 61))
57155	26646075	Patients participating in phase II clinical trials at large institutions may be patients with clinical features resulting in a better prognosis, or perhaps a higher proportion of these patients have favorable molecular features, such as IDH1 mutations and/or MGMT promoter methylation.	('patients', 'Species', '9606', (80, 88))	('MGMT', 'Gene', (259, 263))	('mutations', 'Var', (242, 251))	('MGMT', 'Gene', '4255', (259, 263))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (185, 193))	('IDH1', 'Gene', (237, 241))
57177	26646075	There is evidence that temozolomide-induced damage to the DNA mismatch repair system results in a hypermutated phenotype with further deficiency in mismatch repair.	('mismatch repair', 'MPA', (148, 163))	('hypermutated phenotype', 'MPA', (98, 120))	('deficiency', 'NegReg', (134, 144))	('results in', 'Reg', (85, 95))	('temozolomide', 'Chemical', 'MESH:D000077204', (23, 35))	('damage', 'Var', (44, 50))
57178	26646075	In one pre-clinical study comparing primary and recurrent tumors, temozolomide-treated WHO grade II astrocytomas had mutations in key intracellular signaling pathways, which were not present in the primary tumor and could mediate treatment resistance to cytotoxic and targeted therapeutic agents.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('astrocytomas', 'Disease', 'MESH:D001254', (100, 112))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('temozolomide', 'Chemical', 'MESH:D000077204', (66, 78))	('astrocytomas', 'Disease', (100, 112))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('key intracellular signaling pathways', 'Pathway', (130, 166))
57197	26646075	In addition to their prognostic and biologic significance, IDH mutations may be a tumor-specific target for immunotherapeutics.	('mutations', 'Var', (63, 72))	('IDH', 'Gene', (59, 62))	('IDH', 'Gene', '3417', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
57198	26646075	In a recent study, an immune response generated against unique epitopes expressed on IDH1 mutated gliomas was successful in a mouse model using a peptide-based vaccine.	('mouse', 'Species', '10090', (126, 131))	('mutated', 'Var', (90, 97))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('gliomas', 'Disease', (98, 105))	('IDH1', 'Gene', (85, 89))	('gliomas', 'Disease', 'MESH:D005910', (98, 105))
57199	26646075	EGFR variant III (EGFRvIII) is the most common mutation of the EGFR gene in glioblastoma, is present in 25-30 % of GB patients, and is absent in normal tissue.	('GB', 'Phenotype', 'HP:0012174', (115, 117))	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('EGFR', 'Gene', '1950', (18, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (63, 67))	('variant', 'Var', (5, 12))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', '1950', (0, 4))	('glioblastoma', 'Disease', (76, 88))	('EGFR', 'Gene', '1950', (63, 67))	('patients', 'Species', '9606', (118, 126))
57200	26646075	EGFRvIII mutations are associated with poor long-term survival and are mutually exclusive with IDH mutations and G-CIMP gene expression.	('CIMP', 'Chemical', '-', (115, 119))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (9, 18))	('EGFR', 'Gene', '1950', (0, 4))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', (95, 98))
57202	26646075	Promising results were reported from three phase II trials which added rindopepimut to standard therapy in newly diagnosed GB patients with an EGFRvIII mutation.	('EGFR', 'Gene', (143, 147))	('GB', 'Phenotype', 'HP:0012174', (123, 125))	('EGFR', 'Gene', '1950', (143, 147))	('patients', 'Species', '9606', (126, 134))	('mutation', 'Var', (152, 160))
57203	26646075	The randomized, phase III, ACT IV clinical trial testing the addition of rindopepimut to radiotherapy and temozolomide in EGFRvIII mutated, newly diagnosed GB patients has completed enrollment and these results are anxiously awaited.	('temozolomide', 'Chemical', 'MESH:D000077204', (106, 118))	('mutated', 'Var', (131, 138))	('GB', 'Phenotype', 'HP:0012174', (156, 158))	('EGFR', 'Gene', '1950', (122, 126))	('patients', 'Species', '9606', (159, 167))	('EGFR', 'Gene', (122, 126))
57235	26646075	IDH1 mutation, MGMT promoter methylation, and gene expression profiling can segregate newly diagnosed glioblastoma patients into groups with different prognoses.	('patients', 'Species', '9606', (115, 123))	('glioblastoma', 'Disease', (102, 114))	('MGMT', 'Gene', '4255', (15, 19))	('MGMT', 'Gene', (15, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('IDH1', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
57245	26518695	Measured by rank-sum test Z-scores, K562 CRISPRi screen data achieved the highest association with NEST score in K562 cell than all other cell lines (Fig.	('K562', 'CellLine', 'CVCL:0004', (36, 40))	('NEST', 'MPA', (99, 103))	('K562', 'CellLine', 'CVCL:0004', (113, 117))	('K562', 'Var', (36, 40))
57246	26518695	Similarly, HL60 and A375 CRISPR screen data also achieved higher associations with NEST scores in the same cell line (Additional file 1: Figure S3C).	('associations', 'Interaction', (65, 77))	('A375 CRISPR', 'Var', (20, 31))	('A375', 'CellLine', 'CVCL:0132', (20, 24))	('HL60', 'CellLine', 'CVCL:0002', (11, 15))	('higher', 'PosReg', (58, 64))	('HL60', 'Var', (11, 15))
57247	26518695	Notably, the majority of essential genes selected in CRISPR screen do not overlap between K562, HL60, and A375 (Additional file 1: Table S1).	('K562', 'Var', (90, 94))	('HL60', 'CellLine', 'CVCL:0002', (96, 100))	('A375', 'Var', (106, 110))	('K562', 'CellLine', 'CVCL:0004', (90, 94))	('A375', 'CellLine', 'CVCL:0132', (106, 110))
57254	26518695	H3K27ac NEST scores could also reliably predict the gene essentiality in K562 CRISPRi screen (Additional file 1: Figure S3), suggesting the applicability of NEST analysis on histone modification data.	('H3K27ac', 'Var', (0, 7))	('predict', 'Reg', (40, 47))	('K562', 'CellLine', 'CVCL:0004', (73, 77))	('gene essentiality', 'MPA', (52, 69))
57270	26518695	To systematically evaluate the survival prediction performance, we hypothesized that a good gene-wise survival predictor should show significant higher death risk for oncogenes than for tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('oncogenes', 'Var', (167, 176))	('tumor', 'Disease', (186, 191))
57274	26518695	A positive rank-sum Z-score indicates oncogenes with higher survival risk than tumor suppressors, and a negative Z-score indicates the opposite.	('higher', 'PosReg', (53, 59))	('tumor', 'Disease', (79, 84))	('oncogenes', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
57280	26518695	For example, the inhibitors of EGFR, CSF1R, and CXCR4 were shown to reduce the invasiveness of Glioma cells or block GBM progression.	('Glioma', 'Phenotype', 'HP:0009733', (95, 101))	('EGFR', 'Gene', '1956', (31, 35))	('CSF1R', 'Gene', (37, 42))	('invasiveness of Glioma', 'Disease', 'MESH:D005910', (79, 101))	('EGFR', 'Gene', (31, 35))	('block', 'NegReg', (111, 116))	('reduce', 'NegReg', (68, 74))	('GBM progression', 'CPA', (117, 132))	('CXCR4', 'Gene', '7852', (48, 53))	('inhibitors', 'Var', (17, 27))	('CXCR4', 'Gene', (48, 53))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('CSF1R', 'Gene', '1436', (37, 42))	('invasiveness of Glioma', 'Disease', (79, 101))
57281	26518695	For example, NEST predicted KITLG as indicator of poor GBM survival which is consistent with the finding that downregulation of KITLG inhibits angiogenesis and Glioma growth.	('inhibits', 'NegReg', (134, 142))	('KITLG', 'Gene', '4254', (128, 133))	('Glioma growth', 'Disease', 'MESH:D005910', (160, 173))	('KITLG', 'Gene', (128, 133))	('Glioma growth', 'Disease', (160, 173))	('downregulation', 'Var', (110, 124))	('GBM', 'Phenotype', 'HP:0012174', (55, 58))	('angiogenesis', 'CPA', (143, 155))	('KITLG', 'Gene', '4254', (28, 33))	('KITLG', 'Gene', (28, 33))	('Glioma', 'Phenotype', 'HP:0009733', (160, 166))
57286	26518695	According to the rule of DREAM challenge, all DREAM methods can gene expression as well as any other features they could utilize.	('DREAM', 'Gene', '30818', (25, 30))	('DREAM', 'Gene', '30818', (46, 51))	('DREAM', 'Gene', (25, 30))	('DREAM', 'Gene', (46, 51))	('gene expression', 'Var', (64, 79))
57290	26518695	For example, PLK1, an interaction partner of TP53 in STRING network, was consistently upregulated in cancer cells with inactivated TP53 compared with those with wild type.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('TP53', 'Gene', (45, 49))	('cancer', 'Disease', (101, 107))	('inactivated', 'Var', (119, 130))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('upregulated', 'PosReg', (86, 97))	('PLK1', 'Gene', (13, 17))	('PLK1', 'Gene', '5347', (13, 17))	('TP53', 'Gene', '7157', (45, 49))
57336	25683712	Glucose deprivation reduced colony size and number in Hif-1alpha-/- MEFs expressing either HIGD1A or GFP (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (68, 72))	('Glucose deprivation reduced colony', 'Disease', (0, 34))	('Glucose deprivation reduced colony', 'Disease', 'MESH:D012892', (0, 34))	('Hif-1alpha', 'Gene', '3091', (54, 64))	('GFP', 'Var', (101, 104))	('Hif-1alpha', 'Gene', (54, 64))	('HIGD1A', 'Gene', (91, 97))
57340	25683712	Consistent with these results, tumors derived from Hif-1alpha-/- MEFs expressing HIGD1A were much smaller than control Hif-1alpha-/- MEF tumors (Fig.	('smaller', 'NegReg', (98, 105))	('Hif-1alpha', 'Gene', '3091', (119, 129))	('HIGD1A', 'Var', (81, 87))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Hif-1alpha', 'Gene', (119, 129))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('Hif-1alpha', 'Gene', '3091', (51, 61))	('MEF tumors', 'Disease', (133, 143))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('Hif-1alpha', 'Gene', (51, 61))	('MEF tumors', 'Disease', 'MESH:D009369', (133, 143))	('MEFs', 'CellLine', 'CVCL:9115', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
57344	25683712	Immunoprecipitation assays with extracts derived from MEFs expressing GFP-tagged HIGD1A detected an interaction between murine HIGD1A and Complex III subunit 2 of the mitochondrial electron transport chain (ETC), but not with Complex IV subunit I (Fig.	('HIGD1A', 'Gene', (81, 87))	('MEFs', 'CellLine', 'CVCL:9115', (54, 58))	('interaction', 'Interaction', (100, 111))	('Complex III subunit 2', 'Gene', '67003', (138, 159))	('Complex III subunit 2', 'Gene', (138, 159))	('HIGD1A', 'Gene', (127, 133))	('murine', 'Species', '10090', (120, 126))	('GFP-tagged', 'Var', (70, 80))
57350	25683712	These results indicate that HIGD1A expression can modulate mitochondrial ROS production and oxygen consumption during conditions of glucose deprivation via interaction with the ETC.	('oxygen consumption', 'MPA', (92, 110))	('glucose deprivation', 'Disease', (132, 151))	('modulate', 'Reg', (50, 58))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('HIGD1A', 'Gene', (28, 34))	('mitochondrial ROS production', 'MPA', (59, 87))	('interaction', 'Interaction', (156, 167))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('glucose deprivation', 'Disease', 'MESH:D012892', (132, 151))	('expression', 'Var', (35, 45))
57370	25683712	From genome-wide analyses of aberrant DNA methylation in glioblastoma multiforme (GBM), we identified two candidate regions near the Higd1a promoter that exhibited GBM-specific hypermethylation.	('glioblastoma multiforme', 'Disease', (57, 80))	('Higd1a', 'Gene', '25994', (133, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (57, 80))	('Higd1a', 'Gene', (133, 139))	('aberrant', 'Var', (29, 37))
57379	25683712	DNA methylation at upstream HREs might prevent transactivation of HIGD1A via HIF1 and thereby suppress enhanced HIGD1A expression during growth permissive hypoxic conditions, but allow epigenetic activation when environmental conditions favoring HIGD1A expression are encountered.	('expression', 'MPA', (119, 129))	('prevent', 'NegReg', (39, 46))	('HIGD1A', 'Gene', (112, 118))	('suppress', 'NegReg', (94, 102))	('HIF1', 'Gene', (77, 81))	('methylation', 'Var', (4, 15))	('hypoxic conditions', 'Disease', (155, 173))	('enhanced', 'PosReg', (103, 111))	('HIGD1A', 'Gene', (66, 72))	('hypoxic conditions', 'Disease', 'MESH:D009135', (155, 173))	('transactivation', 'MPA', (47, 62))	('epigenetic activation', 'MPA', (185, 206))	('HIF1', 'Gene', '3091', (77, 81))
57405	25683712	This result is consistent with previous reports linking DNMT1 inhibition with tumor suppressor reactivation in response to environmental stressors in vivo.	('DNMT1', 'Gene', '1786', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('inhibition', 'Var', (62, 72))	('tumor', 'Disease', (78, 83))	('DNMT1', 'Gene', (56, 61))
57409	25683712	Small molecule modulators of the HIG family of mitochondrial proteins may therefore prove useful in the fight against cancer.	('cancer', 'Disease', (118, 124))	('modulators', 'Var', (15, 25))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
57424	25832656	FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties.	('expression', 'MPA', (44, 54))	('PDGF-A', 'Gene', (27, 33))	('abolishing', 'NegReg', (85, 95))	('deficiency', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('FoxM1', 'Gene', (0, 5))	('inhibited', 'NegReg', (17, 26))	('expression', 'Species', '29278', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('STAT3', 'Gene', (38, 43))
57431	25832656	Several studies have demonstrated that gliomagenesis involves aberrant signaling through PDGF pathway.	('glioma', 'Disease', (39, 45))	('aberrant', 'Var', (62, 70))	('PDGF pathway', 'Pathway', (89, 101))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
57433	25832656	Moreover, inhibition of PDGF-A was able to inhibit growth of GBM cell lines in vivo, indicating an important role of PDGF-A in mediating the growth of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('glioma', 'Disease', (151, 157))	('inhibit', 'NegReg', (43, 50))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('inhibition', 'Var', (10, 20))	('growth of GBM cell lines in vivo', 'CPA', (51, 83))	('PDGF-A', 'Gene', (24, 30))
57440	25832656	Inhibition of STAT3 expression in GBM cells and GSCs results in downregulated STAT3 phosphorylation, indicating that the level of STAT3 is important to its phosphorylation.	('STAT3', 'Gene', (14, 19))	('STAT3 phosphorylation', 'MPA', (78, 99))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('expression', 'Species', '29278', (20, 30))	('Inhibition', 'Var', (0, 10))	('downregulated', 'NegReg', (64, 77))
57441	25832656	Moreover, STAT3 may drive downstream targets gene expression in the absence of phosphorylation.	('drive', 'PosReg', (20, 25))	('expression', 'MPA', (50, 60))	('expression', 'Species', '29278', (50, 60))	('STAT3', 'Var', (10, 15))
57469	25832656	When the GBM tumors were characterized into FoxM1high and FoxM1low subpopulation, higher PDGF-A RNA expression was enriched in the FoxM1high subgroup (Fig.	('GBM', 'Phenotype', 'HP:0012174', (9, 12))	('PDGF-A RNA', 'Gene', (89, 99))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('GBM tumors', 'Disease', (9, 19))	('GBM tumors', 'Disease', 'MESH:D005910', (9, 19))	('expression', 'Species', '29278', (100, 110))	('higher', 'PosReg', (82, 88))	('expression', 'MPA', (100, 110))	('FoxM1high', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
57474	25832656	Deletion of FoxM1 in FoxM1fl/fl NSCs resulted in diminished sphere formation ability (Fig.	('sphere formation ability', 'CPA', (60, 84))	('NSC', 'Disease', (32, 35))	('FoxM1', 'Gene', (12, 17))	('FoxM1fl/fl', 'Gene', (21, 31))	('NSC', 'Disease', 'OMIM:617394', (32, 35))	('diminished', 'NegReg', (49, 59))	('Deletion', 'Var', (0, 8))
57479	25832656	Moreover, knocking down FoxM1 in GSC11 and GSC20s cells significantly decreased PDGF-A promoter activity in the cells (Fig.	('knocking down', 'Var', (10, 23))	('PDGF-A', 'Gene', (80, 86))	('decreased', 'NegReg', (70, 79))	('FoxM1', 'Gene', (24, 29))	('GSC20', 'CellLine', 'CVCL:M752', (43, 48))
57481	25832656	The mutants containing mutations in binding site 1, binding site 2, or both sites and the deletion mutant A200 exhibited lower promoter activity than wild-type (wt) PDGF-A promoter in 293T cells (Fig.	('A200', 'Gene', (106, 110))	('293T', 'CellLine', 'CVCL:0063', (184, 188))	('mutations', 'Var', (23, 32))	('lower', 'NegReg', (121, 126))	('promoter activity', 'MPA', (127, 144))
57482	25832656	Also, disruption of one or both of the FoxM1 binding sites significantly attenuated PDGF-A promoter activity in GSC11 and GSC20s cells (Fig.	('FoxM1', 'Gene', (39, 44))	('promoter activity', 'MPA', (91, 108))	('attenuated', 'NegReg', (73, 83))	('PDGF-A', 'Gene', (84, 90))	('disruption', 'Var', (6, 16))	('GSC20', 'CellLine', 'CVCL:M752', (122, 127))
57484	25832656	PDGF-A knockdown also suppressed the expression of stem cell markers CD133, Nestin, SOX2, and OCT4 but upregulated the expression of differentiation marker GFAP (Fig.	('expression', 'MPA', (119, 129))	('suppressed', 'NegReg', (22, 32))	('CD133', 'Gene', (69, 74))	('PDGF-A', 'Gene', (0, 6))	('OCT4', 'Gene', (94, 98))	('Nestin', 'Gene', (76, 82))	('expression', 'Species', '29278', (119, 129))	('SOX2', 'Gene', '6657', (84, 88))	('SOX2', 'Gene', (84, 88))	('expression', 'Species', '29278', (37, 47))	('stem cell', 'CPA', (51, 60))	('expression', 'MPA', (37, 47))	('knockdown', 'Var', (7, 16))	('Nestin', 'Gene', '10763', (76, 82))	('upregulated', 'PosReg', (103, 114))
57488	25832656	S3D,E) or the effect of FoxM1 depletion on the self-renewal of NSCs (Fig.	('NSC', 'Disease', (63, 66))	('depletion', 'Var', (30, 39))	('NSC', 'Disease', 'OMIM:617394', (63, 66))	('FoxM1', 'Gene', (24, 29))
57489	25832656	Exogenous PDGF-AA also only partially reversed the effect of FoxM1 knockdown on the expression of SOX2 (Fig.	('knockdown', 'Var', (67, 76))	('FoxM1', 'Gene', (61, 66))	('expression', 'Species', '29278', (84, 94))	('SOX2', 'Gene', '6657', (98, 102))	('SOX2', 'Gene', (98, 102))
57491	25832656	FoxM1 or PDGF-A knockdown significantly decreased cell proliferation of GSC11 and GSC20s (Fig.	('knockdown', 'Var', (16, 25))	('PDGF-A', 'Gene', (9, 15))	('FoxM1', 'Gene', (0, 5))	('decreased', 'NegReg', (40, 49))	('GSC20', 'CellLine', 'CVCL:M752', (82, 87))	('cell proliferation', 'CPA', (50, 68))
57494	25832656	FoxM1 knockdown significantly decreased cell viability of GSC11, GSC20s and GSC267 cells after TMZ treatment as compared with sh-control (Fig.	('GSC20', 'CellLine', 'CVCL:M752', (65, 70))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))	('FoxM1', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('GSC267', 'CellLine', 'CVCL:M752', (76, 82))	('cell viability', 'CPA', (40, 54))	('decreased', 'NegReg', (30, 39))
57495	25832656	PDGF-A knockdown also significantly decreased cell viability after TMZ treatment, but to a less extent than FoxM1 knockdown (Fig.	('PDGF-A', 'Gene', (0, 6))	('TMZ', 'Chemical', 'MESH:D000077204', (67, 70))	('knockdown', 'Var', (7, 16))	('cell viability', 'CPA', (46, 60))	('decreased', 'NegReg', (36, 45))
57496	25832656	Together, these results indicate that FoxM1 inhibition decreased cell proliferation and increases the chemosensitivity of GSCs to TMZ.	('inhibition', 'Var', (44, 54))	('decreased', 'NegReg', (55, 64))	('cell proliferation', 'CPA', (65, 83))	('FoxM1', 'Gene', (38, 43))	('increases', 'PosReg', (88, 97))	('chemosensitivity', 'CPA', (102, 118))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))
57497	25832656	Knocking down PDGF-A or FoxM1 reduced STAT3 phosphorylation in both GSC11 and GSC20s cells (Fig.	('STAT3 phosphorylation', 'MPA', (38, 59))	('PDGF-A', 'Gene', (14, 20))	('reduced', 'NegReg', (30, 37))	('FoxM1', 'Gene', (24, 29))	('GSC20', 'CellLine', 'CVCL:M752', (78, 83))	('Knocking', 'Var', (0, 8))
57498	25832656	However, surprisingly, knocking down FoxM1 resulted in not only decreased STAT3 phosphorylation but also decreased STAT3 expression (Fig.	('FoxM1', 'Gene', (37, 42))	('expression', 'Species', '29278', (121, 131))	('STAT3 expression', 'MPA', (115, 131))	('knocking down', 'Var', (23, 36))	('STAT3 phosphorylation', 'MPA', (74, 95))	('decreased', 'NegReg', (105, 114))	('decreased', 'NegReg', (64, 73))
57499	25832656	In contrast to FoxM1 knockdown, PDGF-A knockdown decreased STAT3 phosphorylation but did not change STAT3 expression (Fig.	('expression', 'Species', '29278', (106, 116))	('STAT3 phosphorylation', 'MPA', (59, 80))	('knockdown', 'Var', (39, 48))	('decreased', 'NegReg', (49, 58))	('PDGF-A', 'Gene', (32, 38))
57500	25832656	Moreover, deletion of FoxM1 in FoxM1fl/fl NSCs resulted in a strikingly lower level of STAT3 expression compared with the level in FoxM1 wild-type NSCs (Fig.	('NSC', 'Disease', 'OMIM:617394', (147, 150))	('STAT3 expression', 'MPA', (87, 103))	('FoxM1', 'Gene', (22, 27))	('NSC', 'Disease', 'OMIM:617394', (42, 45))	('expression', 'Species', '29278', (93, 103))	('lower', 'NegReg', (72, 77))	('NSC', 'Disease', (147, 150))	('deletion', 'Var', (10, 18))	('FoxM1fl/fl', 'Gene', (31, 41))	('NSC', 'Disease', (42, 45))
57503	25832656	Moreover, STAT3 knockdown inhibited the self-renewal of both GSC11 and GSC20s cells (Fig.	('STAT3', 'Gene', (10, 15))	('inhibited', 'NegReg', (26, 35))	('knockdown', 'Var', (16, 25))	('GSC20', 'CellLine', 'CVCL:M752', (71, 76))	('self-renewal', 'CPA', (40, 52))
57506	25832656	We evaluated the association of STAT3 and FoxM1 expression in the GBM tumors from TCGA dataset which were characterized into FoxM1high and FoxM1low subpopulation as described in Figure 1B, and found that higher STAT3 expression was enriched in the FoxM1high subgroup (Fig.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('expression', 'Species', '29278', (217, 227))	('GBM tumors', 'Disease', (66, 76))	('GBM tumors', 'Disease', 'MESH:D005910', (66, 76))	('expression', 'Species', '29278', (48, 58))	('expression', 'MPA', (217, 227))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('STAT3', 'Gene', (211, 216))	('FoxM1', 'Gene', (42, 47))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('FoxM1high', 'Var', (248, 257))	('higher', 'PosReg', (204, 210))
57510	25832656	Knocking down beta-catenin or inhibiting TCF4, the key transcriptional factor of beta-catenin pathway, by TCF4-DN (dominate-negative TCF4) significantly decreased the transcriptional activity of beta-catenin in GSCs, as indicated by TOPflash activity (Fig.	('inhibiting', 'NegReg', (30, 40))	('beta-catenin', 'Gene', (14, 26))	('TCF4', 'Gene', (41, 45))	('TCF4-DN', 'Var', (106, 113))	('transcriptional activity', 'MPA', (167, 191))	('beta-catenin', 'Gene', '12387', (81, 93))	('beta-catenin', 'Gene', '12387', (195, 207))	('TOPflash', 'Disease', (233, 241))	('TOPflash', 'Disease', 'None', (233, 241))	('decreased', 'NegReg', (153, 162))	('TCF4-DN', 'Chemical', '-', (106, 113))	('beta-catenin', 'Gene', '12387', (14, 26))	('beta-catenin', 'Gene', (81, 93))	('beta-catenin', 'Gene', (195, 207))
57511	25832656	Knocking down FoxM1 also significantly decreased the transcriptional activity of beta-catenin in GSCs (Fig.	('Knocking down', 'Var', (0, 13))	('beta-catenin', 'Gene', '12387', (81, 93))	('FoxM1', 'Gene', (14, 19))	('beta-catenin', 'Gene', (81, 93))	('decreased', 'NegReg', (39, 48))	('transcriptional activity', 'MPA', (53, 77))
57512	25832656	Consistent with this finding, knocking down FoxM1 or beta-catenin or inhibiting TCF4 in GSCs significantly decreased STAT3 mRNA expression (Fig.	('STAT3 mRNA expression', 'MPA', (117, 138))	('beta-catenin', 'Gene', (53, 65))	('decreased', 'NegReg', (107, 116))	('TCF4', 'Gene', (80, 84))	('expression', 'Species', '29278', (128, 138))	('FoxM1', 'Protein', (44, 49))	('inhibiting', 'NegReg', (69, 79))	('knocking down', 'Var', (30, 43))	('beta-catenin', 'Gene', '12387', (53, 65))
57515	25832656	Furthermore, beta-catenin knockdown inhibited FoxM1 binding to the STAT3 promoter, and FoxM1 knockdown inhibited beta-catenin binding to the STAT3 promoter (Fig.	('knockdown', 'Var', (93, 102))	('beta-catenin', 'Gene', (13, 25))	('beta-catenin', 'Gene', '12387', (113, 125))	('inhibited', 'NegReg', (36, 45))	('binding', 'Interaction', (126, 133))	('beta-catenin', 'Gene', '12387', (13, 25))	('inhibited', 'NegReg', (103, 112))	('binding', 'Interaction', (52, 59))	('beta-catenin', 'Gene', (113, 125))	('FoxM1', 'Gene', (87, 92))	('FoxM1', 'Gene', (46, 51))
57518	25832656	However, the pSTAT3 level increased less in sh-FoxM1 than in sh-control cells, indicating that FoxM1 knockdown inhibited STAT3 activation induced by PDGF-AA because of lower expression of total STAT3.	('expression', 'Species', '29278', (174, 184))	('expression', 'MPA', (174, 184))	('STAT3 activation', 'MPA', (121, 137))	('lower', 'NegReg', (168, 173))	('FoxM1', 'Gene', (95, 100))	('inhibited', 'NegReg', (111, 120))	('knockdown', 'Var', (101, 110))
57520	25832656	Both EGF and IL-6 immediately activated STAT3, but the GSCs with FoxM1 knockdown were less responsive to EGF or IL-6 treatment than were the normal control cells (Fig.	('EGF', 'Gene', (105, 108))	('EGF', 'Gene', (5, 8))	('EGF', 'Gene', '1950', (105, 108))	('responsive', 'MPA', (91, 101))	('knockdown', 'Var', (71, 80))	('EGF', 'Gene', '1950', (5, 8))	('FoxM1', 'Gene', (65, 70))	('less', 'NegReg', (86, 90))
57521	25832656	Moreover, SOX2 expression levels were restored in sh-FoxM1-STAT3C GSCs compared to sh-control-vector GSCs (Fig.	('SOX2', 'Gene', (10, 14))	('sh-FoxM1-STAT3C', 'Var', (50, 65))	('restored', 'PosReg', (38, 46))	('expression', 'Species', '29278', (15, 25))	('expression levels', 'MPA', (15, 32))	('SOX2', 'Gene', '6657', (10, 14))
57522	25832656	Next, we examined whether ectopic expression of STAT3C rescued tumor growth inhibition caused by FoxM1 knockdown.	('tumor', 'Disease', (63, 68))	('STAT3C', 'Gene', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('knockdown', 'Var', (103, 112))	('FoxM1', 'Gene', (97, 102))	('expression', 'Species', '29278', (34, 44))
57526	25832656	Furthermore, Sox2 and Ki67, a cellular marker for proliferation, were highly expressed in the tumor tissues of sh-control group and sh-FoxM1+STAT3C group (Fig.	('sh-FoxM1+STAT3C', 'Var', (132, 147))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Ki67', 'Gene', (22, 26))	('tumor', 'Disease', (94, 99))	('Sox2', 'Gene', '6657', (13, 17))	('Sox2', 'Gene', (13, 17))	('highly', 'PosReg', (70, 76))
57530	25832656	Overexpression of FoxM1 in SW1783 and Hs683 cells caused them to exhibit GSC characteristics: SW1783-FoxM1 and Hs683-FoxM1 cells were able to form neurospheres and expressed stem cell markers SSEA-1, SOX2, and Nestin (Fig.	('Nestin', 'Gene', (210, 216))	('form neurospheres', 'CPA', (142, 159))	('expression', 'Species', '29278', (4, 14))	('SW1783', 'CellLine', 'CVCL:1722', (27, 33))	('SOX2', 'Gene', '6657', (200, 204))	('SSEA-1', 'Gene', (192, 198))	('SOX2', 'Gene', (200, 204))	('SW1783', 'CellLine', 'CVCL:1722', (94, 100))	('expressed', 'PosReg', (164, 173))	('SSEA-1', 'Gene', '2526', (192, 198))	('SW1783-FoxM1', 'Var', (94, 106))	('FoxM1', 'Gene', (18, 23))	('Nestin', 'Gene', '10763', (210, 216))	('Hs683-FoxM1', 'Var', (111, 122))
57532	25832656	In contrast, knockdown of STAT3 in SW1783-FoxM1 and Hs683-FoxM1 cells abolished elevated expression of stem cell markers SSEA-1, SOX2, CD133, OCT4 and Nestin (Fig.	('Nestin', 'Gene', (151, 157))	('expression', 'MPA', (89, 99))	('expression', 'Species', '29278', (89, 99))	('elevated', 'PosReg', (80, 88))	('CD133', 'Gene', (135, 140))	('SW1783', 'CellLine', 'CVCL:1722', (35, 41))	('abolished', 'NegReg', (70, 79))	('SOX2', 'Gene', '6657', (129, 133))	('SSEA-1', 'Gene', (121, 127))	('SOX2', 'Gene', (129, 133))	('Nestin', 'Gene', '10763', (151, 157))	('STAT3', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('SSEA-1', 'Gene', '2526', (121, 127))	('OCT4', 'Protein', (142, 146))
57534	25832656	Furthermore, SW1783 and Hs683 cells did not form brain tumors in nude mice, but SW1783-FoxM1 and Hs683-FoxM1 cells did form brain tumors, which possessed features of human GBM, including necrosis and invasion (Fig.	('SW1783', 'CellLine', 'CVCL:1722', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('GBM', 'Phenotype', 'HP:0012174', (172, 175))	('brain tumors', 'Disease', 'MESH:D001932', (49, 61))	('brain tumors', 'Phenotype', 'HP:0030692', (49, 61))	('brain tumor', 'Phenotype', 'HP:0030692', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('human', 'Species', '9606', (166, 171))	('SW1783-FoxM1', 'Var', (80, 92))	('necrosis', 'Disease', 'MESH:D009336', (187, 195))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('brain tumors', 'Disease', (49, 61))	('invasion', 'CPA', (200, 208))	('SW1783', 'CellLine', 'CVCL:1722', (80, 86))	('necrosis', 'Disease', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('brain tumors', 'Phenotype', 'HP:0030692', (124, 136))	('brain tumors', 'Disease', 'MESH:D001932', (124, 136))	('brain tumor', 'Phenotype', 'HP:0030692', (124, 135))	('nude mice', 'Species', '10090', (65, 74))	('form', 'Reg', (119, 123))	('brain tumors', 'Disease', (124, 136))
57580	24810052	In the present study, we show a significant loss of cell viability with>1 muM celastrol after 24 h of treatment in U251N (Figure 1b and Supplementary Figure S1), which was particularly marked under nutrient-rich conditions (LD50: 4.07+-0.29 muM (Serum-) versus 3.16+-0.09 muM (Serum+); P=2.67 x 10-12) (Figure 1c).	('muM', 'Gene', (74, 77))	('muM', 'Gene', '56925', (272, 275))	('muM', 'Gene', '56925', (241, 244))	('cell viability', 'CPA', (52, 66))	('U251N', 'Var', (115, 120))	('muM', 'Gene', (272, 275))	('muM', 'Gene', (241, 244))	('celastrol', 'Chemical', 'MESH:C050414', (78, 87))	('loss', 'NegReg', (44, 48))	('U251N', 'CellLine', 'CVCL:0021', (115, 120))	('muM', 'Gene', '56925', (74, 77))
57584	24810052	Further corroborating these results, inhibition of celastrol-mediated JNK activation with SP600125, as measured by immunoblotting for phospho-JNK (Supplementary Figure S2), had no effect on celastrol's dose-response in glioblastoma (LD50: 2.5+-0.2 muM without SP versus 2.2+-0.58 muM with 10 muM SP and 1.89+-0.71 muM with 20 muM SP; P=0.0834; Figure 1f).	('muM', 'Gene', '56925', (314, 317))	('muM', 'Gene', '56925', (280, 283))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('muM', 'Gene', (314, 317))	('JNK', 'Gene', (142, 145))	('muM', 'Gene', (280, 283))	('celastrol', 'Chemical', 'MESH:C050414', (51, 60))	('muM', 'Gene', '56925', (248, 251))	('JNK', 'Gene', '5599', (142, 145))	('muM', 'Gene', (248, 251))	('glioblastoma', 'Disease', (219, 231))	('muM', 'Gene', '56925', (326, 329))	('SP', 'Chemical', 'MESH:C000604007', (260, 262))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('JNK', 'Gene', (70, 73))	('muM', 'Gene', (326, 329))	('SP600125', 'Var', (90, 98))	('muM', 'Gene', '56925', (292, 295))	('SP', 'Chemical', 'MESH:C000604007', (330, 332))	('JNK', 'Gene', '5599', (70, 73))	('celastrol', 'Chemical', 'MESH:C050414', (190, 199))	('muM', 'Gene', (292, 295))	('SP', 'Chemical', 'MESH:C000604007', (296, 298))	('SP', 'Chemical', 'MESH:C000604007', (90, 92))	('SP600125', 'Chemical', 'MESH:C432165', (90, 98))
57665	24810052	In the yeast homolog of HSP70, Ssa1, mutations to cysteine residues (C264 and C303) were individually sufficient to render HSF-1 unresponsive both to celastrol and 4-hydroxynonenal (4-HNE), a model organic electrophile.	('HSP70', 'Gene', (24, 29))	('unresponsive', 'MPA', (129, 141))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (164, 180))	('Ssa1', 'Gene', (31, 35))	('Ssa1', 'Gene', '851259', (31, 35))	('mutations', 'Var', (37, 46))	('yeast', 'Species', '4932', (7, 12))	('cysteine', 'Chemical', 'MESH:D003545', (50, 58))	('HSP70', 'Gene', '3308', (24, 29))	('celastrol', 'Chemical', 'MESH:C050414', (150, 159))	('HSF-1', 'Gene', (123, 128))	('C264', 'Var', (69, 73))	('4-HNE', 'Chemical', 'MESH:C027576', (182, 187))	('C303', 'Var', (78, 82))
57666	24810052	Similarly, conserved cysteine residues (C267 and C306) in HSP72, but not HSP70, were necessary for redox sensing in response to oxidation by methylene blue.	('HSP72', 'Gene', (58, 63))	('HSP72', 'Gene', '3303', (58, 63))	('Si', 'Chemical', 'MESH:D012825', (0, 2))	('C267', 'Var', (40, 44))	('redox sensing', 'MPA', (99, 112))	('C306', 'Var', (49, 53))	('HSP70', 'Gene', (73, 78))	('HSP70', 'Gene', '3308', (73, 78))	('methylene blue', 'Chemical', 'MESH:D008751', (141, 155))	('cysteine', 'Chemical', 'MESH:D003545', (21, 29))	('response to oxidation by methylene blue', 'MPA', (116, 155))
57671	24810052	In line with these results, celastrol induces cytoplasmic vacuolation in several human cancer cell lines in conjunction with elevated membrane-bound LC3 (LC3-II).	('LC3-II', 'Gene', '84557', (154, 160))	('cancer', 'Disease', (87, 93))	('LC3-II', 'Gene', (154, 160))	('celastrol', 'Chemical', 'MESH:C050414', (28, 37))	('LC3', 'Gene', '84557', (149, 152))	('LC3', 'Gene', (149, 152))	('celastrol', 'Var', (28, 37))	('induces', 'Reg', (38, 45))	('LC3', 'Gene', '84557', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('human', 'Species', '9606', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cytoplasmic vacuolation', 'MPA', (46, 69))	('LC3', 'Gene', (154, 157))
57704	24810052	U251N cells were seeded at a density of 10 000 per well into 96-well cell culture plates and left to adhere for 24 h in a final volume of 0.2 ml serum-supplemented DMEM media (10% FBS, 1% Pen-Strep).	('U251N', 'CellLine', 'CVCL:0021', (0, 5))	('DMEM media', 'Chemical', '-', (164, 174))	('Pen', 'Gene', (188, 191))	('Pen', 'Gene', '27344', (188, 191))	('U251N', 'Var', (0, 5))
57707	24810052	U251N cells were seeded at a density of 300 000 per well into six-well cell culture plates and left to adhere for 24 h in a final volume of 2 ml serum-supplemented DMEM media (10% FBS, 1% Pen-Strep).	('U251N', 'CellLine', 'CVCL:0021', (0, 5))	('DMEM media', 'Chemical', '-', (164, 174))	('Pen', 'Gene', (188, 191))	('Pen', 'Gene', '27344', (188, 191))	('U251N', 'Var', (0, 5))
57709	24810052	U251N, U87, and U343 cells were seeded at a density of 50 000 per well into 24-well cell culture plates and left to adhere for 24 h in a final volume of 0.5 ml serum-supplemented DMEM media (10% FBS, 1% Pen-Strep).	('Pen', 'Gene', '27344', (203, 206))	('U251N', 'CellLine', 'CVCL:0021', (0, 5))	('DMEM media', 'Chemical', '-', (179, 189))	('U87', 'CellLine', 'CVCL:0022', (7, 10))	('U251N', 'Var', (0, 5))	('Pen', 'Gene', (203, 206))
57814	34001278	The final DAR was calculated from the A333nm:A280nm ratio and was determined to be 3.36 for anti-IL13Ralpha2::PBD.	('IL13Ralpha2', 'Gene', (97, 108))	('IL13Ralpha2', 'Gene', '3598', (97, 108))	('PBD', 'Chemical', 'MESH:C438462', (110, 113))	('A333nm', 'Var', (38, 44))
57839	34001278	Lack of DIPG-24 response is consistent with the lower expression of IL13Ralpha2 in the assayed cell models, as DIPG-24 has reduced expression compared to SF-8628.	('expression', 'MPA', (54, 64))	('IL13Ralpha2', 'Gene', (68, 79))	('SF-8628', 'Chemical', '-', (154, 161))	('lower', 'NegReg', (48, 53))	('expression', 'MPA', (131, 141))	('DIPG-24', 'Var', (111, 118))	('IL13Ralpha2', 'Gene', '3598', (68, 79))	('DIPG-24', 'Chemical', '-', (111, 118))	('reduced', 'NegReg', (123, 130))	('DIPG-24', 'Chemical', '-', (8, 15))
57862	34001278	Thus, we selected pyrrolobenzodiazepine (PBD) as the payload for the IL13Ralpha2 ADC as PBD is known to promote cell death in model systems often resistant to standard chemotherapy agents or standard ADC cytotoxic payloads.	('IL13Ralpha2', 'Gene', '3598', (69, 80))	('PBD', 'Chemical', 'MESH:C438462', (88, 91))	('pyrrolobenzodiazepine', 'Chemical', 'MESH:C438462', (18, 39))	('ADC', 'Gene', (200, 203))	('ADC', 'Gene', (81, 84))	('IL13Ralpha2', 'Gene', (69, 80))	('PBD', 'Chemical', 'MESH:C438462', (41, 44))	('death', 'Disease', 'MESH:D003643', (117, 122))	('promote', 'PosReg', (104, 111))	('death', 'Disease', (117, 122))	('ADC', 'Gene', '113451', (200, 203))	('PBD', 'Var', (88, 91))	('ADC', 'Gene', '113451', (81, 84))
57873	34001278	While ADC therapies can also potentially illicit immunogenic responses, clinical use of bevacizumab monoclonal antibody therapy in glioblastoma has demonstrated a reduced need for corticosteroids as a consequence of treatment suggesting monoclonal antibodies (and by extension ADC agents) may have lessened immunogenicity in brain tumors compared to CAR-T cell therapy.	('ADC', 'Gene', '113451', (277, 280))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('CAR', 'Gene', (350, 353))	('brain tumors', 'Disease', 'MESH:D001932', (325, 337))	('brain tumors', 'Phenotype', 'HP:0030692', (325, 337))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('brain tumors', 'Disease', (325, 337))	('ADC', 'Gene', '113451', (6, 9))	('bevacizumab', 'Chemical', 'MESH:D000068258', (88, 99))	('lessened', 'NegReg', (298, 306))	('brain tumor', 'Phenotype', 'HP:0030692', (325, 336))	('monoclonal antibodies', 'Var', (237, 258))	('ADC', 'Gene', (6, 9))	('CAR', 'Gene', '653108', (350, 353))	('ADC', 'Gene', (277, 280))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
57880	34001278	In glioblastoma, IL13RA2 has been shown to cooperate with mutant EGFRvIII to mediate growth, while EGFR mutations including EGFRvIII are believed to not be widely recurrent in DIPG[25, 53]which may limit the importance of IL13RA2 in DIPG progression.	('mutant', 'Var', (58, 64))	('EGFR', 'Gene', (99, 103))	('P', 'Chemical', 'MESH:D010758', (235, 236))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (65, 69))	('growth', 'MPA', (85, 91))	('P', 'Chemical', 'MESH:D010758', (178, 179))	('EGFR', 'Gene', (124, 128))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('IL13RA2', 'Gene', '3598', (222, 229))	('IL13RA2', 'Gene', '3598', (17, 24))	('EGFR', 'Gene', '1956', (99, 103))	('IL13RA2', 'Gene', (222, 229))	('IL13RA2', 'Gene', (17, 24))
57896	34001278	Transcriptome sequencing data is available through the Database of Genotypes and Phenotypes (dbGaP) under accession IDs phs000900.v1.p1 and phs001526.v1.p1, and through the European Genome-Phenome Archive (EGA) under accession ID EGAD00001006450.	('P', 'Chemical', 'MESH:D010758', (81, 82))	('accession IDs', 'Disease', 'MESH:C535742', (106, 119))	('P', 'Chemical', 'MESH:D010758', (189, 190))	('phs000900.v1.p1', 'Var', (120, 135))	('phs001526.v1.p1', 'Var', (140, 155))	('P', 'Chemical', 'MESH:D010758', (97, 98))	('accession IDs', 'Disease', (106, 119))
57946	33919596	Doxycycline induced mitochondrial dysfunction, oxidative stress and ultimately energy deficiency in multiple GBM cell lines.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (20, 45))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('mitochondrial dysfunction', 'Disease', (20, 45))	('oxidative stress', 'Phenotype', 'HP:0025464', (47, 63))	('energy deficiency', 'Disease', 'MESH:D011502', (79, 96))	('oxidative stress', 'MPA', (47, 63))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (20, 45))	('Doxycycline', 'Var', (0, 11))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))	('energy deficiency', 'Disease', (79, 96))
57958	33919596	Mice bearing intracranial GBM treated with imipramine had increased survival as a result of tumor autophagy.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('increased', 'PosReg', (58, 67))	('survival', 'CPA', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('imipramine', 'Chemical', 'MESH:D007099', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('imipramine', 'Var', (43, 53))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (92, 97))
57960	33919596	Another TCA, clomipramine, proved to be efficacious in treating GBM cells that have a phenylalanine for leucine mutation in the mitochondrial respiratory chain complex III cytochrome b subunit, a mutation enriched in GBM.	('clomipramine', 'Chemical', 'MESH:D002997', (13, 25))	('GBM', 'Phenotype', 'HP:0012174', (64, 67))	('leucine', 'Chemical', 'MESH:D007930', (104, 111))	('phenylalanine', 'Chemical', 'MESH:D010649', (86, 99))	('cytochrome b', 'Gene', (172, 184))	('GBM', 'Phenotype', 'HP:0012174', (217, 220))	('phenylalanine for leucine mutation', 'Var', (86, 120))	('cytochrome b', 'Gene', '4519', (172, 184))
57970	33919596	IP187B inhibits IL6/signal transducer and activator of transcription 3 (STAT3), NF-kappaB, and insulin-like growth factor receptor pathways and has demonstrated additive efficacy when combined with epidermal growth factor receptor (EGFR) inhibitors against primary GBM cells and intracranial GBM xenografts.	('IL6/signal transducer and activator of transcription 3', 'Gene', '3569;6774', (16, 70))	('STAT3', 'Gene', '6774', (72, 77))	('STAT3', 'Gene', (72, 77))	('epidermal growth factor receptor', 'Gene', '1956', (198, 230))	('inhibits', 'NegReg', (7, 15))	('insulin-like growth factor receptor pathways', 'Pathway', (95, 139))	('NF-kappaB', 'Gene', '4790', (80, 89))	('pa', 'Chemical', 'MESH:D011478', (131, 133))	('GBM', 'Phenotype', 'HP:0012174', (292, 295))	('pa', 'Chemical', 'MESH:D011478', (86, 88))	('GBM', 'Phenotype', 'HP:0012174', (265, 268))	('EGFR', 'Gene', '1956', (232, 236))	('epidermal growth factor receptor', 'Gene', (198, 230))	('EGFR', 'Gene', (232, 236))	('NF-kappaB', 'Gene', (80, 89))	('IP187B', 'Var', (0, 6))
57977	33919596	The phosphodiesterase inhibitor, ibudilast, inhibits macrophage migratory inhibitory factor (MIF), a protein upregulated in a subset of MGMT methylated GBM tumors that have worse prognosis.	('upregulated', 'PosReg', (109, 120))	('MIF', 'Gene', (93, 96))	('MIF', 'Gene', '4282', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('methylated', 'Var', (141, 151))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('MGMT', 'Gene', '4255', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('MGMT', 'Gene', (136, 140))	('inhibits', 'NegReg', (44, 52))	('ibudilast', 'Chemical', 'MESH:C038366', (33, 42))	('tumors', 'Disease', (156, 162))	('GBM', 'Phenotype', 'HP:0012174', (152, 155))
57988	33919596	Consistent with this, combining sirolimus with chloroquine and TMZ resulted in increased apoptosis in GBM cell lines, a finding likely due to an increase in DNA damage because of decreased HR repair and activation of the apoptotic cascade.	('decreased', 'NegReg', (179, 188))	('TMZ', 'Chemical', 'MESH:D000077204', (63, 66))	('pa', 'Chemical', 'MESH:D011478', (194, 196))	('HR repair', 'CPA', (189, 198))	('chloroquine', 'Chemical', 'MESH:D002738', (47, 58))	('apoptotic', 'Pathway', (221, 230))	('apoptosis', 'CPA', (89, 98))	('increase', 'PosReg', (145, 153))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('chloroquine', 'Var', (47, 58))	('sirolimus', 'Chemical', 'MESH:D020123', (32, 41))	('TMZ', 'Var', (63, 66))	('DNA damage', 'MPA', (157, 167))
57990	33919596	The inhibition of NHEJ and CAV3.2 decreased growth and stemness through activation of apoptotic pathways and attenuation of AKT/mTOR signaling.	('activation', 'PosReg', (72, 82))	('NHEJ', 'Gene', (18, 22))	('mTOR', 'Gene', (128, 132))	('mTOR', 'Gene', '2475', (128, 132))	('attenuation', 'NegReg', (109, 120))	('decreased', 'NegReg', (34, 43))	('AKT', 'Gene', (124, 127))	('CAV3.2', 'Gene', '8912', (27, 33))	('CAV3.2', 'Gene', (27, 33))	('inhibition', 'Var', (4, 14))	('pa', 'Chemical', 'MESH:D011478', (96, 98))	('apoptotic pathways', 'Pathway', (86, 104))	('decreased growth', 'Phenotype', 'HP:0001510', (34, 50))	('AKT', 'Gene', '207', (124, 127))
58001	33919596	DS00329 decreased Cyclin A, B, and D1 protein abundance and increased p21, resulting in G1 phase arrest and apoptosis in U251 and U87 cells.	('p21', 'Gene', '1026', (70, 73))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('D1 protein', 'Protein', (35, 45))	('p21', 'Gene', (70, 73))	('DS00329', 'Chemical', '-', (0, 7))	('Cyclin A', 'Gene', '890', (18, 26))	('arrest', 'Disease', (97, 103))	('U87', 'Gene', (130, 133))	('apoptosis', 'CPA', (108, 117))	('decreased', 'NegReg', (8, 17))	('U87', 'Gene', '641648', (130, 133))	('DS00329', 'Var', (0, 7))	('increased', 'PosReg', (60, 69))	('Cyclin A', 'Gene', (18, 26))
58007	33919596	Notably, the combination of penfluridol and TMZ resulted in synergistically prolonged survival in mice bearing orthotopic xenografts.	('TMZ', 'Var', (44, 47))	('penfluridol', 'Chemical', 'MESH:D010395', (28, 39))	('TMZ', 'Chemical', 'MESH:D000077204', (44, 47))	('prolonged', 'PosReg', (76, 85))	('survival', 'CPA', (86, 94))	('mice', 'Species', '10090', (98, 102))
58025	33919596	Inhibition of PI3K with LY294002 or PX-886 blocked the growth of GBM cells in combination with gamitrinib, a mitochondrial heat shock protein (HSP)-90 inhibitor.	('heat shock protein (HSP)-90', 'Gene', (123, 150))	('LY294002', 'Var', (24, 32))	('shock', 'Phenotype', 'HP:0031273', (128, 133))	('heat shock protein (HSP)-90', 'Gene', '3320', (123, 150))	('blocked', 'NegReg', (43, 50))	('growth of GBM cells', 'CPA', (55, 74))	('PX-886', 'Chemical', '-', (36, 42))	('gamitrinib', 'Chemical', '-', (95, 105))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('PX-886', 'Var', (36, 42))
58043	33919596	DSFNPs increased disulfiram drug uptake within the CNS and prolonged disulfiram half-life in vivo.	('increased', 'PosReg', (7, 16))	('disulfiram drug uptake', 'MPA', (17, 39))	('prolonged', 'PosReg', (59, 68))	('DSFNPs', 'Chemical', '-', (0, 6))	('disulfiram', 'Chemical', 'MESH:D004221', (17, 27))	('DSFNPs', 'Var', (0, 6))	('disulfiram', 'Chemical', 'MESH:D004221', (69, 79))	('disulfiram half-life', 'MPA', (69, 89))
58045	33919596	Notably, DSFNPs induced mild regression of intracranial medulloblastoma xenografts in comparison to unencapsulated disulfiram, suggesting that use against GBM might be feasible.	('intracranial medulloblastoma', 'Disease', 'MESH:D008527', (43, 71))	('DSFNPs', 'Var', (9, 15))	('pa', 'Chemical', 'MESH:D011478', (89, 91))	('intracranial medulloblastoma', 'Disease', (43, 71))	('DSFNPs', 'Chemical', '-', (9, 15))	('GBM', 'Phenotype', 'HP:0012174', (155, 158))	('regression', 'CPA', (29, 39))	('disulfiram', 'Chemical', 'MESH:D004221', (115, 125))	('medulloblastoma', 'Phenotype', 'HP:0002885', (56, 71))
58077	33919596	Specifically, in HT1080 cells and flank xenografts, clomiphene allosterically inhibited mutant IDH1R132H decreasing tumor size and the ability of IDH1R132H to reduce alpha-ketoglutarate.	('inhibited', 'NegReg', (78, 87))	('decreasing', 'NegReg', (105, 115))	('reduce alpha-ketoglutarate', 'MPA', (159, 185))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (166, 185))	('reduce alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (159, 185))	('IDH', 'Gene', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('HT1080', 'CellLine', 'CVCL:0317', (17, 23))	('mutant', 'Var', (88, 94))	('clomiphene', 'Chemical', 'MESH:D002996', (52, 62))	('IDH', 'Gene', '3417', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('IDH', 'Gene', (95, 98))	('IDH', 'Gene', '3417', (95, 98))	('tumor', 'Disease', (116, 121))
58134	33919596	A combination of chloroquine, sirolimus and TMZ resulted in apoptosis and decreased growth of intracranial GBM, while tri-therapy with chloroquine, crizotinib and sorafinib was efficacious against 3D patient-derived cell cultures.	('TMZ', 'Var', (44, 47))	('crizotinib', 'Chemical', 'MESH:D000077547', (148, 158))	('sorafinib', 'Chemical', '-', (163, 172))	('chloroquine', 'Chemical', 'MESH:D002738', (17, 28))	('apoptosis', 'CPA', (60, 69))	('chloroquine', 'Var', (17, 28))	('growth', 'CPA', (84, 90))	('tri', 'Chemical', '-', (118, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (44, 47))	('decreased growth', 'Phenotype', 'HP:0001510', (74, 90))	('patient', 'Species', '9606', (200, 207))	('decreased', 'NegReg', (74, 83))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))	('sirolimus', 'Var', (30, 39))	('chloroquine', 'Chemical', 'MESH:D002738', (135, 146))	('resulted', 'Reg', (48, 56))	('sirolimus', 'Chemical', 'MESH:D020123', (30, 39))
58194	33919596	Mechanistic studies suggested that this response involved inhibition of carbonic anhydrase II (CAII) downstream of the proto-oncogene, BCL-3, and that this pathway promotes chemoresistance in patients with a methylated MGMT promoter.	('pa', 'Chemical', 'MESH:D011478', (156, 158))	('MGMT', 'Gene', '4255', (219, 223))	('BCL-3', 'Gene', (135, 140))	('CAII', 'Gene', '760', (95, 99))	('chemoresistance', 'CPA', (173, 188))	('carbonic anhydrase II', 'Gene', (72, 93))	('patients', 'Species', '9606', (192, 200))	('pa', 'Chemical', 'MESH:D011478', (192, 194))	('promotes', 'PosReg', (164, 172))	('BCL-3', 'Gene', '602', (135, 140))	('inhibition', 'NegReg', (58, 68))	('carbonic anhydrase II', 'Gene', '760', (72, 93))	('methylated', 'Var', (208, 218))	('MGMT', 'Gene', (219, 223))	('CAII', 'Gene', (95, 99))
58207	33919596	Checkmate 548 was another Phase III trial investigating 550 patients with newly diagnosed, MGMT methylated GBM comparing nivolumab to TMZ both with RT.	('pa', 'Chemical', 'MESH:D011478', (114, 116))	('MGMT', 'Gene', (91, 95))	('patients', 'Species', '9606', (60, 68))	('pa', 'Chemical', 'MESH:D011478', (60, 62))	('methylated', 'Var', (96, 106))	('tri', 'Chemical', '-', (36, 39))	('nivolumab', 'Chemical', 'MESH:D000077594', (121, 130))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (134, 137))	('MGMT', 'Gene', '4255', (91, 95))
58221	33919596	In a retrospective analysis of 1093 patients with HGG, metformin was linked to increased OS and PFS in patients with grade III glioma, while no benefit was found in grade IV tumors.	('PFS', 'Disease', (96, 99))	('III glioma', 'Disease', 'MESH:D005910', (123, 133))	('increased', 'PosReg', (79, 88))	('III glioma', 'Disease', (123, 133))	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('patients', 'Species', '9606', (36, 44))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('metformin', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patients', 'Species', '9606', (103, 111))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
58222	33919596	It was speculated that this was due to the greater proportion of IDH mutations in grade III tumors.	('mutations', 'Var', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', '3417', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('grade III', 'Disease', (82, 91))	('tumors', 'Disease', (92, 98))
58224	33919596	However, if patients were taking metformin prior to their glioma diagnosis, they had a significant survival benefit in comparison to those who began the drug after diagnosis.	('metformin', 'Chemical', 'MESH:D008687', (33, 42))	('pa', 'Chemical', 'MESH:D011478', (12, 14))	('patients', 'Species', '9606', (12, 20))	('pa', 'Chemical', 'MESH:D011478', (122, 124))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('survival benefit', 'CPA', (99, 115))	('glioma', 'Disease', (58, 64))	('metformin', 'Var', (33, 42))
58288	33633561	In this line, sorting nexin (SNX)-10 deficiency upregulates LAMP2A and so, CMA activation, probably due to a dysregulation of cathepsin A trafficking into lysosomes and thus, protecting LAMP2A from its degradation (You et al.,).	('upregulates', 'PosReg', (48, 59))	('LAMP2A', 'Gene', (186, 192))	('LAMP2A', 'Gene', '16784', (186, 192))	('cathepsin A', 'Gene', (126, 137))	('cathepsin A', 'Gene', '5476', (126, 137))	('LAMP2A', 'Gene', '16784', (60, 66))	('LAMP2A', 'Gene', (60, 66))	('sorting nexin (SNX)-10', 'Gene', (14, 36))	('activation', 'PosReg', (79, 89))	('CMA', 'Gene', (75, 78))	('sorting nexin (SNX)-10', 'Gene', '29887', (14, 36))	('deficiency', 'Var', (37, 47))	('degradation', 'MPA', (202, 213))
58301	33633561	Another evidence that supports this mutual regulation of macroautophagy and CMA is that protein kinase Calpha (PKCalpha) mediated phosphorylation of ULK1, on the one hand, prevents autolysosome formation, but on the other hand, enhances its interaction with HSC70 and increases its degradation through CMA (Wang et al.,).	('HSC70', 'Gene', '3312', (258, 263))	('interaction', 'Interaction', (241, 252))	('increases', 'PosReg', (268, 277))	('PKCalpha', 'Gene', (111, 119))	('ULK1', 'Gene', (149, 153))	('degradation', 'MPA', (282, 293))	('enhances', 'PosReg', (228, 236))	('ULK1', 'Gene', '8408', (149, 153))	('PKCalpha', 'Gene', '5578', (111, 119))	('protein kinase Calpha', 'Gene', '5578', (88, 109))	('phosphorylation', 'Var', (130, 145))	('prevents', 'NegReg', (172, 180))	('protein kinase Calpha', 'Gene', (88, 109))	('HSC70', 'Gene', (258, 263))	('autolysosome formation', 'MPA', (181, 203))
58311	33633561	Liver lysosomes from long-lived both Pou1f1/Pit1 mutant (Snell) mice and growth hormone receptor (ghr) knockout mice also present increased CMA substrate uptake activity (Endicott et al.,), further associating the beneficial impact of maintaining CMA with healthspan and longevity.	('rat', 'Species', '10116', (149, 152))	('CMA substrate uptake activity', 'MPA', (140, 169))	('mutant', 'Var', (49, 55))	('growth hormone receptor', 'Gene', (73, 96))	('growth hormone receptor', 'Gene', '14600', (73, 96))	('Pit1', 'Gene', (44, 48))	('Pou1f1', 'Gene', '18736', (37, 43))	('ghr', 'Gene', (98, 101))	('mice', 'Species', '10090', (64, 68))	('ghr', 'Gene', '14600', (98, 101))	('increased', 'PosReg', (130, 139))	('Pit1', 'Gene', '18736', (44, 48))	('Pou1f1', 'Gene', (37, 43))	('mice', 'Species', '10090', (112, 116))
58320	33633561	In this line, p38MAPK, which phosphorylates LAMP2A causing its lysosomal membrane accumulation and active conformational change (Li et al.,), has been recently identified as a regulator of neuronal and neural stem cell (NSC) activity during brain aging (Moreno-Cugnon et al.,), which support the idea that alterations in CMA regulation may be associated to brain aging.	('associated', 'Reg', (343, 353))	('lysosomal membrane accumulation', 'MPA', (63, 94))	('rat', 'Species', '10116', (310, 313))	('alterations', 'Var', (306, 317))	('p38MAPK', 'Var', (14, 21))	('LAMP2A', 'Gene', (44, 50))	('LAMP2A', 'Gene', '16784', (44, 50))	('brain aging', 'Disease', (357, 368))	('active conformational change', 'MPA', (99, 127))
58332	33633561	Interestingly, lipid and carbohydrate metabolic alterations caused by altered CMA have been described to be associated with physiological aging of the brain (Hallett et al.,) and neurodegenerative diseases (Alfaro et al.,).	('rat', 'Species', '10116', (52, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (25, 37))	('altered', 'Var', (70, 77))	('rat', 'Species', '10116', (190, 193))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (179, 205))	('rat', 'Species', '10116', (33, 36))	('associated', 'Reg', (108, 118))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (179, 205))	('neurodegenerative diseases', 'Disease', (179, 205))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (179, 204))	('lipid', 'Chemical', 'MESH:D008055', (15, 20))	('carbohydrate metabolic alterations', 'Phenotype', 'HP:0011013', (25, 59))	('CMA', 'Gene', (78, 81))
58333	33633561	Not only that, but macrophage-specific LAMP2A deficient mice also exhibited significant intracellular lipid accumulation (Qiao et al.,), extending the impact of CMA to immune cells, which has been linked to brain homeostasis and disease (Li and Barres,; Dulken et al.,).	('lipid', 'Chemical', 'MESH:D008055', (102, 107))	('LAMP2A', 'Gene', (39, 45))	('age', 'Gene', '5973', (26, 29))	('LAMP2A', 'Gene', '16784', (39, 45))	('brain homeostasis and disease', 'Disease', 'MESH:D001927', (207, 236))	('mice', 'Species', '10090', (56, 60))	('intracellular lipid accumulation', 'MPA', (88, 120))	('deficient', 'Var', (46, 55))	('age', 'Gene', (26, 29))
58339	33633561	Indeed, ubiquitylation events in the putative motif of the catalytic region may also modulate the degradation of still inactive CHK1 (Kirchner et al.,), suggesting that many post-translational modifications within KFERQ-like motifs may modulate CHK1 degradation via CMA and consequently, regulate DNA repair response.	('regulate', 'Reg', (288, 296))	('post-translational modifications', 'Var', (174, 206))	('CHK1', 'Gene', '1111', (245, 249))	('degradation', 'MPA', (250, 261))	('modulate', 'Reg', (236, 244))	('CHK1', 'Gene', (128, 132))	('DNA repair response', 'MPA', (297, 316))	('CHK1', 'Gene', (245, 249))	('modulate', 'Reg', (85, 93))	('CHK1', 'Gene', '1111', (128, 132))
58340	33633561	On the one hand, tumor suppressor proteins such as p73 (Nguyen et al.,) or mutant p53 (Vakifahmetoglu-Norberg et al.,), and transcription factors MEF2A (Zhang et al.,) and MEF2D (Yang et al.,), previously associated to embryonic and adult neurogenesis processes, have been denominated as CMA substrates.	('p73', 'Gene', '7161', (51, 54))	('MEF2D', 'Gene', '4209', (172, 177))	('p73', 'Gene', (51, 54))	('tumor', 'Disease', (17, 22))	('rat', 'Species', '10116', (297, 300))	('MEF2A', 'Gene', '4205', (146, 151))	('MEF2D', 'Gene', (172, 177))	('MEF2A', 'Gene', (146, 151))	('embryonic', 'Disease', 'MESH:D020964', (219, 228))	('mutant', 'Var', (75, 81))	('p53', 'Gene', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('embryonic', 'Disease', (219, 228))
58347	33633561	Moreover, mice with an extra copy of Arf/p53 display delayed exhaustion of NSCs and enhanced cognitive activity (Carrasco-Garcia et al.,).	('cognitive activity', 'CPA', (93, 111))	('mice', 'Species', '10090', (10, 14))	('extra copy', 'Var', (23, 33))	('Carrasco-Garcia', 'Disease', 'MESH:C536767', (113, 128))	('Arf/p53', 'Gene', (37, 44))	('Carrasco-Garcia', 'Disease', (113, 128))	('enhanced', 'PosReg', (84, 92))
58355	33633561	PD is mostly sporadic, except in a 5-10% familial, and mainly related to alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2) mutations (Campbell et al.,; Tolosa et al.,).	('LRRK2', 'Gene', (123, 128))	('LRRK2', 'Gene', '120892', (123, 128))	('PD', 'Disease', 'MESH:D010300', (0, 2))	('leucine-rich repeat kinase 2', 'Gene', '120892', (93, 121))	('related', 'Reg', (62, 69))	('mutations', 'Var', (130, 139))	('leucine-rich repeat kinase 2', 'Gene', (93, 121))
58358	33633561	In the same line, pathogenic mutant or even dopamine-modified species of alpha-synuclein and LRRK2 are not able to be degraded by CMA but present a significantly higher affinity to bind to LAMP2A protein than other CMA substrates, blocking the degradation of the later ones (Cuervo et al.,; Martinez-Vicente et al.,; Orenstein et al.,).	('LAMP2A', 'Gene', '16784', (189, 195))	('LAMP2A', 'Gene', (189, 195))	('degradation', 'MPA', (244, 255))	('higher', 'PosReg', (162, 168))	('LRRK2', 'Gene', (93, 98))	('mutant', 'Var', (29, 35))	('blocking', 'NegReg', (231, 239))	('dopamine', 'Chemical', 'MESH:D004298', (44, 52))	('LRRK2', 'Gene', '120892', (93, 98))	('rat', 'Species', '10116', (224, 227))	('bind', 'Interaction', (181, 185))
58360	33633561	A familial PD-associated mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) has been also described as an inhibitor of CMA activity, by promoting an induced aberrant interaction with LAMP2A, HSC70, and HSP90 (Kabuta et al.,).	('HSC70', 'Gene', '3312', (195, 200))	('promoting', 'PosReg', (140, 149))	('UCH-L1', 'Gene', (72, 78))	('LAMP2A', 'Gene', '16784', (187, 193))	('LAMP2A', 'Gene', (187, 193))	('mutation', 'Var', (25, 33))	('HSP90', 'Gene', (206, 211))	('ubiquitin C-terminal hydrolase L1', 'Gene', (37, 70))	('PD', 'Disease', 'MESH:D010300', (11, 13))	('ubiquitin C-terminal hydrolase L1', 'Gene', '7345', (37, 70))	('HSP90', 'Gene', '3320', (206, 211))	('HSC70', 'Gene', (195, 200))	('interaction', 'Interaction', (170, 181))	('UCH-L1', 'Gene', '7345', (72, 78))
58362	33633561	In this line, mutations in LAMP2 gene promoter itself have been also associated with sporadic PD patients (Pang et al.,), and there is a decrease in LAMP2A and HSC70 expression in the substantia nigra and amygdala of PD brains compared to control samples (Alvarez-Erviti et al.,).	('LAMP2A', 'Gene', '16784', (149, 155))	('decrease', 'NegReg', (137, 145))	('HSC70', 'Gene', (160, 165))	('associated', 'Reg', (69, 79))	('PD', 'Disease', 'MESH:D010300', (217, 219))	('PD', 'Disease', 'MESH:D010300', (94, 96))	('patients', 'Species', '9606', (97, 105))	('LAMP2', 'Gene', (27, 32))	('expression', 'MPA', (166, 176))	('mutations', 'Var', (14, 23))	('HSC70', 'Gene', '3312', (160, 165))	('LAMP2A', 'Gene', (149, 155))
58383	33633561	In AD, the translocated mutant tau products at the lysosomal membrane hamper the binding and translocation of other CMA substrates, decreasing their activity (Wang et al.,).	('mutant', 'Var', (24, 30))	('rat', 'Species', '10116', (125, 128))	('decreasing', 'NegReg', (132, 142))	('hamper', 'NegReg', (70, 76))	('tau', 'Gene', (31, 34))	('activity', 'MPA', (149, 157))	('binding', 'Interaction', (81, 88))	('translocation', 'MPA', (93, 106))	('AD', 'Phenotype', 'HP:0002511', (3, 5))	('AD', 'Disease', 'MESH:D000544', (3, 5))	('AD', 'Disease', (3, 5))	('products', 'Protein', (35, 43))	('tau', 'Gene', '4137', (31, 34))
58384	33633561	Not only this, but reduced targeting to the lysosomes has been also observed in a mutant form of tau (Caballero et al.,), corroborating a general impaired CMA activity in AD.	('impaired', 'NegReg', (146, 154))	('tau', 'Gene', '4137', (97, 100))	('CMA activity', 'MPA', (155, 167))	('tau', 'Gene', (97, 100))	('rat', 'Species', '10116', (129, 132))	('AD', 'Disease', 'MESH:D000544', (171, 173))	('AD', 'Disease', (171, 173))	('AD', 'Phenotype', 'HP:0002511', (171, 173))	('mutant', 'Var', (82, 88))
58387	33633561	Together with this, AD-associated ubiquilin is degraded by CMA (Rothenberg et al.,), reinforcing the impact of this type of autophagy in AD pathogenesis.	('degraded', 'NegReg', (47, 55))	('AD', 'Disease', 'MESH:D000544', (137, 139))	('AD', 'Disease', 'MESH:D000544', (20, 22))	('AD', 'Disease', (137, 139))	('AD', 'Disease', (20, 22))	('ubiquilin', 'Chemical', '-', (34, 43))	('AD', 'Phenotype', 'HP:0002511', (20, 22))	('AD', 'Phenotype', 'HP:0002511', (137, 139))	('CMA', 'Var', (59, 62))
58388	33633561	Interestingly, a recent study showed that tagging beta-amyloid oligomers with multiple KFERQ motifs promoted their entering in endosomes and lysosomes, protecting human primary cultured cortical neurons from neurotoxicity (Dou et al.,).	('protecting', 'Reg', (152, 162))	('neurotoxicity', 'Disease', 'MESH:D020258', (208, 221))	('KFERQ', 'Gene', (87, 92))	('motifs', 'Var', (93, 99))	('beta-amyloid oligomers', 'Protein', (50, 72))	('promoted', 'PosReg', (100, 108))	('neurotoxicity', 'Disease', (208, 221))	('human', 'Species', '9606', (163, 168))
58390	33633561	Huntington's disease (HD) is a dominantly inherited pathology caused by the accumulation of mutant huntingtin protein (HTT) that contains an expanded N-terminal polyglutamine (polyQ) tract (Bauer et al.,).	('N-terminal polyglutamine', 'MPA', (150, 174))	('polyQ', 'Chemical', 'MESH:C097188', (176, 181))	('HTT', 'Gene', (119, 122))	("Huntington's disease", 'Disease', (0, 20))	('HD', 'Disease', 'MESH:D006816', (22, 24))	('expanded', 'PosReg', (141, 149))	("Huntington's disease", 'Disease', 'MESH:D006816', (0, 20))	('huntingtin', 'Gene', (99, 109))	('N-terminal polyglutamine', 'Chemical', '-', (150, 174))	('mutant', 'Var', (92, 98))	('caused by', 'Reg', (62, 71))	('huntingtin', 'Gene', '3064', (99, 109))
58392	33633561	The use of an adaptor that contains two copies of polyQ binding sequences and two different KFERQ motifs, directs specifically mutant HTT to the CMA machinery for its degradation, ameliorating symptoms, and extending the life span of an HD mouse model (Bauer et al.,).	('mutant', 'Var', (127, 133))	('life span', 'CPA', (221, 230))	('mouse', 'Species', '10090', (240, 245))	('ameliorating', 'PosReg', (180, 192))	('rat', 'Species', '10116', (186, 189))	('HTT', 'Gene', (134, 137))	('HD', 'Disease', 'MESH:D006816', (237, 239))	('extending', 'PosReg', (207, 216))	('symptoms', 'MPA', (193, 201))	('degradation', 'MPA', (167, 178))	('polyQ', 'Chemical', 'MESH:C097188', (50, 55))
58397	33633561	Impaired formation of multivesicular bodies due to ESCRT-III dysfunction in the membrane of the late endosomes reduces autophagy activity and induces autophagosome accumulation (Wong and Cuervo,).	('multivesicular bodies', 'Disease', (22, 43))	('autophagosome accumulation', 'CPA', (150, 176))	('multivesicular bodies', 'Disease', 'MESH:D001835', (22, 43))	('ESCRT-III', 'Gene', (51, 60))	('reduces', 'NegReg', (111, 118))	('induces', 'Reg', (142, 149))	('autophagy activity', 'CPA', (119, 137))	('dysfunction', 'Var', (61, 72))
58399	33633561	On the other hand, animal models for mutant prion protein (PrP) disease present downregulation of LAMP2A and HSC70 proteins, and that the overexpression of polo-like kinase 3 (PLK3) induces PrP degradation by CMA (Wang et al.,).	('HSC70', 'Gene', '3312', (109, 114))	('PrP', 'Protein', (190, 193))	('induces', 'Reg', (182, 189))	('HSC70', 'Gene', (109, 114))	('mutant', 'Var', (37, 43))	('degradation', 'MPA', (194, 205))	('PLK3', 'Gene', (176, 180))	('LAMP2A', 'Gene', (98, 104))	('LAMP2A', 'Gene', '16784', (98, 104))	('downregulation', 'NegReg', (80, 94))	('overexpression', 'PosReg', (138, 152))
58400	33633561	Overall, either by the negative effect of the mutant proteins or by the reduction on the expression of the machinery itself, a downregulation of CMA has been described in most neurodegenerative diseases.	('reduction', 'NegReg', (72, 81))	('expression', 'MPA', (89, 99))	('neurodegenerative diseases', 'Disease', (176, 202))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (176, 202))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (176, 201))	('proteins', 'Protein', (53, 61))	('downregulation', 'NegReg', (127, 141))	('mutant', 'Var', (46, 52))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (176, 202))	('CMA', 'Disease', (145, 148))	('negative', 'NegReg', (23, 31))
58408	33633561	However, other studies claim that blocking CMA-mediated HIF1alpha degradation induces resistance to TMZ (Lo Dico et al.,) and that TMZ resistant cells are unable to increase cytoplasmic ROS levels and activate CMA, preventing thus GBM cell toxicity (Lo Dico et al.,).	('increase', 'PosReg', (165, 173))	('cytoplasmic ROS levels', 'MPA', (174, 196))	('induces', 'Reg', (78, 85))	('toxicity', 'Disease', 'MESH:D064420', (240, 248))	('TMZ', 'Chemical', 'MESH:D000077204', (131, 134))	('toxicity', 'Disease', (240, 248))	('blocking', 'Var', (34, 42))	('increase cytoplasmic ROS levels', 'Phenotype', 'HP:0025464', (165, 196))	('HIF1alpha', 'Gene', (56, 65))	('HIF1alpha', 'Gene', '3091', (56, 65))	('CMA-mediated', 'Gene', (43, 55))	('CMA', 'Enzyme', (210, 213))	('ROS', 'Chemical', 'MESH:D017382', (186, 189))	('resistance to TMZ', 'MPA', (86, 103))	('TMZ', 'Chemical', 'MESH:D000077204', (100, 103))	('GBM', 'Phenotype', 'HP:0012174', (231, 234))
58412	33633561	Overall, studies regarding CMA in GBM have focused on the impact of the modulation of LAMP2A expression by itself (Figure 3).	('LAMP2A', 'Gene', '16784', (86, 92))	('modulation', 'Var', (72, 82))	('LAMP2A', 'Gene', (86, 92))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))
58417	33633561	Importantly, macroautophagy modulators such as 3-methyladenine, LY294002, vinblastine, or rapamycin do not alter CMA activity (Finn et al.,).	('rapamycin', 'Chemical', 'MESH:D020123', (90, 99))	('LY294002', 'Chemical', 'MESH:C085911', (64, 72))	('LY294002', 'Var', (64, 72))	('CMA', 'MPA', (113, 116))	('vinblastine', 'Chemical', 'MESH:D014747', (74, 85))	('Finn', 'Species', '1754191', (127, 131))	('3-methyladenine', 'Chemical', 'MESH:C025946', (47, 62))
58421	33633561	On the other hand, treatment with compounds such as P140 (Macri et al.,), vitamin E (Cao et al.,), protein synthesis inhibitors anisomycin and cycloheximide (Finn et al.,) or p38MAPK inhibitor (Finn et al.,) downregulate CMA, a strategy that may be beneficial for cancer context.	('CMA', 'Disease', (221, 224))	('anisomycin', 'Chemical', 'MESH:D000841', (128, 138))	('P140', 'Var', (52, 56))	('downregulate', 'NegReg', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('Finn', 'Species', '1754191', (194, 198))	('cycloheximide', 'Chemical', 'MESH:D003513', (143, 156))	('rat', 'Species', '10116', (230, 233))	('Finn', 'Species', '1754191', (158, 162))	('vitamin E', 'Chemical', 'MESH:D014810', (74, 83))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
58426	33633561	Alterations in the expression of CMA regulators and the blocking effect of mutant CMA substrates show the reduced activity of this process in disorders such as PD or AD.	('CMA', 'Gene', (82, 85))	('expression', 'MPA', (19, 29))	('activity', 'MPA', (114, 122))	('PD', 'Disease', 'MESH:D010300', (160, 162))	('AD', 'Disease', (166, 168))	('rat', 'Species', '10116', (91, 94))	('AD', 'Disease', 'MESH:D000544', (166, 168))	('AD', 'Phenotype', 'HP:0002511', (166, 168))	('mutant', 'Var', (75, 81))	('rat', 'Species', '10116', (4, 7))	('reduced', 'NegReg', (106, 113))
58457	33066689	OV can also be selected or engineered to be tumor-specific by genetic modifications that limit their pathogenicity and/-or enhance tumor immunogenicity.	('enhance', 'PosReg', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('limit', 'NegReg', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('genetic modifications', 'Var', (62, 83))	('pathogenicity', 'MPA', (101, 114))	('tumor', 'Disease', (44, 49))
58480	33066689	gamma134.5 is a viral antagonistic protein known to block protein kinase R (PKR) antiviral signaling in infected cells.	('block', 'NegReg', (52, 57))	('infected', 'Disease', 'MESH:D007239', (104, 112))	('PKR', 'Gene', '5610', (76, 79))	('gamma134.5', 'Var', (0, 10))	('protein kinase R', 'Gene', (58, 74))	('infected', 'Disease', (104, 112))	('protein kinase R', 'Gene', '5610', (58, 74))	('PKR', 'Gene', (76, 79))
58481	33066689	This deletion was shown to prevent encephalitis in mice infected with the mutant virus by eliciting an abortive infection in non-tumoral cells.	('encephalitis', 'Disease', 'MESH:D004660', (35, 47))	('encephalitis', 'Disease', (35, 47))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('abortive infection', 'Disease', (103, 121))	('eliciting', 'Reg', (90, 99))	('prevent', 'NegReg', (27, 34))	('abortive infection', 'Disease', 'MESH:D000031', (103, 121))	('infected', 'Disease', 'MESH:D007239', (56, 64))	('encephalitis', 'Phenotype', 'HP:0002383', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutant', 'Var', (74, 80))	('infected', 'Disease', (56, 64))
58484	33066689	This virus is a double mutant constructed by the insertion of Escherichia coli lacZ gene into the coding sequence for viral ICP6 gene and deletion of both copies of gamma134.5 loci within the viral genome.	('lacZ', 'Gene', (79, 83))	('ICP6', 'Gene', (124, 128))	('deletion', 'Var', (138, 146))	('Escherichia coli', 'Species', '562', (62, 78))
58488	33066689	Although deletion of gamma134.5 loci and ICP6 strongly improves viral tumor restriction, it also attenuates virus replication and treatment efficacy.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ICP6', 'Gene', (41, 45))	('deletion', 'Var', (9, 17))	('treatment efficacy', 'CPA', (130, 148))	('viral tumor', 'Disease', 'None', (64, 75))	('viral tumor', 'Disease', (64, 75))	('virus replication', 'CPA', (108, 125))	('improves', 'PosReg', (55, 63))	('attenuates', 'NegReg', (97, 107))
58494	33066689	This virus also has deletion of ICP6 and both gamma134.5 loci, but, in this construction, the human GADD34 gene was placed under the Nestin promoter.	('GADD34', 'Gene', (100, 106))	('Nestin', 'Gene', '10763', (133, 139))	('deletion', 'Var', (20, 28))	('human', 'Species', '9606', (94, 99))	('ICP6', 'Gene', (32, 36))	('Nestin', 'Gene', (133, 139))	('GADD34', 'Gene', '23645', (100, 106))
58503	33066689	Following a different strategy, HSV-1 C134 was developed as a chimeric virus that includes not only the deletion of gamma134.5 loci but also the expression of human cytomegalovirus (HCMV) IRS1 gene.	('gamma134.5', 'Gene', (116, 126))	('HCMV', 'Species', '10359', (182, 186))	('HSV-1', 'Species', '10298', (32, 37))	('IRS1', 'Gene', '3667', (188, 192))	('human cytomegalovirus', 'Species', '10359', (159, 180))	('IRS1', 'Gene', (188, 192))	('C13', 'Gene', '3229', (38, 41))	('C13', 'Gene', (38, 41))	('deletion', 'Var', (104, 112))	('rat', 'Species', '10116', (24, 27))
58505	33066689	HSV-1 G47Delta is a triple mutant virus based on G207 to increase the oncolytic effect.	('HSV-1', 'Gene', (0, 5))	('G47Delta', 'Var', (6, 14))	('HSV-1', 'Species', '10298', (0, 5))	('increase', 'PosReg', (57, 65))	('oncolytic effect', 'CPA', (70, 86))
58507	33066689	As in wild type (WT) HSV, alpha47 is followed by US11 and deletion of alpha47 gene, and US11 promoter places the lytic factor US11 under control of immediate-early alpha47 promoter, increasing tumor lysis after virus infection.	('alpha47', 'Gene', (70, 77))	('virus infection', 'Disease', 'MESH:D001102', (211, 226))	('virus infection', 'Disease', (211, 226))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('increasing', 'PosReg', (182, 192))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('deletion', 'Var', (58, 66))	('tumor', 'Disease', (193, 198))
58508	33066689	HSV-1 G47Delta has enhanced viral growth and displays a higher tumor lytic effect after intracerebral administration inoculation in mice.	('rat', 'Species', '10116', (110, 113))	('tumor', 'Disease', (63, 68))	('viral growth', 'CPA', (28, 40))	('intracerebral', 'Disease', (88, 101))	('G47Delta', 'Var', (6, 14))	('HSV-1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('HSV-1', 'Species', '10298', (0, 5))	('mice', 'Species', '10090', (132, 136))	('higher', 'PosReg', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('intracerebral', 'Disease', 'MESH:D002543', (88, 101))	('enhanced', 'PosReg', (19, 27))
58509	33066689	A different strategy to improve tumor-specific oncolytic activity is retargeting HSV to a tumor specific protein by modifying the gD entry protein.	('modifying', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('oncolytic activity', 'MPA', (47, 65))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('rat', 'Species', '10116', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
58514	33066689	This virus includes deletion of gamma134.5 loci, GFP linked to ICP6 carboxyl terminus, and expression of human Vstat120 gene under immediate early IE4/5 HSV promoter.	('human', 'Species', '9606', (105, 110))	('deletion', 'Var', (20, 28))	('Vstat120', 'Chemical', '-', (111, 119))	('Vstat120', 'Gene', (111, 119))
58515	33066689	Vstat120 encodes for the extracellular fragment of brain-specific angiogenesis inhibitor 1 (BAI1) and has a potent antiangiogenic and antitumor effect.	('Vstat120', 'Chemical', '-', (0, 8))	('BAI1', 'Gene', '575', (92, 96))	('BAI1', 'Gene', (92, 96))	('tumor', 'Disease', (138, 143))	('brain-specific angiogenesis inhibitor 1', 'Gene', (51, 90))	('antiangiogenic', 'CPA', (115, 129))	('Vstat120', 'Var', (0, 8))	('brain-specific angiogenesis inhibitor 1', 'Gene', '575', (51, 90))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
58516	33066689	RAMBO has shown an increase in survival and tumor reduction in vivo compared with a control HSV and a reduction in the vascular volume fraction in the tumor due to delivery of Vstat120.	('Vstat120', 'Var', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('survival', 'CPA', (31, 39))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Vstat120', 'Chemical', '-', (176, 184))	('increase', 'PosReg', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('reduction', 'NegReg', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('vascular volume fraction in', 'MPA', (119, 146))	('tumor', 'Disease', (44, 49))	('tumor reduction', 'Disease', 'MESH:D007022', (44, 59))	('tumor reduction', 'Disease', (44, 59))
58519	33066689	Similar results were obtained with HSV-1 R8306 in which gamma134.5 genes were replaced by murine IL-4.	('IL-4', 'Gene', '16189', (97, 101))	('HSV-1', 'Species', '10298', (35, 40))	('gamma134.5', 'Var', (56, 66))	('IL-4', 'Gene', (97, 101))	('murine', 'Species', '10090', (90, 96))
58529	33066689	HSV-1 G47Delta phase I clinical trial showed limited toxicity, and a phase II trial resulted in increased survival of treated patients.	('increased', 'PosReg', (96, 105))	('survival', 'CPA', (106, 114))	('HSV-1', 'Gene', (0, 5))	('G47Delta', 'Var', (6, 14))	('HSV-1', 'Species', '10298', (0, 5))	('patients', 'Species', '9606', (126, 134))	('toxicity', 'Disease', 'MESH:D064420', (53, 61))	('toxicity', 'Disease', (53, 61))
58541	33066689	The first generation of CRad started with Onyx-015, a chimeric adenovirus generated from two and five serotypes that has a deletion in the E1B-55kD gene and was approved in China for the treatment of head and neck cancer in 2005.	('deletion', 'Var', (123, 131))	('head and neck cancer', 'Phenotype', 'HP:0012288', (200, 220))	('rat', 'Species', '10116', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('neck cancer', 'Disease', 'MESH:D006258', (209, 220))	('neck cancer', 'Disease', (209, 220))	('rat', 'Species', '10116', (14, 17))	('adenovirus', 'Species', '10508', (63, 73))	('E1B-55kD', 'Gene', (139, 147))
58542	33066689	E1B-55kD protein binds and inhibits p53 in infected cells allowing viral replication.	('binds', 'Interaction', (17, 22))	('inhibits', 'NegReg', (27, 35))	('p53', 'Protein', (36, 39))	('infected', 'Disease', (43, 51))	('E1B-55kD', 'Var', (0, 8))	('viral replication', 'CPA', (67, 84))	('infected', 'Disease', 'MESH:D007239', (43, 51))
58543	33066689	Due to this modification, Onyx-015 is deficient for replicating in non-tumor cells.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('modification', 'Var', (12, 24))
58544	33066689	This virus showed a powerful antitumoral effect in both p53 wild type (wt) and p53 mutant glioma xenograft mouse tumor models, inducing a relevant tumor regression.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (147, 152))	('p53', 'Gene', (79, 82))	('glioma', 'Disease', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mutant', 'Var', (83, 89))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
58552	33066689	Although partial deletion of early gene E1A makes the virus more selective for Rb lacking cells, excessive accumulation of E1A protein can induce toxicity in normal cells.	('E1A', 'Gene', (40, 43))	('E1A', 'Var', (123, 126))	('accumulation', 'MPA', (107, 119))	('induce', 'Reg', (139, 145))	('toxicity', 'Disease', (146, 154))	('Rb', 'Chemical', 'MESH:D012413', (79, 81))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('partial deletion', 'Var', (9, 25))
58556	33066689	In addition, ICOVIR-5 showed less percentage of normal cells infected and stronger antitumoral effect as compared to Delta-24 and Delta-24-RGD in vitro.	('Delta-', 'Chemical', '-', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ICOVIR-5', 'Chemical', '-', (13, 21))	('Delta-24-RGD', 'Chemical', '-', (130, 142))	('infected', 'Disease', (61, 69))	('tumor', 'Disease', (87, 92))	('Delta-', 'Chemical', '-', (117, 123))	('ICOVIR-5', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('infected', 'Disease', 'MESH:D007239', (61, 69))	('stronger', 'PosReg', (74, 82))
58557	33066689	An orthotopic murine model of U87 tumor cell xenografts treated with ICOVIR-5 demonstrated longer survival than no treatment as well as a comparable survival rate to Delta-24-RGD.	('murine', 'Species', '10090', (14, 20))	('longer', 'PosReg', (91, 97))	('tumor', 'Disease', (34, 39))	('rat', 'Species', '10116', (85, 88))	('ICOVIR-5', 'Chemical', '-', (69, 77))	('Delta-24-RGD', 'Chemical', '-', (166, 178))	('rat', 'Species', '10116', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('ICOVIR-5', 'Var', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
58564	33066689	In comparison with ICOVIR-15, ICOVIR-17 showed potent oncolytic activity in vitro as well as an increased survival in a murine GBM tumor model.	('increased', 'PosReg', (96, 105))	('GBM tumor', 'Disease', 'MESH:D005910', (127, 136))	('ICOVIR-17', 'Var', (30, 39))	('ICOVIR-15', 'Chemical', '-', (19, 28))	('survival', 'CPA', (106, 114))	('GBM tumor', 'Disease', (127, 136))	('GBM', 'Phenotype', 'HP:0012174', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('murine', 'Species', '10090', (120, 126))	('oncolytic', 'CPA', (54, 63))	('ICOVIR', 'Chemical', '-', (19, 25))	('ICOVIR', 'Chemical', '-', (30, 36))
58572	33066689	Delta-24-RGDOX showed an efficient CD4+ and CD8+ activation in pre-clinical models.	('Delta-24-RGDOX', 'Chemical', '-', (0, 14))	('CD8', 'Gene', (44, 47))	('Delta-24-RGDOX', 'Var', (0, 14))	('CD8', 'Gene', '925', (44, 47))
58573	33066689	Delta-24-GREAT elicited antiglioma specific immune response in an immunocompetent model, increasing mice survival and developing immune memory that protected animals from a tumor rechallenge.	('Delta-24-GREAT', 'Chemical', '-', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('glioma', 'Disease', 'MESH:D005910', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('mice', 'Species', '10090', (100, 104))	('increasing', 'PosReg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('immune memory', 'CPA', (129, 142))	('Delta-24-GREAT', 'Var', (0, 14))	('glioma', 'Disease', (28, 34))
58583	33066689	Intratumoral administration of Ad-RTS-hIL-12 is now under a phase I/II clinical trial in patients with pediatric brain tumors in combination with oral administration of veledimix (NCT03330197) (Table 3).	('Ad-RTS-hIL-12', 'Chemical', '-', (31, 44))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('brain tumors', 'Disease', 'MESH:D001932', (113, 125))	('brain tumors', 'Phenotype', 'HP:0030692', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('brain tumors', 'Disease', (113, 125))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('rat', 'Species', '10116', (21, 24))	('tumor', 'Disease', (5, 10))	('rat', 'Species', '10116', (3, 6))	('Ad-RTS-hIL-12', 'Var', (31, 44))	('brain tumor', 'Phenotype', 'HP:0030692', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('rat', 'Species', '10116', (159, 162))
58593	33066689	Coinfection with high doses of rVV-p53 (2 x 107 pfu) with a low dose of a recombinant rVV-mIL12 (10 pfu) resulted in a strong tumor inhibition with an increase in the immune response after intratumoral injection in a nude mouse glioma model.	('pfu', 'Chemical', '-', (48, 51))	('rVV-p53', 'Var', (31, 38))	('tumor', 'Disease', (194, 199))	('mouse', 'Species', '10090', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('infection', 'Disease', (2, 11))	('infection', 'Disease', 'MESH:D007239', (2, 11))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('pfu', 'Chemical', '-', (100, 103))	('VV', 'Species', '10245', (32, 34))	('inhibition', 'NegReg', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('VV', 'Species', '10245', (87, 89))	('immune response', 'CPA', (167, 182))	('rVV-mIL12', 'Chemical', '-', (86, 95))	('tumor', 'Disease', (126, 131))	('glioma', 'Disease', (228, 234))	('rat', 'Species', '10116', (192, 195))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('glioma', 'Disease', 'MESH:D005910', (228, 234))	('increase', 'PosReg', (151, 159))
58599	33066689	A safety dose assay in non-human primates has proven that vvDD has no adverse effects in contrast with the WR unmodified strain that produced several complications, such as fever, skin rash, or the presence of virus in multiple organs.	('fever', 'Disease', 'MESH:D005334', (173, 178))	('fever', 'Disease', (173, 178))	('fever', 'Phenotype', 'HP:0001945', (173, 178))	('human', 'Species', '9606', (27, 32))	('skin rash', 'Disease', (180, 189))	('skin rash', 'Disease', 'MESH:D005076', (180, 189))	('vvDD', 'Var', (58, 62))	('skin rash', 'Phenotype', 'HP:0000988', (180, 189))
58605	33066689	Following this approach, TG6002 was developed as a double-deleted recombinant VV virus which has been tested for the treatment of gliomas.	('VV', 'Species', '10245', (78, 80))	('TG6002', 'Var', (25, 31))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('gliomas', 'Disease', (130, 137))	('TG6002', 'Chemical', '-', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
58609	33066689	TG6002 virus can replicate in glioma cells and induce cell death in vitro.	('cell death', 'CPA', (54, 64))	('TG6002', 'Var', (0, 6))	('TG6002', 'Chemical', '-', (0, 6))	('glioma', 'Disease', (30, 36))	('induce', 'Reg', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (30, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
58631	33066689	MYXV-M011L-KO intratumor administration in a GBM tumor model of immunocompetent mice showed a synergistic effect with temozolomide co-treatment in prolonging animal survival (Table 1).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MYXV-M011L-KO', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('MYXV', 'Species', '10273', (0, 4))	('GBM tumor', 'Disease', 'MESH:D005910', (45, 54))	('GBM tumor', 'Disease', (45, 54))	('tumor', 'Disease', (49, 54))	('rat', 'Species', '10116', (33, 36))	('M011L', 'Mutation', 'p.M011L', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Disease', (19, 24))	('rat', 'Species', '10116', (17, 20))	('temozolomide', 'Chemical', 'MESH:D000077204', (118, 130))	('animal survival', 'CPA', (158, 173))	('prolonging', 'PosReg', (147, 157))
58643	33066689	Additionally, H-1PV was able to enhance immunogenicity within the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('H-1PV', 'Var', (14, 19))	('immunogenicity', 'MPA', (40, 54))	('tumor', 'Disease', (66, 71))	('enhance', 'PosReg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
58661	33066689	MV-NIS is another modification of the MV-Edm, in this case the recombinant virus expresses the human sodium iodide symporter (NIS) to improve the monitoring of MV infection in vivo in brain tumors with a non-invasive method by using systemic administration of 123I, 124I, 125I, or 99mTc isotopes and measuring the isotope accumulation in virus-replicating cells.	('MV', 'Species', '11234', (0, 2))	('human', 'Species', '9606', (95, 100))	('brain tumors', 'Disease', 'MESH:D001932', (184, 196))	('NIS', 'Chemical', 'MESH:D009532', (3, 6))	('NIS', 'Chemical', 'MESH:D009532', (126, 129))	('brain tumors', 'Disease', (184, 196))	('rat', 'Species', '10116', (250, 253))	('isotope accumulation', 'MPA', (314, 334))	('brain tumor', 'Phenotype', 'HP:0030692', (184, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('123I', 'Var', (260, 264))	('sodium iodide', 'Chemical', 'MESH:D012974', (101, 114))	('infection', 'Disease', (163, 172))	('infection', 'Disease', 'MESH:D007239', (163, 172))	('MV', 'Species', '11234', (160, 162))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('brain tumors', 'Phenotype', 'HP:0030692', (184, 196))	('MV', 'Species', '11234', (38, 40))
58665	33066689	Instead, this virus expresses a single chain antibody that binds to epidermal growth factor receptor (EGFR) fused to the C terminal end of the virus H protein.	('epidermal growth factor receptor', 'Gene', (68, 100))	('binds', 'Interaction', (59, 64))	('fused', 'Var', (108, 113))	('epidermal growth factor receptor', 'Gene', '1956', (68, 100))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
58666	33066689	Amplification of EGFR is one of the most frequent genetic alterations in GBM.	('Amplification', 'Var', (0, 13))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('EGFR', 'Gene', '1956', (17, 21))	('rat', 'Species', '10116', (62, 65))	('EGFR', 'Gene', (17, 21))
58670	33066689	MV-141.7 and MV-AC133 are two other recombinant viruses in which the H protein has been modified to retarget the virus to the CD133 receptor.	('MV', 'Species', '11234', (0, 2))	('modified', 'Var', (88, 96))	('retarget', 'NegReg', (100, 108))	('AC133', 'Gene', (16, 21))	('AC133', 'Gene', '8842', (16, 21))	('CD133', 'Gene', (126, 131))	('H protein', 'Protein', (69, 78))	('CD133', 'Gene', '8842', (126, 131))	('MV', 'Species', '11234', (13, 15))
58672	33066689	MV-141.7 resulted in a better survival rate in comparison with MV-Edm in the treatment of a orthotopic glioma mouse model (Table 2).	('MV', 'Species', '11234', (0, 2))	('MV-141.7', 'Var', (0, 8))	('better', 'PosReg', (23, 29))	('survival', 'CPA', (30, 38))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('MV', 'Species', '11234', (63, 65))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('mouse', 'Species', '10090', (110, 115))	('rat', 'Species', '10116', (39, 42))	('glioma', 'Disease', (103, 109))
58683	33066689	In order to reduce unspecific neurotoxicity, several viral modifications have been developed, such as the deletion of the G encoding gene from the viral genome in the VSV-DeltaG viral vector.	('G encoding', 'Gene', (122, 132))	('neurotoxicity', 'Disease', 'MESH:D020258', (30, 43))	('VSV', 'Species', '11276', (167, 170))	('deletion', 'Var', (106, 114))	('neurotoxicity', 'Disease', (30, 43))
58686	33066689	This modification impedes the M protein ability to block the IFN-beta mRNA transport from the nucleus to the cytoplasm and thus affects the antagonistic activity of IFN, limiting the virus replication to tumor cells incapable of producing IFN, allowing infected normal cells to produce a normal IFN response and therefore limiting the virus spread.	('modification', 'Var', (5, 17))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('infected', 'Disease', (253, 261))	('antagonistic activity', 'MPA', (140, 161))	('IFN', 'Gene', (61, 64))	('IFN', 'Gene', '3439', (239, 242))	('IFN', 'Gene', '3439', (295, 298))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('impedes', 'NegReg', (18, 25))	('IFN', 'Gene', (239, 242))	('IFN', 'Gene', '3439', (165, 168))	('M protein', 'Protein', (30, 39))	('IFN', 'Gene', (295, 298))	('limiting', 'NegReg', (322, 330))	('affects', 'Reg', (128, 135))	('IFN', 'Gene', '3439', (61, 64))	('virus', 'MPA', (335, 340))	('limiting', 'NegReg', (170, 178))	('tumor', 'Disease', (204, 209))	('IFN', 'Gene', (165, 168))	('infected', 'Disease', 'MESH:D007239', (253, 261))
58699	33066689	This mutant combined both strategies used to develop VSV DeltaM51 and VSV-CT9.	('VSV', 'Species', '11276', (70, 73))	('DeltaM51', 'Var', (57, 65))	('VSV', 'Species', '11276', (53, 56))	('DeltaM51', 'DELETION', 'None', (57, 65))	('CT9', 'Gene', (74, 77))	('rat', 'Species', '10116', (28, 31))	('CT9', 'Gene', '676', (74, 77))
58700	33066689	VSV-CT9-M51 showed less neurotoxicity in normal cells than both VSV-CT9 and VSV DeltaM51 while retaining the ability to infect, spread within, and kill human GBM in a mouse model after systemic administration, also triggering higher type I IFN dependent responses in the animals.	('triggering', 'Reg', (215, 225))	('VSV', 'Species', '11276', (76, 79))	('IFN', 'Gene', '3439', (240, 243))	('human', 'Species', '9606', (152, 157))	('neurotoxicity', 'Disease', (24, 37))	('CT9', 'Gene', '676', (68, 71))	('DeltaM51', 'Var', (80, 88))	('CT9', 'Gene', '676', (4, 7))	('neurotoxicity', 'Disease', 'MESH:D020258', (24, 37))	('VSV', 'Species', '11276', (64, 67))	('CT9', 'Gene', (68, 71))	('VSV', 'Species', '11276', (0, 3))	('IFN', 'Gene', (240, 243))	('CT9', 'Gene', (4, 7))	('DeltaM51', 'DELETION', 'None', (80, 88))	('infect', 'Reg', (120, 126))	('higher', 'PosReg', (226, 232))	('rat', 'Species', '10116', (202, 205))	('GBM', 'Phenotype', 'HP:0012174', (158, 161))	('mouse', 'Species', '10090', (167, 172))
58701	33066689	Another attenuation strategy that has been proposed to reduce virulence of VSV is gene rearrangement.	('rat', 'Species', '10116', (22, 25))	('gene rearrangement', 'Var', (82, 100))	('virulence', 'MPA', (62, 71))	('VSV', 'Species', '11276', (75, 78))
58703	33066689	VSV-p1-GFP and VSV-p1-RFP showed a high cytopathic effect and induced death after infecting U87 GBM cells in vitro, having at the same time lower toxicity in non-tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('lower', 'NegReg', (140, 145))	('VSV-p1-GFP', 'Var', (0, 10))	('VSV', 'Species', '11276', (15, 18))	('tumor', 'Disease', (162, 167))	('cytopathic effect', 'CPA', (40, 57))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('toxicity', 'Disease', (146, 154))	('VSV', 'Species', '11276', (0, 3))	('RFP', 'Gene', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('RFP', 'Gene', '2358', (22, 25))
58716	33066689	Preclinical animal models have reported an apoptotic effect using NDV in GBM treatment, an increase in the median survival from 28 to 64 months in the mouse models, as well as a synergistic effect with TMZ (Table 2).	('NDV', 'Var', (66, 69))	('GBM', 'Gene', (73, 76))	('mouse', 'Species', '10090', (151, 156))	('median survival', 'CPA', (107, 122))	('synergistic', 'Interaction', (178, 189))	('increase', 'PosReg', (91, 99))	('NDV', 'Species', '11176', (66, 69))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('TMZ', 'Chemical', 'MESH:D000077204', (202, 205))	('apoptotic effect', 'CPA', (43, 59))
58731	33066689	Finally, PVS-RIPO can halt tumor growth in a murine GBM flank tumor model and increase the mice's OS after intracranial virus administration.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mice', 'Species', '10090', (91, 95))	('flank tumor', 'Disease', 'MESH:D021501', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (27, 32))	('flank tumor', 'Disease', (56, 67))	('tumor', 'Disease', (62, 67))	('increase', 'PosReg', (78, 86))	('PVS-RIPO', 'Var', (9, 17))	('rat', 'Species', '10116', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('murine', 'Species', '10090', (45, 51))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('halt', 'NegReg', (22, 26))
58736	33066689	An interventional phase II study with 122 enrolled adult patients (NCT02986178) and a phase Ib with 12 malignant glioma children (NCT03043391) are ongoing (Table 3).	('malignant glioma', 'Disease', (103, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('NCT02986178', 'Var', (67, 78))	('patients', 'Species', '9606', (57, 65))	('children', 'Species', '9606', (120, 128))	('malignant glioma', 'Disease', 'MESH:D005910', (103, 119))
58859	32143288	Currently, only a small subset of patients with glioblastoma or BMs with microsatellite instable or mismatch repair deficient tumors, resulting in a higher tumor mutational burden, may benefit from ICI.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('deficient tumors', 'Disease', (116, 132))	('mismatch', 'Protein', (100, 108))	('deficient tumors', 'Disease', 'MESH:D009369', (116, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('microsatellite', 'Var', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Disease', (156, 161))	('glioblastoma', 'Disease', (48, 60))	('higher', 'PosReg', (149, 155))	('tumor', 'Disease', (126, 131))
58862	32143288	Recently, both the HDAC inhibitor mocetinostat and inhibition of HDAC6 independently demonstrated a synergistic effect in combination with ICI, resulting in increased anti-tumor activity in NSCLC and ovarian cancer cell lines by increasing tumor antigen presentation and decreasing immune suppressive cell types.	('mocetinostat', 'Chemical', 'MESH:C523184', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('NSCLC and ovarian cancer', 'Disease', 'MESH:D010051', (190, 214))	('HDAC6', 'Gene', '10013', (65, 70))	('tumor', 'Disease', (240, 245))	('immune suppressive cell types', 'CPA', (282, 311))	('increasing', 'PosReg', (229, 239))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('HDAC6', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('decreasing immune suppressive cell', 'Phenotype', 'HP:0002721', (271, 305))	('increased', 'PosReg', (157, 166))	('inhibition', 'Var', (51, 61))	('decreasing', 'NegReg', (271, 281))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
58925	32241267	One defining feature of genes that function during tumourigenesis is their dysregulated expression in cancer tumours, and accumulating evidence has shown that expressions of SEMA3 members are altered in multiple cancer types.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('SEMA', 'Gene', (174, 178))	('tumour', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('expression', 'MPA', (88, 98))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('cancer tumours', 'Disease', (102, 116))	('dysregulated', 'Var', (75, 87))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('expressions', 'MPA', (159, 170))	('cancer tumours', 'Disease', 'MESH:D009369', (102, 116))	('SEMA', 'Gene', '7869', (174, 178))	('altered', 'Reg', (192, 199))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
58931	32241267	We found that the altered expression of SEMA3s were generally associated with patient overall survival, however the direction of the association varied depending on the member queried and the cancer type tested as shown in Fig.	('expression', 'MPA', (26, 36))	('patient', 'Species', '9606', (78, 85))	('altered', 'Var', (18, 25))	('associated', 'Reg', (62, 72))	('SEMA', 'Gene', '7869', (40, 44))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('SEMA', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
58973	32241267	For example, SEMA3C was associated with cell resistance to the treatment of Pipobroman (treatment for CML), Ifosfamide (treatment for recurrent testicular cancer and germ cell tumours, sarcomas, Non-Hodgkin's lymphoma, Hodgkin's disease, non-small cell and small cell lung, cancer, bladder cancer, head and neck cancer, and cervix cancer), and Carmustine (treatment of brain tumours, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas); and SEMA3Fwas associated with cell resistance to Vemurafenib (treatment for late-stage melanoma), Dabrafenib (treatment for late-stage melanoma and metastatic non-small cell lung cancer with BRAF V600E or V600K mutations), and Bafetinib (for CML) (Fig.	('multiple myeloma', 'Disease', (384, 400))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (614, 636))	('cell resistance', 'CPA', (481, 496))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	("Non-Hodgkin's lymphoma", 'Disease', (195, 217))	('cancer', 'Disease', 'MESH:D009369', (630, 636))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (500, 511))	('cell tumours', 'Disease', 'MESH:D009369', (171, 183))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('Dabrafenib', 'Chemical', 'MESH:C561627', (549, 559))	("non-Hodgkin's lymphomas", 'Disease', 'MESH:D008228', (425, 448))	('bladder cancer', 'Disease', 'MESH:D001749', (282, 296))	('lung cancer', 'Disease', 'MESH:D008175', (625, 636))	('cancer', 'Disease', (331, 337))	('cell tumours', 'Disease', (171, 183))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (429, 448))	('SEMA3C', 'Gene', '10512', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('V600E', 'Mutation', 'rs113488022', (647, 652))	('lung cancer', 'Disease', (625, 636))	('brain tumours', 'Disease', (369, 382))	('melanoma', 'Disease', (538, 546))	('melanoma', 'Disease', (586, 594))	('SEMA3F', 'Gene', (455, 461))	('V600K mutations', 'Var', (656, 671))	('head and neck cancer', 'Disease', 'MESH:D006258', (298, 318))	("Hodgkin's disease", 'Disease', (219, 236))	("Hodgkin's disease", 'Disease', (402, 419))	('sarcomas', 'Disease', 'MESH:D012509', (185, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (625, 636))	('brain tumours', 'Disease', 'MESH:D001932', (369, 382))	('cancer', 'Disease', (274, 280))	('melanoma', 'Disease', 'MESH:D008545', (538, 546))	("Hodgkin's disease", 'Disease', 'MESH:D006689', (402, 419))	('SEMA3F', 'Gene', '6405', (455, 461))	('CML', 'Disease', 'MESH:D015464', (693, 696))	('cancer', 'Disease', (630, 636))	('CML', 'Disease', (693, 696))	('lymphoma', 'Phenotype', 'HP:0002665', (209, 217))	('cancer', 'Disease', (312, 318))	('tumours', 'Phenotype', 'HP:0002664', (375, 382))	('lymphoma', 'Phenotype', 'HP:0002665', (439, 447))	('head and neck cancer', 'Phenotype', 'HP:0012288', (298, 318))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('Pipobroman', 'Chemical', 'MESH:D010885', (76, 86))	('V600K', 'Mutation', 'rs121913227', (656, 661))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('BRAF', 'Gene', '673', (642, 646))	('lymphomas', 'Phenotype', 'HP:0002665', (439, 448))	('multiple myeloma', 'Phenotype', 'HP:0006775', (384, 400))	('Carmustine', 'Chemical', 'MESH:D002330', (344, 354))	('multiple myeloma', 'Disease', 'MESH:D009101', (384, 400))	('cancer', 'Disease', (155, 161))	('bladder cancer', 'Disease', (282, 296))	('sarcomas', 'Phenotype', 'HP:0100242', (185, 193))	('SEMA3C', 'Gene', (13, 19))	('sarcomas', 'Disease', (185, 193))	('cervix cancer', 'Disease', (324, 337))	('cancer', 'Disease', (290, 296))	('brain tumours', 'Phenotype', 'HP:0030692', (369, 382))	("Hodgkin's disease", 'Disease', 'MESH:D006689', (219, 236))	("non-Hodgkin's lymphomas", 'Disease', (425, 448))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('melanoma', 'Disease', 'MESH:D008545', (586, 594))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('cervix cancer', 'Phenotype', 'HP:0030079', (324, 337))	('cervix cancer', 'Disease', 'MESH:D002583', (324, 337))	('tumour', 'Phenotype', 'HP:0002664', (375, 381))	('Bafetinib', 'Chemical', 'MESH:C506918', (678, 687))	('melanoma', 'Phenotype', 'HP:0002861', (538, 546))	('melanoma', 'Phenotype', 'HP:0002861', (586, 594))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('BRAF', 'Gene', (642, 646))	('CML', 'Disease', 'MESH:D015464', (102, 105))	('CML', 'Disease', (102, 105))	('testicular cancer', 'Phenotype', 'HP:0010788', (144, 161))	("Non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (195, 217))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (199, 217))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (429, 447))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('bladder cancer', 'Phenotype', 'HP:0009725', (282, 296))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (610, 636))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
59000	32241267	In addition to the observation that expression of a specific isoform of SEMA3 gene vary greatly among tumours, we found that their expression varied even within each histological subtype/tissue of origin, such as in the cases of gene expression variation in different molecular subtypes of BRCA, HNSC, BLCA, OVand KIRC, as well as in different immune subtypes.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('SEMA', 'Gene', '7869', (72, 76))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('SEMA', 'Gene', (72, 76))	('expression', 'MPA', (131, 141))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('BRCA', 'Gene', '672', (290, 294))	('variation', 'Var', (245, 254))	('tumours', 'Disease', (102, 109))	('varied', 'Reg', (142, 148))	('BRCA', 'Gene', (290, 294))
59019	32241267	However, our study showed that altered expression of SEMA3C associated with poor prognosis in THCA, KIRC, KIRP, HNSC, PAAD, LUAD and CESA, but also associated with survival advantage in UVM, MESO, and DLBC which is all cell context dependent.	('survival advantage', 'CPA', (164, 182))	('altered', 'Var', (31, 38))	('THCA', 'Chemical', '-', (94, 98))	('SEMA3C', 'Gene', '10512', (53, 59))	('associated', 'Reg', (148, 158))	('expression', 'MPA', (39, 49))	('SEMA3C', 'Gene', (53, 59))	('associated', 'Reg', (60, 70))	('THCA', 'Disease', (94, 98))
59080	31690770	Copy number variation (CNV) was more frequent in recurrent tumors and CDKN2A/B loss was significantly enriched.	('Copy number variation', 'Var', (0, 21))	('frequent', 'Reg', (37, 45))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('CDKN2A', 'Gene', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CDKN2A', 'Gene', '1029', (70, 76))
59081	31690770	In addition, overall mutations in cell cycle pathway are more common in relapse tumors.	('relapse tumors', 'Disease', 'None', (72, 86))	('relapse tumors', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cell cycle pathway', 'Pathway', (34, 52))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('common', 'Reg', (62, 68))	('mutations', 'Var', (21, 30))
59088	31690770	For example, the existence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and 1p/19q deletion suggests low-grade oligodendroglioma (WHO II), while additional aberrations, including 9p and 10q loss, CDKN2A/B or RB1 deficiency and p14ARF methylation, indicates a progression to anaplastic oligodendroglioma (WHO III).	('CDKN2A', 'Gene', '1029', (204, 210))	('RB1', 'Gene', '5925', (216, 219))	('p14ARF', 'Gene', '1029', (235, 241))	('IDH1', 'Gene', (63, 67))	('deficiency', 'Var', (220, 230))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('methylation', 'Var', (242, 253))	('p14ARF', 'Gene', (235, 241))	('IDH1', 'Gene', '3417', (63, 67))	('isocitrate', 'Chemical', 'MESH:D007523', (30, 40))	('oligodendroglioma', 'Disease', 'MESH:D009837', (119, 136))	('oligodendroglioma', 'Disease', 'MESH:D009837', (293, 310))	('oligodendroglioma', 'Disease', (119, 136))	('RB1', 'Gene', (216, 219))	('CDKN2A', 'Gene', (204, 210))	('glioma', 'Phenotype', 'HP:0009733', (304, 310))	('mutation', 'Var', (71, 79))	('loss', 'NegReg', (198, 202))	('oligodendroglioma', 'Disease', (293, 310))
59089	31690770	Additionally, IDH1/2 mutation is associated with prolonged PFS and OS and higher response rate to temozolomide (TMZ), and 1p/19q codeletion is a biomarker to predict better response to combined radiotherapy and chemotherapy.	('TMZ', 'Chemical', 'MESH:C047246', (112, 115))	('IDH1', 'Gene', '3417', (14, 18))	('higher', 'PosReg', (74, 80))	('temozolomide', 'Chemical', 'MESH:C047246', (98, 110))	('response', 'MPA', (81, 89))	('mutation', 'Var', (21, 29))	('PFS', 'CPA', (59, 62))	('prolonged', 'PosReg', (49, 58))	('IDH1', 'Gene', (14, 18))	('1p/19q codeletion', 'Var', (122, 139))
59100	31690770	By comparing molecular features of primary and recurrent gliomas, some characteristics were notably enriched in recurrent group but relatively rare in primary tumors, including the occurrence of CNV, co-occurance of IDH1 and TERT, inactivated cell cycle signaling pathway and low TMB, which may provide clinical insights on tumor relapse and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('primary tumors', 'Disease', 'MESH:D001932', (151, 165))	('TMB', 'Gene', (280, 283))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('IDH1', 'Gene', '3417', (216, 220))	('co-occurance', 'Var', (200, 212))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('TERT', 'Gene', (225, 229))	('inactivated cell cycle signaling pathway', 'Pathway', (231, 271))	('TERT', 'Gene', '7015', (225, 229))	('primary tumors', 'Disease', (151, 165))	('tumor', 'Disease', (159, 164))	('gliomas', 'Disease', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('CNV', 'Disease', (195, 198))	('tumor', 'Disease', (324, 329))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('IDH1', 'Gene', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
59105	31690770	In particular, all IDH1 mutations were found to substitute Arginine residue at codon 132, of which 93% were R132H (27/29).	('R132H', 'Mutation', 'p.R132H', (108, 113))	('Arginine', 'Chemical', 'MESH:D001127', (59, 67))	('IDH1', 'Gene', (19, 23))	('Arginine residue', 'MPA', (59, 75))	('R132H', 'Var', (108, 113))	('IDH1', 'Gene', '3417', (19, 23))	('mutations', 'Var', (24, 33))
59106	31690770	In contrast, R132G and R132C substitutions were rare and identified only once.	('R132C', 'Var', (23, 28))	('R132G', 'Var', (13, 18))	('R132G', 'Mutation', 'p.R132G', (13, 18))	('R132C', 'Mutation', 'p.R132C', (23, 28))
59107	31690770	Missense and indel variants in PTEN, NOTCH1 and EGFR were found to be scattered throughout the genes (Supplementary Fig S1B).	('PTEN', 'Gene', (31, 35))	('EGFR', 'Gene', '1956', (48, 52))	('NOTCH1', 'Gene', '4851', (37, 43))	('NOTCH1', 'Gene', (37, 43))	('PTEN', 'Gene', '5728', (31, 35))	('EGFR', 'Gene', (48, 52))	('indel variants', 'Var', (13, 27))	('Missense', 'Var', (0, 8))
59108	31690770	Regarding copy number variants, amplification of EGFR, PDGFRA, CDK4, KIT and loss of CDKN2A/2B were the most common copy number aberrations.	('KIT', 'Gene', (69, 72))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('PDGFRA', 'Gene', (55, 61))	('amplification', 'Var', (32, 45))	('CDKN2A', 'Gene', (85, 91))	('PDGFRA', 'Gene', '5156', (55, 61))	('CDKN2A', 'Gene', '1029', (85, 91))	('common', 'Reg', (109, 115))	('loss', 'NegReg', (77, 81))	('KIT', 'Gene', '3815', (69, 72))	('CDK4', 'Gene', (63, 67))	('CDK4', 'Gene', '1019', (63, 67))
59109	31690770	FGFR3/TACCA3 and EGFR/EGFR rearrangements were detected in 3 and 2 tumors respectively.	('FGFR3', 'Gene', '2261', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('rearrangements', 'Var', (27, 41))	('FGFR3', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', '1956', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('detected', 'Reg', (47, 55))	('tumors', 'Disease', (67, 73))	('EGFR', 'Gene', (22, 26))	('EGFR', 'Gene', (17, 21))
59110	31690770	Interestingly, synchronous amplification was observed in 1/3 FGFR3 and 2/2 EGFR tumors, suggesting the strong association between CNV and SV variants in gliomas as previous described.	('gliomas', 'Phenotype', 'HP:0009733', (153, 160))	('gliomas', 'Disease', (153, 160))	('FGFR3', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('gliomas', 'Disease', 'MESH:D005910', (153, 160))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('variants', 'Var', (141, 149))	('tumors', 'Disease', (80, 86))	('EGFR', 'Gene', '1956', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('FGFR3', 'Gene', '2261', (61, 66))	('glioma', 'Phenotype', 'HP:0009733', (153, 159))	('EGFR', 'Gene', (75, 79))
59113	31690770	Genomic landscape studies have uncovered some co-occurring or mutually exclusive mutations in different cancer types.	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
59114	31690770	For instance, EGFR mutated exclusively with other known oncogenic drivers like KRAS, ROS1, MET and ALK aberrations in NSCLC.	('EGFR', 'Gene', '1956', (14, 18))	('ROS1', 'Gene', (85, 89))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('KRAS', 'Gene', '3845', (79, 83))	('ALK', 'Gene', (99, 102))	('ROS1', 'Gene', '6098', (85, 89))	('mutated', 'Var', (19, 26))	('NSCLC', 'Disease', (118, 123))	('ALK', 'Gene', '238', (99, 102))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('KRAS', 'Gene', (79, 83))
59115	31690770	Concurrent PDGFRA and EGFR alterations, exclusive of EGFR amplification and IDH1 mutation were described in GBM and low-grade gliomas respectively.	('IDH1', 'Gene', (76, 80))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('PDGFRA', 'Gene', (11, 17))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('EGFR', 'Gene', (22, 26))	('PDGFRA', 'Gene', '5156', (11, 17))	('GBM', 'Disease', (108, 111))	('IDH1', 'Gene', '3417', (76, 80))	('EGFR', 'Gene', '1956', (22, 26))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('described', 'Reg', (95, 104))	('EGFR', 'Gene', (53, 57))	('gliomas', 'Disease', (126, 133))	('EGFR', 'Gene', '1956', (53, 57))	('alterations', 'Var', (27, 38))
59119	31690770	Interestingly, when looking at the somatic interactions in primary and recurrent gliomas, there were some co-occurrence and mutual exclusivity of mutations only existing in the recurrent subset, including TERT and IDH1 (p = 0.050), IDH1 and TP53 (p = 0.002) (Fig.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('mutations', 'Var', (146, 155))	('TP53', 'Gene', '7157', (241, 245))	('IDH1', 'Gene', (214, 218))	('IDH1', 'Gene', (232, 236))	('TP53', 'Gene', (241, 245))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('IDH1', 'Gene', '3417', (214, 218))	('gliomas', 'Disease', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('IDH1', 'Gene', '3417', (232, 236))	('TERT', 'Gene', (205, 209))	('TERT', 'Gene', '7015', (205, 209))
59125	31690770	Moreover, the incidence of CDK4 (18% vs. 3%), somatic mutations of MLL3 (24% vs. 6%), PDGFRA (18% vs. 5%) and IDH1 (53% vs. 31%) were more frequent in recurrent patients, which are likely to be linked to poor survival.	('MLL3', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (110, 114))	('PDGFRA', 'Gene', '5156', (86, 92))	('frequent', 'Reg', (139, 147))	('PDGFRA', 'Gene', (86, 92))	('mutations', 'Var', (54, 63))	('recurrent', 'Disease', (151, 160))	('patients', 'Species', '9606', (161, 169))	('CDK4', 'Gene', (27, 31))	('MLL3', 'Gene', '58508', (67, 71))	('CDK4', 'Gene', '1019', (27, 31))	('IDH1', 'Gene', (110, 114))
59126	31690770	Additionally, recurrent gliomas, as well as high grade gliomas, featured more frequent copy number variants (65% recurrent versus 39% primary tumors, 60% high grade versus 20% in low grade tumors) (Fig.	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('primary tumors', 'Disease', 'MESH:D001932', (134, 148))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('variants', 'Var', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Disease', (142, 148))	('primary tumors', 'Disease', (134, 148))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('gliomas', 'Disease', (24, 31))	('gliomas', 'Disease', (55, 62))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('copy number variants', 'Var', (87, 107))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
59128	31690770	Indeed, for primary tumors, patients carrying CNV exhibited a significantly inferior DFS (HR = 4.59, 95% CI = 1.63-12.93) and OS (HR = 4.89, 95% CI = 1.56-15.35) rate (Fig.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('DFS', 'MPA', (85, 88))	('primary tumors', 'Disease', 'MESH:D001932', (12, 26))	('primary tumors', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('patients', 'Species', '9606', (28, 36))	('inferior', 'NegReg', (76, 84))	('CNV', 'Var', (46, 49))
59132	31690770	In contrast, MAPK pathway showed higher mutation frequency in primary gliomas, though not statistically significant.	('mutation', 'Var', (40, 48))	('higher', 'PosReg', (33, 39))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('MAPK pathway', 'Pathway', (13, 25))	('gliomas', 'Disease', (70, 77))	('gliomas', 'Disease', 'MESH:D005910', (70, 77))	('gliomas', 'Phenotype', 'HP:0009733', (70, 77))
59133	31690770	Consistent with the hypothesis, patients harboring cell cycle dysregulation showed significantly shorter DFS compared to the unchanged group.	('patients', 'Species', '9606', (32, 40))	('DFS', 'MPA', (105, 108))	('dysregulation', 'Var', (62, 75))	('shorter', 'NegReg', (97, 104))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (51, 75))
59138	31690770	Moreover, mutations in mismatch repair (MMR) genes often showed higher TMB (median TMB = 14) than MMR negative tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('higher', 'PosReg', (64, 70))	('TMB', 'CPA', (71, 74))	('tumors', 'Disease', (111, 117))	('MMR) genes', 'Gene', (40, 50))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (10, 19))
59148	31690770	It is clear that DNA copy number alterations, especially amplification on chromosome 7 (including EGFR/MET/CDK6) and chromosome 4 (including PDGFRA) and loss on chromosome 9 (including CDKN2A/B), are common in gliomas.	('EGFR', 'Gene', (98, 102))	('gliomas', 'Disease', (210, 217))	('CDKN2A', 'Gene', '1029', (185, 191))	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('PDGFRA', 'Gene', (141, 147))	('loss', 'NegReg', (153, 157))	('amplification', 'Var', (57, 70))	('PDGFRA', 'Gene', '5156', (141, 147))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('CDK6', 'Gene', (107, 111))	('EGFR', 'Gene', '1956', (98, 102))	('CDK6', 'Gene', '1021', (107, 111))	('CDKN2A', 'Gene', (185, 191))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
59153	31690770	Likewise, it has been suggested that alterations in this pathway are more frequent in higher-grade (Grades III and IV) gliomas, but the incidence in different grade tumors are similar.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('frequent', 'Reg', (74, 82))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Disease', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('gliomas', 'Disease', (119, 126))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('alterations', 'Var', (37, 48))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
59156	31690770	Patients with both mutations in TERT promoter IDH1/2 were found to have had the best OS.	('TERT', 'Gene', '7015', (32, 36))	('IDH1', 'Gene', (46, 50))	('mutations', 'Var', (19, 28))	('IDH1', 'Gene', '3417', (46, 50))	('Patients', 'Species', '9606', (0, 8))	('TERT', 'Gene', (32, 36))
59161	31690770	Additionally, patients with MMR gene mutations correspond to higher TMB in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('gliomas', 'Disease', (75, 82))	('higher', 'PosReg', (61, 67))	('gliomas', 'Disease', 'MESH:D005910', (75, 82))	('MMR gene', 'Gene', (28, 36))	('gliomas', 'Phenotype', 'HP:0009733', (75, 82))	('mutations', 'Var', (37, 46))	('TMB', 'MPA', (68, 71))	('patients', 'Species', '9606', (14, 22))
59164	31690770	Furthermore, a recent study, irrelevant to immunotherapy, has implicated that high TMB leads to better prognosis in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('better', 'PosReg', (96, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (116, 121))	('high TMB', 'Var', (78, 86))
59180	31484350	They are a subpopulation of lymphocytes characterized by the expression of CD3+ and CD56+ wich are surface markers common to T lymphocytes and natural killer NK cells.	('CD56', 'Gene', '4684', (84, 88))	('CD56', 'Gene', (84, 88))	('CD3+', 'Var', (75, 79))
59186	31484350	Within the heterogeneous T cell population two main subpopulations can be distinguished, one coexpressing the CD3 and CD56 molecules (range: 40% to 80%), while the other presenting a CD3+ CD56- phenotype (range: 20% to 60%).	('CD56', 'Gene', (188, 192))	('CD3', 'Var', (110, 113))	('CD56', 'Gene', '4684', (118, 122))	('CD56', 'Gene', '4684', (188, 192))	('CD56', 'Gene', (118, 122))
59228	31484350	Blocking of CD56 with the anti-CD56 monoclonal antibody and knockdown of CD56 in CIK cells by short interfering RNA (siRNA) significantly reduced CIK-mediated lysis of three CD56+ hematopoietic tumor cell lines.	('CD56', 'Gene', '4684', (73, 77))	('reduced', 'NegReg', (138, 145))	('hematopoietic tumor', 'Disease', 'MESH:D019337', (180, 199))	('CD56', 'Gene', '4684', (31, 35))	('CD56', 'Gene', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CD56', 'Gene', (73, 77))	('CD56', 'Gene', '4684', (12, 16))	('knockdown', 'Var', (60, 69))	('hematopoietic tumor', 'Phenotype', 'HP:0004377', (180, 199))	('CD56', 'Gene', (31, 35))	('hematopoietic tumor', 'Disease', (180, 199))	('CIK-mediated lysis', 'CPA', (146, 164))	('CD56', 'Gene', (12, 16))	('CD56', 'Gene', '4684', (174, 178))
59238	31484350	Binding of the Fas with its ligand (FasL), a 40-kDa membrane protein, leads to recruitment of the adaptor protein Fas-associated death domain (FADD) and activation by FADD of procaspase-8, resulting in the formation of the death-inducing signaling complex (DISC).	('caspase-8', 'Gene', (178, 187))	('recruitment', 'MPA', (79, 90))	('men', 'Species', '9606', (86, 89))	('activation', 'PosReg', (153, 163))	('caspase-8', 'Gene', '841', (178, 187))	('death-inducing signaling complex', 'MPA', (223, 255))	('FADD', 'Var', (167, 171))	('FasL', 'Gene', '356', (36, 40))	('FasL', 'Gene', (36, 40))	('Binding', 'Interaction', (0, 7))
59257	31484350	The recurrence rate of HCC was significantly lower in the immunotherapy group (45%, 59 patients) than in the control group (57%, 77 patients) p = 0.01.	('HCC', 'Gene', '619501', (23, 26))	('lower', 'NegReg', (45, 50))	('patients', 'Species', '9606', (87, 95))	('HCC', 'Gene', (23, 26))	('patients', 'Species', '9606', (132, 140))	('immunotherapy', 'Var', (58, 71))
59278	31484350	The proportion of patients who had an adverse event was significantly higher in in the immunotherapy group than in the control group (62% vs. 41%; p = 0.002) but the difference with serious adverse events was not significantly different between the two groups (7.8% vs. 3.5%; p = 0.15).	('higher', 'PosReg', (70, 76))	('immunotherapy', 'Var', (87, 100))	('patients', 'Species', '9606', (18, 26))
59357	31484350	The analysis showed that the CIK group significantly improved Ag-NORs (MD 20.71, 95% CI 2 0.94 to 20.47, p = 0.00001) compared with the non-CIK therapy group.	('CIK', 'Var', (29, 32))	('improved', 'PosReg', (53, 61))	('Ag-NORs', 'MPA', (62, 69))	('Ag-NORs', 'Chemical', 'MESH:C051963', (62, 69))
59358	31484350	The plasma level of CEA was significantly decreased in the CIK group compared to the non-CIK group (MD 3.96, 95% CI 1.64-6.28, p = 0.0008).	('CEA', 'Gene', '1048', (20, 23))	('CIK', 'Var', (59, 62))	('CEA', 'Gene', (20, 23))	('decreased', 'NegReg', (42, 51))
59362	31484350	Only the incidence of fever in the CIK group was significantly higher compared to chemotherapy alone.	('fever', 'Phenotype', 'HP:0001945', (22, 27))	('fever', 'Disease', (22, 27))	('CIK', 'Var', (35, 38))	('fever', 'Disease', 'MESH:D005334', (22, 27))
59369	31484350	It showed that the OS was significantly increased in the CIK cell group (HR 0.55; 95% CI: 0.35-0.87, P < 0.05).	('HR', 'Gene', '3164', (73, 75))	('CIK cell', 'Var', (57, 65))	('increased', 'PosReg', (40, 49))
59383	31484350	This includes those who carry the BRCA1 and BRCA2 gene mutation with a hereditary breast-ovarian cancer syndrome.	('BRCA1', 'Gene', '672', (34, 39))	('BRCA1', 'Gene', (34, 39))	('hereditary breast-ovarian cancer syndrome', 'Disease', 'MESH:D061325', (71, 112))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('BRCA2', 'Gene', (44, 49))	('BRCA2', 'Gene', '675', (44, 49))	('mutation', 'Var', (55, 63))	('hereditary breast-ovarian cancer syndrome', 'Disease', (71, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))
59396	31484350	That of the patients treated with DC-CIK cells was significantly improved compared to control group (p < 0.0001).	('improved', 'PosReg', (65, 73))	('patients', 'Species', '9606', (12, 20))	('DC-CIK', 'Var', (34, 40))
59397	31484350	The overall analysis showed a significant increase in the DC-CIK treatment group of T cells CD3+, CD4+, CD4+CD8+, natural killer T cells CD3+CD56+, monocytes CD16+ (p <= 0.05) compared to non-DC-CIK group.	('CD4', 'Gene', '920', (98, 101))	('CD4', 'Gene', (104, 107))	('DC-CIK', 'Var', (58, 64))	('men', 'Species', '9606', (70, 73))	('CD56', 'Gene', '4684', (141, 145))	('CD16', 'Gene', '2214', (158, 162))	('CD4', 'Gene', '920', (104, 107))	('CD56', 'Gene', (141, 145))	('CD8', 'Gene', (108, 111))	('CD8', 'Gene', '925', (108, 111))	('CD4', 'Gene', (98, 101))	('CD16', 'Gene', (158, 162))	('increase', 'PosReg', (42, 50))
59400	31484350	The levels of CEA, alpha-fetoprotein AFP, cancer and carbohydrate antigen CA tumor markers were significantly decreased (p < 0.00001) after DC-CIK treatment.	('levels', 'MPA', (4, 10))	('CEA', 'Gene', (14, 17))	('DC-CIK', 'Var', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('decreased', 'NegReg', (110, 119))	('carbohydrate antigen CA', 'MPA', (53, 76))	('men', 'Species', '9606', (152, 155))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('alpha-fetoprotein AFP', 'MPA', (19, 40))	('carbohydrate', 'Chemical', 'MESH:D002241', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('CEA', 'Gene', '1048', (14, 17))
59416	31484350	Gene expression-based subtypes are: proneural (PN) aberrations in the platelet-derived growth factor receptor alpha (PDGFRA), mesenchymal (MES) aberrations in neurofibromatosis type I (NF1), and classical (CL) aberrations in epidermal growth factor receptor (EGFR).	('aberrations', 'Var', (51, 62))	('PDGFRA', 'Gene', (117, 123))	('epidermal growth factor receptor', 'Gene', '1956', (225, 257))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (70, 115))	('neurofibromatosis type I', 'Disease', (159, 183))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (159, 176))	('PDGFRA', 'Gene', '5156', (117, 123))	('platelet-derived growth factor receptor alpha', 'Gene', (70, 115))	('EGFR', 'Gene', '1956', (259, 263))	('neurofibromatosis type I', 'Disease', 'MESH:D009456', (159, 183))	('epidermal growth factor receptor', 'Gene', (225, 257))	('EGFR', 'Gene', (259, 263))	('NF1', 'Gene', (185, 188))	('NF1', 'Gene', '4763', (185, 188))
59418	31484350	Genetic driver mutations in GBM subtypes can create unique differences in their microenvironments.	('men', 'Species', '9606', (92, 95))	('microenvironments', 'MPA', (80, 97))	('GBM', 'Gene', (28, 31))	('mutations', 'Var', (15, 24))
59427	31484350	The incidences of total and >= grade 3 treatment-emergent adverse events (TEAEs) were higher in the CIK immunotherapy group than the control group.	('CIK', 'Var', (100, 103))	('higher', 'PosReg', (86, 92))	('men', 'Species', '9606', (44, 47))
59436	31484350	There was a significant improvement in the OS over 1-year (p = 0.0002) and over 3-years p < 0.0001) in the CIK cell therapy group compared to non-CIK group.	('improvement', 'PosReg', (24, 35))	('CIK', 'Var', (107, 110))	('men', 'Species', '9606', (31, 34))
59444	31484350	The results showed an increase in the median OS in DC-CIK treatment group 28 months compared to 11 months control group.	('increase', 'PosReg', (22, 30))	('men', 'Species', '9606', (63, 66))	('DC-CIK', 'Var', (51, 57))
59445	31484350	There was also a significant increase in median PFS in DC-CIK treatment group compared to control group (p = 0.0212).	('DC-CIK', 'Var', (55, 61))	('PFS', 'MPA', (48, 51))	('men', 'Species', '9606', (67, 70))	('increase', 'PosReg', (29, 37))
59457	31484350	There was a significant decrease in progressive disease PD rates and nonresponse (OR = 0.24, CI = 0.07-0.80, p = 0.02) of DC-CIK immunotherapy group compared to control group.	('progressive disease PD', 'Disease', (36, 58))	('DC-CIK', 'Var', (122, 128))	('nonresponse', 'CPA', (69, 80))	('progressive disease PD', 'Disease', 'MESH:D010300', (36, 58))	('decrease', 'NegReg', (24, 32))
59504	30682793	ApoEVs altered RNA splicing in recipient cells, partly through transfer of splicing factor RBM11, resulting in more oncogenic isoforms of MDM4 and Cyclin D1 thereby promoting therapy resistance and an aggressive migratory phenotype.	('Cyclin D1', 'Gene', '595', (147, 156))	('more', 'PosReg', (111, 115))	('RBM11', 'Gene', '54033', (91, 96))	('MDM4', 'Gene', '4194', (138, 142))	('aggressive migratory phenotype', 'CPA', (201, 231))	('MDM4', 'Gene', (138, 142))	('oncogenic isoforms', 'MPA', (116, 134))	('transfer', 'Var', (63, 71))	('RBM11', 'Gene', (91, 96))	('therapy resistance', 'CPA', (175, 193))	('promoting', 'PosReg', (165, 174))	('Cyclin D1', 'Gene', (147, 156))
59506	30682793	Indeed, investigation of the p53-mediated response following lung cancer cell irradiation revealed the protein TSAP6 enhanced EV production in cells, highlighting a novel function of the p53 protein in regulation of EV secretion.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('p53', 'Gene', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('p53', 'Gene', '7157', (187, 190))	('p53', 'Gene', (29, 32))	('enhanced', 'PosReg', (117, 125))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('protein', 'Var', (103, 110))	('EV production', 'MPA', (126, 139))	('p53', 'Gene', '7157', (29, 32))	('TSAP6', 'Gene', (111, 116))	('TSAP6', 'Gene', '55240', (111, 116))
59522	30682793	In addition to mediating transfer of microRNA/mRNA/lncRNA and proteins to confer a drug resistant phenotype upon recipient cells, EVs have also been shown to act as drug decoys, thus shielding target tumour cells.	('tumour', 'Disease', (200, 206))	('drug resistant phenotype', 'MPA', (83, 107))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('EVs', 'Var', (130, 133))
59525	30682793	Transfer of EV-TrpC5 to recipient cells was demonstrated to result in transfer of resistance.	('TrpC5', 'Gene', '7224', (15, 20))	('Transfer', 'Var', (0, 8))	('result in', 'Reg', (60, 69))	('TrpC5', 'Gene', (15, 20))	('transfer', 'MPA', (70, 78))
59544	30682793	It was postulated that EV-nitrated Hsp60 could interact with the immune system, but its anti-cancer properties are yet to be fully elucidated.	('cancer', 'Disease', (93, 99))	('Hsp60', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('interact', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Hsp60', 'Gene', '3329', (35, 40))	('EV-nitrated', 'Var', (23, 34))
59590	30682793	Tumour-derived EVs containing miR-3091-3p internalised by hepatocytes suppressed autophagy-related protein 9b (Atg9b) expression.	('miR-3091-3p', 'Var', (30, 41))	('autophagy-related protein 9b', 'Gene', (81, 109))	('suppressed', 'NegReg', (70, 80))	('autophagy-related protein 9b', 'Gene', '285973', (81, 109))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'MPA', (118, 128))	('Atg9b', 'Gene', (111, 116))	('Atg9b', 'Gene', '285973', (111, 116))
59594	30682793	Under stress conditions autophagy is increased, and dysregulation of this highly conserved mechanism is linked to diseases including cancer.	('linked', 'Reg', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('dysregulation', 'Var', (52, 65))	('increased', 'PosReg', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('autophagy', 'CPA', (24, 33))
59621	30682793	The EVs also inhibited MCF-7 proliferation and induced cell apoptosis in vitro along with inhibiting tumour growth in vivo.	('MCF-7', 'Gene', (23, 28))	('induced', 'Reg', (47, 54))	('tumour growth', 'Disease', (101, 114))	('inhibited', 'NegReg', (13, 22))	('EVs', 'Var', (4, 7))	('inhibiting', 'NegReg', (90, 100))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('MCF-7', 'CellLine', 'CVCL:0031', (23, 28))	('tumour growth', 'Disease', 'MESH:D006130', (101, 114))	('cell apoptosis', 'CPA', (55, 69))
59645	30623119	They tend to be smaller and multifocal at diagnosis, H3K27M or NF1 related and lack EGFR amplification.	('H3K27M', 'Var', (53, 59))	('lack', 'NegReg', (79, 83))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('NF1', 'Gene', (63, 66))	('NF1', 'Gene', '4763', (63, 66))
59775	26873924	The current version of the UROBORUS pipeline can only detect those circRNAs supported by exon-exon junctions, and may miss those circRNAs derived from an intron region or intergenic region.	('miss', 'NegReg', (118, 122))	('UROBORUS', 'Chemical', '-', (27, 35))	('exon-exon', 'Var', (89, 98))
59784	26317392	An important goal of studying cancer genomics is to identify critical pathways that, when perturbed by somatic genomic alterations (SGAs) such as somatic mutations, copy number alterations and epigenomic alterations, cause cancers and underlie different clinical phenotypes.	('cancers', 'Disease', (223, 230))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('copy number alterations', 'Var', (165, 188))	('epigenomic alterations', 'Var', (193, 215))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cause', 'Reg', (217, 222))	('S', 'Chemical', 'MESH:D013455', (132, 133))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
59788	26317392	Somatic genome alterations (SGAs) such as somatic mutations, somatic copy number alterations and epigenomic alterations are major causes of cancers.	('S', 'Chemical', 'MESH:D013455', (28, 29))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('epigenomic alterations', 'Var', (97, 119))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('S', 'Chemical', 'MESH:D013455', (0, 1))
59793	26317392	For example, a mutation leading to constitutive activation of the epidermal growth factor receptor (EGFR) gene may lead to over-expression of its target genes.	('over-expression', 'MPA', (123, 138))	('mutation', 'Var', (15, 23))	('EGFR', 'Gene', '1956', (100, 104))	('epidermal growth factor receptor', 'Gene', (66, 98))	('EGFR', 'Gene', (100, 104))	('activation', 'PosReg', (48, 58))	('epidermal growth factor receptor', 'Gene', '1956', (66, 98))	('lead to', 'Reg', (115, 122))
59805	26317392	A natural explanation for this phenomenon is that, if one mutation is sufficient to perturb the signal of a pathway and leads to the development of cancer, perturbation of other proteins is not required, and therefore co-occurrence of perturbations is seldom observed.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('leads to', 'Reg', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutation', 'Var', (58, 66))	('signal', 'MPA', (96, 102))	('perturb', 'Reg', (84, 91))
59814	26317392	Under such a setting, mutual exclusivity and co-expression of SGA-affected genes can further be used as auxiliary objective functions to constrain the search space and to enhance the confidence of the results.	('SGA-affected genes', 'Gene', (62, 80))	('enhance', 'PosReg', (171, 178))	('co-expression', 'Var', (45, 58))	('confidence', 'MPA', (183, 193))	('S', 'Chemical', 'MESH:D013455', (62, 63))
59824	26317392	We removed the genes that exhibit both amplifications and deletions (with the smaller fraction being over 10%) in a given set of tumors that are supposed to have a common signal perturbed as inconsistent genes.	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('deletions', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
59861	26317392	For example, AURKA was found overexpressed in the early stage ovarian tumors, therefore suggesting that the alteration of AURKA could be an early event of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (155, 169))	('ovarian tumors', 'Phenotype', 'HP:0100615', (62, 76))	('ovarian tumor', 'Phenotype', 'HP:0100615', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('AURKA', 'Gene', (13, 18))	('ovarian tumors', 'Disease', 'MESH:D010051', (62, 76))	('ovarian tumors', 'Disease', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('overexpressed', 'PosReg', (29, 42))	('AURKA', 'Gene', '6790', (122, 127))	('ovarian cancer', 'Disease', (155, 169))	('alteration', 'Var', (108, 118))	('AURKA', 'Gene', '6790', (13, 18))	('AURKA', 'Gene', (122, 127))
59869	26317392	Among them, expression of CENPE and CCNB2 correlates with worse clinical outcomes of patients with breast or ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (109, 124))	('CCNB2', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('expression', 'Var', (12, 22))	('CENPE', 'Gene', '1062', (26, 31))	('breast or ovarian cancers', 'Disease', 'MESH:D010051', (99, 124))	('CCNB2', 'Gene', '9133', (36, 41))	('patients', 'Species', '9606', (85, 93))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('CENPE', 'Gene', (26, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))	('breast or ovarian cancers', 'Disease', (99, 124))
59877	26317392	For example, the RMs annotated with U_GO0007067 (mitotic nuclear division) found from GBM and ovarian cancer have 18 and 17 genes respectively, in which 15 genes are in common, and the union of the two RMs includes 20 genes.	('ovarian cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GBM', 'Disease', (86, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('U_GO0007067', 'Var', (36, 47))
59878	26317392	As expected, literature studies indicate that almost all the above genes and most of other significant overlapping RMs are related to cancers (S4 Table), including those involved in U_GO0009611 (response to wounding) and U_GO0006974 (cellular response to DNA damage stimulus).	('S', 'Chemical', 'MESH:D013455', (143, 144))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('U_GO0006974', 'Var', (221, 232))	('U_GO0009611', 'Var', (182, 193))	('related', 'Reg', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
59898	26317392	We further investigated whether the identified PMs could be mapped to known signaling pathways, concluding that, indeed, many PMs were enriched in known pathways, including 51 PMs that were enriched in a known pathway with both p-values and q-values of at most 0.01.	('PMs', 'Var', (126, 129))	('PMs', 'Chemical', 'MESH:D011399', (47, 50))	('PMs', 'Chemical', 'MESH:D011399', (126, 129))	('PMs', 'Chemical', 'MESH:D011399', (176, 179))	('enriched', 'Reg', (135, 143))
59908	26317392	It is of highly significance that our algorithm predicts that the amplification of CCNE1 gene conveys the identical information as to the mutation or deletion of RB1.	('RB1', 'Gene', (162, 165))	('deletion', 'Var', (150, 158))	('CCNE1', 'Gene', (83, 88))	('CCNE1', 'Gene', '898', (83, 88))	('RB1', 'Gene', '5925', (162, 165))	('mutation', 'Var', (138, 146))
59909	26317392	As shown in Fig 4B, the protein encoded by CCNE1 inhibits that of RB1 (Fig 4B); both amplification of CCNE1 and mutation/deletion of RB1 have the same effect on a common signal, leading to aberrant regulation of cell cycle entry and thereby causing cancers.	('aberrant', 'PosReg', (189, 197))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('CCNE1', 'Gene', (102, 107))	('cancers', 'Disease', (249, 256))	('RB1', 'Gene', (133, 136))	('amplification', 'Var', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('CCNE1', 'Gene', '898', (102, 107))	('RB1', 'Gene', '5925', (133, 136))	('RB1', 'Gene', (66, 69))	('CCNE1', 'Gene', (43, 48))	('causing', 'Reg', (241, 248))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('regulation', 'MPA', (198, 208))	('mutation/deletion', 'Var', (112, 129))	('cell cycle entry', 'CPA', (212, 228))	('CCNE1', 'Gene', '898', (43, 48))	('RB1', 'Gene', '5925', (66, 69))	('leading to', 'Reg', (178, 188))
59917	26317392	MLLT3, NF1, and COL24A1 are either deleted or mutated while MDM2 is amplified in tumors (Fig 4E).	('tumors', 'Disease', (81, 87))	('MLLT3', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('COL24A1', 'Gene', (16, 23))	('MLLT3', 'Gene', '4300', (0, 5))	('mutated', 'Var', (46, 53))	('NF1', 'Gene', (7, 10))	('COL24A1', 'Gene', '255631', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('NF1', 'Gene', '4763', (7, 10))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
59919	26317392	Inhibition of MDM2 induces cell apoptosis and reactivates p53 in GBM cells, resulting in inhibition of GBM cell growth in vitro and in GBM xenografts in mice.	('GBM cell growth', 'CPA', (103, 118))	('inhibition', 'NegReg', (89, 99))	('MDM2', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cell apoptosis', 'CPA', (27, 41))	('p53', 'Gene', (58, 61))	('mice', 'Species', '10090', (153, 157))	('induces', 'Reg', (19, 26))	('reactivates', 'Var', (46, 57))
59920	26317392	Inactivation of NF1 by germline mutations are predisposed to the development of benign and malignant tumors of peripheral and central nervous system including GBMs.	('NF1', 'Gene', (16, 19))	('malignant tumors of peripheral', 'Disease', 'MESH:D010524', (91, 121))	('germline mutations', 'Var', (23, 41))	('NF1', 'Gene', '4763', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('malignant tumors of peripheral and central nervous system', 'Phenotype', 'HP:0100836', (91, 148))	('predisposed', 'Reg', (46, 57))	('malignant tumors of peripheral', 'Disease', (91, 121))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('Inactivation', 'Var', (0, 12))
59921	26317392	Loss of NF1 also renders cancer cell resistant to apoptosis.	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('NF1', 'Gene', '4763', (8, 11))	('renders', 'Reg', (17, 24))	('resistant to apoptosis', 'CPA', (37, 59))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('Loss', 'Var', (0, 4))
59924	26317392	Depletion of LRP1 led to an increase in cell apoptosis, thus corroborating with our findings that amplification of LRP1 inhibits apoptosis.	('inhibits', 'NegReg', (120, 128))	('LRP1', 'Gene', '4035', (115, 119))	('apoptosis', 'CPA', (129, 138))	('cell apoptosis', 'CPA', (40, 54))	('LRP1', 'Gene', '4035', (13, 17))	('Depletion', 'Var', (0, 9))	('amplification', 'Var', (98, 111))	('LRP1', 'Gene', (115, 119))	('LRP1', 'Gene', (13, 17))	('increase', 'PosReg', (28, 36))
59925	26317392	Since LRP1 mutations have not been reported in cancers, we predict that these mutations exert a similar effect as their gene amplification events.	('mutations', 'Var', (11, 20))	('LRP1', 'Gene', (6, 10))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('LRP1', 'Gene', '4035', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('S', 'Chemical', 'MESH:D013455', (0, 1))
59926	26317392	Taken together, our identification of alterations in this PM in GBM validated the established functions of these oncogenic drivers in tumor initiation and progression in GBMs and other types of cancers.	('tumor initiation', 'Disease', (134, 150))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('alterations', 'Var', (38, 49))	('tumor initiation', 'Disease', 'MESH:D009369', (134, 150))
59946	26317392	Fig 5B shows that the PMs from the DBSGs are significantly enriched in the input tumors, with a mean of log (base 2) p-values of -11.11; on the other hand, the enrichment p-values derived from the random tumor sets are much less significant, with a mean of log p-values of -1.92 (which corresponds to a p-value of 0.26, a non-significant p-value).	('PMs', 'Chemical', 'MESH:D011399', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('input tumors', 'Disease', 'MESH:D009369', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (204, 209))	('DBSGs', 'Chemical', '-', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('input tumors', 'Disease', (75, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('DBSGs', 'Var', (35, 40))	('tumor', 'Disease', (81, 86))
59971	26317392	Since genes in a PM are randomly perturbed by nature, a strong association between genes in a pair of PM and RM usually indicates that perturbation of genes in a PM causes differential expressions of genes in the RM.	('perturbation', 'Var', (135, 147))	('expressions', 'MPA', (185, 196))	('S', 'Chemical', 'MESH:D013455', (0, 1))
59972	26317392	However, it should be noted that such associations may also result from a selection bias, for example, mutation of one gene and over-expression of another are both enriched in a particular tumor subtype, leading to an apparent association even though they do not have a causal relationship.	('particular tumor', 'Disease', (178, 194))	('leading to', 'Reg', (204, 214))	('particular tumor', 'Disease', 'MESH:D009369', (178, 194))	('over-expression', 'PosReg', (128, 143))	('mutation', 'Var', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
59978	26137500	Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs Cancer stem cells (CSCs) or cancer initiating cells (CICs) maintain self-renewal and multilineage differentiation properties of various tumors, as well as the cellular heterogeneity consisting of several subpopulations within tumors.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Glioblastoma', 'Disease', (0, 12))	('epigenetic plasticity', 'Var', (31, 52))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('Cancer', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (142, 148))	('multilineage differentiation properties', 'CPA', (199, 238))	('tumors', 'Disease', (340, 346))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', (250, 256))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('self-renewal', 'CPA', (182, 194))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))
59979	26137500	CSCs display the malignant phenotype, self-renewal ability, altered genomic stability, specific epigenetic signature, and most of the time can be phenotyped by cell surface markers (e.g., CD133, CD24, and CD44).	('self-renewal ability', 'CPA', (38, 58))	('malignant phenotype', 'CPA', (17, 36))	('CD133', 'Var', (188, 193))	('CD24', 'Gene', '100133941', (195, 199))	('CD24', 'Gene', (195, 199))	('CD44', 'Gene', '960', (205, 209))	('altered', 'Reg', (60, 67))	('genomic stability', 'CPA', (68, 85))	('CD44', 'Gene', (205, 209))
59982	26137500	Another level of complexity in glioblastoma multiforme (GBM) tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs, and the potential for non-GSCs to revert (dedifferentiate) to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell population.	('epigenetic alteration', 'Var', (211, 232))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('glioblastoma multiforme (GBM) tumors', 'Disease', 'MESH:D005909', (31, 67))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
59987	26137500	The highly aggressive nature of GBM is due to multiple genetic alterations which result in augmented cytoprotective and survival pathways as well as numerous defects in the apoptotic signaling machinery and epigenetic alterations (Fig.	('epigenetic alterations', 'Var', (207, 229))	('survival', 'CPA', (120, 128))	('numerous defects', 'Disease', 'MESH:D005128', (149, 165))	('numerous defects', 'Disease', (149, 165))	('augmented', 'PosReg', (91, 100))	('apoptotic', 'CPA', (173, 182))
59996	26137500	Primary GBM frequently displays molecular alterations in EGFR, PDGFRA, PTEN, p53 tumor suppressor protein, NF1, CDKN2A/B, and telomerase reverse transcriptase (TERT) promoter mutations (see Fig.	('PDGFRA', 'Gene', (63, 69))	('telomerase reverse transcriptase', 'Gene', '7015', (126, 158))	('PDGFRA', 'Gene', '5156', (63, 69))	('PTEN', 'Gene', '5728', (71, 75))	('mutations', 'Var', (175, 184))	('CDKN2A/B', 'Gene', (112, 120))	('p53', 'Gene', '7157', (77, 80))	('EGFR', 'Gene', (57, 61))	('tumor', 'Disease', (81, 86))	('NF1', 'Gene', '4763', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p53', 'Gene', (77, 80))	('CDKN2A/B', 'Gene', '1029;1030', (112, 120))	('TERT', 'Gene', (160, 164))	('NF1', 'Gene', (107, 110))	('alterations', 'Reg', (42, 53))	('telomerase reverse transcriptase', 'Gene', (126, 158))	('TERT', 'Gene', '7015', (160, 164))	('PTEN', 'Gene', (71, 75))	('EGFR', 'Gene', '1956', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
59999	26137500	A high frequency of isocitrate dehydrogenase 1 (IDH1) mutations and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation among young adult patients with primary GBM compared to other subtypes correlates with increased survival.	('primary GBM', 'Disease', (167, 178))	('MGMT', 'Gene', (108, 112))	('patients', 'Species', '9606', (153, 161))	('IDH1', 'Gene', '3417', (48, 52))	('MGMT', 'Gene', '4255', (108, 112))	('mutations', 'Var', (54, 63))	('methylation', 'Var', (123, 134))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (68, 106))	('isocitrate dehydrogenase 1', 'Gene', (20, 46))	('isocitrate dehydrogenase 1', 'Gene', '3417', (20, 46))	('increased', 'PosReg', (222, 231))	('IDH1', 'Gene', (48, 52))	('O6-methylguanine-DNA methyltransferase', 'Gene', (68, 106))
60000	26137500	The classical subtype is associated with a high frequency of EGFR aberrations and low expression of p53 tumor suppressor protein mutations.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p53', 'Gene', (100, 103))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', (104, 109))	('low', 'NegReg', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('expression', 'MPA', (86, 96))	('p53', 'Gene', '7157', (100, 103))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('aberrations', 'Var', (66, 77))
60006	26137500	Heterogeneity among tumor cells arises within a single tumor as a result of genetic and epigenetic changes (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('epigenetic changes', 'Var', (88, 106))	('genetic', 'Var', (76, 83))	('tumor', 'Disease', (20, 25))
60027	26137500	Significantly, these authors demonstrated that silencing CD133 in human GBM neurospheres using lentivirus-mediated short hairpin RNA impaired the self-renewal and tumorigenic capacity of neurosphere cells.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('human', 'Species', '9606', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('impaired', 'NegReg', (133, 141))	('silencing', 'Var', (47, 56))	('tumor', 'Disease', (163, 168))	('CD133', 'Gene', (57, 62))	('self-renewal', 'CPA', (146, 158))
60035	26137500	Interestingly, both the glycolytic pathway and ALDH1A3 activities were robustly elevated in Mes but not PN GSCs, and inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs.	('ALDH1A3', 'Gene', '220', (131, 138))	('glycolytic pathway', 'Pathway', (24, 42))	('elevated', 'PosReg', (80, 88))	('ALDH1A3', 'Gene', (47, 54))	('Mes', 'Chemical', '-', (164, 167))	('Mes', 'Chemical', '-', (92, 95))	('activities', 'MPA', (55, 65))	('ALDH1A3', 'Gene', '220', (47, 54))	('attenuated', 'NegReg', (139, 149))	('inhibition', 'Var', (117, 127))	('ALDH1A3', 'Gene', (131, 138))	('growth', 'CPA', (154, 160))
60073	26137500	DNA methylation results in covalent modification of cytosine nucleotides at the C5 position of particular areas of unmethylated CpG dinucleotides.	('cytosine nucleotides', 'Chemical', 'MESH:D003597', (52, 72))	('results in', 'Reg', (16, 26))	('covalent modification', 'MPA', (27, 48))	('methylation', 'Var', (4, 15))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (128, 145))	('cytosine nucleotides', 'MPA', (52, 72))
60081	26137500	Epigenetic modifications regulate intratumoral heterogeneity, which is usually regulated by specific GSC niches, particularly, perivascular and hypoxic region microenvironments.	('Epigenetic modifications', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('regulate', 'Reg', (25, 33))	('tumor', 'Disease', (39, 44))
60082	26137500	Recently, Nabilsi et al investigated the extent to which epigenetic differences contribute to intratumoral cellular heterogeneity by developing a high-throughput method, termed MAPit-patch.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('epigenetic differences', 'Var', (57, 79))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('contribute', 'Reg', (80, 90))
60087	26137500	Mechanistic studies revealed that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity, which is required for the adaptation of GBM cells to their microenvironment.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('epigenetic regulation', 'Var', (34, 55))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PRC2', 'Gene', (59, 63))
60090	26137500	They showed that one of the miRNAs, miRNA-148a, inhibited GBM cell stem-like properties and tumor-propagating potential.	('GBM cell stem-like properties', 'CPA', (58, 87))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('miRNA-148a', 'Var', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inhibited', 'NegReg', (48, 57))	('tumor', 'Disease', (92, 97))
60092	26137500	Among many alterations, amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in GBM.	('EGFR', 'Gene', (98, 102))	('found', 'Reg', (124, 129))	('rearrangements', 'Var', (42, 56))	('epidermal growth factor receptor', 'Gene', '1956', (64, 96))	('amplification', 'Var', (24, 37))	('EGFR', 'Gene', '1956', (98, 102))	('epidermal growth factor receptor', 'Gene', (64, 96))
60093	26137500	The most common variant is EGFR variant III (EGFRvIII) and this variant could be a marker for GSCs showing that epigenetic mechanisms have a role in maintaining heterogeneous EGFRvIII expression.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('EGFR', 'Gene', (175, 179))	('heterogeneous', 'MPA', (161, 174))	('EGFR', 'Gene', (45, 49))	('variant III', 'Var', (32, 43))	('expression', 'MPA', (184, 194))	('EGFR', 'Gene', '1956', (175, 179))	('EGFR', 'Gene', '1956', (45, 49))
60094	26137500	Demethylation induced a 20%-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII.	('EGFR', 'Gene', '1956', (62, 66))	('increase', 'PosReg', (32, 40))	('EGFR', 'Gene', (62, 66))	('Demethylation', 'Var', (0, 13))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))
60096	26137500	Two main features of cancer are aberrant gene function and altered patterns of gene expression, and evidence shows that epigenetic changes in collaboration with genetic alterations cause dysregulation in cancer.	('cancer', 'Disease', (204, 210))	('altered', 'Reg', (59, 66))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('dysregulation', 'MPA', (187, 200))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cause', 'Reg', (181, 186))	('epigenetic changes', 'Var', (120, 138))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('aberrant', 'Var', (32, 40))	('patterns', 'MPA', (67, 75))
60105	26137500	For example, several drugs that target epigenetic alterations, including HDAC inhibitors and DNA methyltransferase (DNMT), approved for hematological malignancies, are available for solid tumor therapy.	('HDAC', 'Gene', (73, 77))	('hematological malignancies', 'Disease', (136, 162))	('hematological malignancies', 'Disease', 'MESH:D019337', (136, 162))	('epigenetic alterations', 'Var', (39, 61))	('solid tumor', 'Disease', (182, 193))	('DNA methyltransferase', 'Gene', (93, 114))	('DNMT', 'Gene', '1786', (116, 120))	('DNMT', 'Gene', (116, 120))	('hematological malignancies', 'Phenotype', 'HP:0004377', (136, 162))	('solid tumor', 'Disease', 'MESH:D009369', (182, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('DNA methyltransferase', 'Gene', '1786', (93, 114))
60160	25360666	The 4 GBM tumors assessed in this study could be classified according to the four GBM gene expression subclasses defined by The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov/) as follows: proneural (SID227 and SID238), classical (SID233) and mesenchymal (SID186).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('GBM tumors', 'Disease', (6, 16))	('GBM tumors', 'Disease', 'MESH:D005910', (6, 16))	('proneural', 'CPA', (198, 207))	('SID227 and SID238', 'Disease', 'None', (209, 226))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mesenchymal', 'CPA', (252, 263))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Cancer Genome Atlas', 'Disease', (128, 147))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (128, 147))	('SID233', 'Var', (240, 246))
60191	25360666	U373 MG cells treated with AC4ManNAz exhibited a dose-dependent increase in fluorescence that indicated the accumulation of biotin moieties on the cell surface, whereas untreated cells showed only a background level of fluorescence after exposure to the biotin-phosphine probe.	('AC4ManNAz', 'Chemical', 'MESH:C000622612', (27, 36))	('biotin-phosphine', 'Chemical', '-', (254, 270))	('biotin', 'Chemical', 'MESH:D001710', (254, 260))	('biotin moieties', 'MPA', (124, 139))	('AC4ManNAz', 'Var', (27, 36))	('accumulation', 'PosReg', (108, 120))	('U373 MG', 'CellLine', 'CVCL:2219', (0, 7))	('increase', 'PosReg', (64, 72))	('fluorescence', 'MPA', (76, 88))	('biotin', 'Chemical', 'MESH:D001710', (124, 130))
60193	25360666	As quantified by flow cytometry, the AC4ManNAz-treated U373 MG cells displayed about 280-450 fold greater Alexa488-specific fluorescence intensity than the control vehicle-treated cells.	('AC4ManNAz', 'Chemical', 'MESH:C000622612', (37, 46))	('Alexa488-specific fluorescence intensity', 'MPA', (106, 146))	('U373 MG', 'CellLine', 'CVCL:2219', (55, 62))	('Alexa488', 'Chemical', '-', (106, 114))	('AC4ManNAz-treated', 'Var', (37, 54))	('greater', 'PosReg', (98, 105))
60200	25360666	As expected, U373 MG cells subjected to metabolic incorporation of AC4ManNAz followed by Staudinger ligation with biotin phosphine were intensely stained with streptavidin-Alexa Fluor 488 on the cell surface, with no apparent intracellular staining (Fig.	('U373 MG', 'CellLine', 'CVCL:2219', (13, 20))	('AC4ManNAz', 'Chemical', 'MESH:C000622612', (67, 76))	('stained', 'Reg', (146, 153))	('biotin phosphine', 'Chemical', '-', (114, 130))	('rat', 'Species', '10116', (57, 60))	('AC4ManNAz', 'Var', (67, 76))	('Alexa Fluor 488', 'Chemical', '-', (172, 187))
60302	25360666	The technology developed involves metabolic labeling of sialylated glycans with AC4ManNAz, a synthetic azido sugar.	('AC4ManNAz', 'Chemical', 'MESH:C000622612', (80, 89))	('sialylated', 'Protein', (56, 66))	('AC4ManNAz', 'Var', (80, 89))	('glycans', 'Chemical', 'MESH:D011134', (67, 74))	('azido sugar', 'Chemical', '-', (103, 114))
60323	25360666	Inhibition of PTPRZ1 expression with small interfering RNA suppresses glioblastoma growth in vitro and in vivo.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('PTPRZ1', 'Gene', '5803', (14, 20))	('PTPRZ1', 'Gene', (14, 20))	('Inhibition', 'NegReg', (0, 10))	('glioblastoma', 'Disease', (70, 82))	('suppresses', 'NegReg', (59, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('small interfering', 'Var', (37, 54))
60333	25360666	The polysialylated form of the cell surface glycoprotein neural cell adhesion molecule (PSA-NCAM) is overexpressed in human GBM and is considered as an adverse prognostic factor for GBM patients.	('N', 'Chemical', 'MESH:D009584', (92, 93))	('overexpressed', 'PosReg', (101, 114))	('PSA-NCAM', 'Gene', (88, 96))	('human', 'Species', '9606', (118, 123))	('polysialylated', 'Var', (4, 18))	('patients', 'Species', '9606', (186, 194))
60358	24911215	Knock down of Beclin1 or ATG5 significantly suppressed drug combination lethality.	('Beclin1', 'Gene', '8678', (14, 21))	('suppressed', 'NegReg', (44, 54))	('s', 'Chemical', 'MESH:D013455', (51, 52))	('drug', 'CPA', (55, 59))	('ATG5', 'Gene', (25, 29))	('Beclin1', 'Gene', (14, 21))	('s', 'Chemical', 'MESH:D013455', (50, 51))	('s', 'Chemical', 'MESH:D013455', (44, 45))	('s', 'Chemical', 'MESH:D013455', (30, 31))	('Knock down', 'Var', (0, 10))	('ATG5', 'Gene', '9474', (25, 29))
60365	24911215	In some tumor cells mutant activated forms of ERBB1 are expressed, notably in lung cancer and in glioblastoma.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('s', 'Chemical', 'MESH:D013455', (3, 4))	('lung cancer', 'Disease', (78, 89))	('s', 'Chemical', 'MESH:D013455', (18, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('ERBB1', 'Gene', (46, 51))	('s', 'Chemical', 'MESH:D013455', (41, 42))	('s', 'Chemical', 'MESH:D013455', (104, 105))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('ERBB1', 'Gene', '1956', (46, 51))	('tumor', 'Disease', (8, 13))	('glioblastoma', 'Disease', (97, 109))	('mutant', 'Var', (20, 26))	('s', 'Chemical', 'MESH:D013455', (62, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (97, 109))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('s', 'Chemical', 'MESH:D013455', (61, 62))
60440	24911215	Lapatinib is an inhibitor of ERBB1, ERBB2 and ERBB4, and knock down of ERBB1, and to a greater extent ERBB1/3/4, enhanced sorafenib lethality, at doses as low as 2 muM, in GBM12 cells (Figure 1E).	('ERBB2', 'Gene', '2064', (36, 41))	('s', 'Chemical', 'MESH:D013455', (148, 149))	('ERBB4', 'Gene', '2066', (46, 51))	('s', 'Chemical', 'MESH:D013455', (122, 123))	('ERBB4', 'Gene', (46, 51))	('s', 'Chemical', 'MESH:D013455', (11, 12))	('ERBB1/3/4', 'Gene', (102, 111))	('s', 'Chemical', 'MESH:D013455', (153, 154))	('sorafenib', 'Chemical', 'MESH:D000077157', (122, 131))	('ERBB1', 'Gene', (71, 76))	('ERBB1', 'Gene', (102, 107))	('s', 'Chemical', 'MESH:D013455', (160, 161))	('s', 'Chemical', 'MESH:D013455', (150, 151))	('Lapatinib', 'Chemical', 'MESH:D000077341', (0, 9))	('s', 'Chemical', 'MESH:D013455', (182, 183))	('muM', 'Gene', '56925', (164, 167))	('ERBB1', 'Gene', '1956', (71, 76))	('ERBB1', 'Gene', '1956', (102, 107))	('ERBB1', 'Gene', (29, 34))	('ERBB2', 'Gene', (36, 41))	('ERBB1/3/4', 'Gene', '1956;2065;2066', (102, 111))	('muM', 'Gene', (164, 167))	('knock down', 'Var', (57, 67))	('ERBB1', 'Gene', '1956', (29, 34))	('enhanced', 'PosReg', (113, 121))
60443	24911215	Knock down of the PDGFRbeta enhanced lapatinib lethality in GBM12 cells at lapatinib concentrations as low as 0.5 muM (Figure 1F).	('PDGFRbeta', 'Gene', (18, 27))	('s', 'Chemical', 'MESH:D013455', (70, 71))	('s', 'Chemical', 'MESH:D013455', (108, 109))	('enhanced', 'PosReg', (28, 36))	('s', 'Chemical', 'MESH:D013455', (101, 102))	('muM', 'Gene', '56925', (114, 117))	('rat', 'Species', '10116', (92, 95))	('s', 'Chemical', 'MESH:D013455', (98, 99))	('lapatinib lethality', 'MPA', (37, 56))	('lapatinib', 'Chemical', 'MESH:D000077341', (37, 46))	('muM', 'Gene', (114, 117))	('lapatinib', 'Chemical', 'MESH:D000077341', (75, 84))	('Knock down', 'Var', (0, 10))	('PDGFRbeta', 'Gene', '5159', (18, 27))
60444	24911215	Knock down of the PDGFRalpha enhanced lapatinib lethality in GBM5 cells (Figure 1G).	('enhanced', 'PosReg', (29, 37))	('lapatinib', 'Chemical', 'MESH:D000077341', (38, 47))	('s', 'Chemical', 'MESH:D013455', (70, 71))	('PDGFRalpha', 'Gene', '5156', (18, 28))	('PDGFRalpha', 'Gene', (18, 28))	('Knock down', 'Var', (0, 10))	('lapatinib lethality', 'MPA', (38, 57))
60449	24911215	Lapatinib and sorafenib also interacted to kill multiple other tumor cell types (hepatoma; renal; pancreatic), including breast cancer cells made anoikis resistant or resistant to lapatinib as a single agent (Figures 3A-3C).	('pancreatic', 'Disease', 'MESH:D010195', (98, 108))	('s', 'Chemical', 'MESH:D013455', (139, 140))	('lapatinib', 'Chemical', 'MESH:D000077341', (180, 189))	('s', 'Chemical', 'MESH:D013455', (156, 157))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('s', 'Chemical', 'MESH:D013455', (169, 170))	('pancreatic', 'Disease', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('hepatoma', 'Disease', 'MESH:D006528', (81, 89))	('tumor', 'Disease', (63, 68))	('interacted', 'Var', (29, 39))	('s', 'Chemical', 'MESH:D013455', (191, 192))	('s', 'Chemical', 'MESH:D013455', (152, 153))	('s', 'Chemical', 'MESH:D013455', (78, 79))	('s', 'Chemical', 'MESH:D013455', (215, 216))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('s', 'Chemical', 'MESH:D013455', (158, 159))	('Lapatinib', 'Chemical', 'MESH:D000077341', (0, 9))	('s', 'Chemical', 'MESH:D013455', (14, 15))	('s', 'Chemical', 'MESH:D013455', (125, 126))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('hepatoma', 'Disease', (81, 89))	('breast cancer', 'Disease', (121, 134))	('s', 'Chemical', 'MESH:D013455', (171, 172))	('s', 'Chemical', 'MESH:D013455', (195, 196))	('sorafenib', 'Chemical', 'MESH:D000077157', (14, 23))
60459	24911215	Knock down of Beclin1 or ATG5 suppressed the lethal effect of [sorafenib + lapatinib] treatment (Figures 5D and 5E).	('Beclin1', 'Gene', '8678', (14, 21))	('s', 'Chemical', 'MESH:D013455', (63, 64))	('ATG5', 'Gene', '9474', (25, 29))	('sorafenib', 'Chemical', 'MESH:D000077157', (63, 72))	('s', 'Chemical', 'MESH:D013455', (103, 104))	('suppressed', 'NegReg', (30, 40))	('ATG5', 'Gene', (25, 29))	('Beclin1', 'Gene', (14, 21))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('s', 'Chemical', 'MESH:D013455', (37, 38))	('s', 'Chemical', 'MESH:D013455', (30, 31))	('lethal effect of', 'MPA', (45, 61))	('Knock down', 'Var', (0, 10))	('lapatinib', 'Chemical', 'MESH:D000077341', (75, 84))
60464	24911215	Knock down of BAX+BAK but not of NOXA+PUMA significantly reduced killing by sorafenib and lapatinib treatment (Figure 6C).	('s', 'Chemical', 'MESH:D013455', (76, 77))	('killing', 'MPA', (65, 72))	('sorafenib', 'Chemical', 'MESH:D000077157', (76, 85))	('NOXA', 'Chemical', 'MESH:C008586', (33, 37))	('lapatinib', 'Chemical', 'MESH:D000077341', (90, 99))	('BAX', 'Gene', (14, 17))	('BAX', 'Gene', '581', (14, 17))	('s', 'Chemical', 'MESH:D013455', (43, 44))	('reduced', 'NegReg', (57, 64))	('Knock down', 'Var', (0, 10))	('BAK', 'Chemical', '-', (18, 21))
60466	24911215	Knock down of CD95 death receptor expression or knock down of the linker protein FADD expression reduced [lapatinib + sorafenib] toxicity (Figure 6D).	('toxicity', 'Disease', (129, 137))	('FADD', 'Gene', (81, 85))	('FADD', 'Gene', '8772', (81, 85))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))	('sorafenib', 'Chemical', 'MESH:D000077157', (118, 127))	('reduced', 'NegReg', (97, 104))	('CD95', 'Gene', (14, 18))	('lapatinib', 'Chemical', 'MESH:D000077341', (106, 115))	('knock down', 'Var', (48, 58))	('CD95', 'Gene', '355', (14, 18))
60474	24911215	Inhibition of the JNK pathway protected cells from drug combination toxicity (Figure 6H).	('toxicity', 'Disease', (68, 76))	('JNK', 'Gene', '5599', (18, 21))	('s', 'Chemical', 'MESH:D013455', (44, 45))	('Inhibition', 'Var', (0, 10))	('JNK', 'Gene', (18, 21))	('toxicity', 'Disease', 'MESH:D064420', (68, 76))
60475	24911215	Inhibition of JNK signaling blocked drug-induced activation of BAX; knock down of CD95 reduced JNK activation (Figure 6I).	('JNK', 'Gene', (14, 17))	('s', 'Chemical', 'MESH:D013455', (18, 19))	('JNK', 'Gene', '5599', (14, 17))	('reduced', 'NegReg', (87, 94))	('BAX', 'Gene', (63, 66))	('JNK', 'Gene', (95, 98))	('CD95', 'Gene', (82, 86))	('BAX', 'Gene', '581', (63, 66))	('knock down', 'Var', (68, 78))	('JNK', 'Gene', '5599', (95, 98))	('CD95', 'Gene', '355', (82, 86))
60481	24911215	For example, Akhavan et al recently showed that de-repression of PDGFRbeta, predominantly due to ERK1/2 activity, promotes resistance to ERBB1 inhibitors in glioblastoma.	('glioblastoma', 'Disease', (157, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('s', 'Chemical', 'MESH:D013455', (36, 37))	('de-repression', 'Var', (48, 61))	('PDGFRbeta', 'Gene', (65, 74))	('s', 'Chemical', 'MESH:D013455', (121, 122))	('ERK1/2', 'Gene', (97, 103))	('Akhavan', 'Disease', 'None', (13, 20))	('ERBB1', 'Gene', (137, 142))	('ERK1/2', 'Gene', '5595;5594', (97, 103))	('PDGFRbeta', 'Gene', '5159', (65, 74))	('s', 'Chemical', 'MESH:D013455', (57, 58))	('promotes', 'PosReg', (114, 122))	('s', 'Chemical', 'MESH:D013455', (56, 57))	('s', 'Chemical', 'MESH:D013455', (152, 153))	('ERBB1', 'Gene', '1956', (137, 142))	('s', 'Chemical', 'MESH:D013455', (127, 128))	('s', 'Chemical', 'MESH:D013455', (125, 126))	('Akhavan', 'Disease', (13, 20))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('s', 'Chemical', 'MESH:D013455', (164, 165))
60482	24911215	Since sorafenib is a potent PDGFRalpha/beta inhibitor; has the ability to down-regulate MCL-1 expression and can suppress signaling through the ERK1/2 pathway, a logical hypothesis would be that sorafenib could enhance lapatinib toxicity; (3) as best described in lung cancer, ERBB receptors can undergo secondary mutations in the presence of ERBB inhibitors rendering them inhibitor resistant.	('sorafenib', 'Chemical', 'MESH:D000077157', (6, 15))	('signaling', 'MPA', (122, 131))	('s', 'Chemical', 'MESH:D013455', (100, 101))	('s', 'Chemical', 'MESH:D013455', (386, 387))	('suppress', 'NegReg', (113, 121))	('s', 'Chemical', 'MESH:D013455', (304, 305))	('MCL-1', 'Gene', (88, 93))	('toxicity', 'Disease', 'MESH:D064420', (229, 237))	('s', 'Chemical', 'MESH:D013455', (290, 291))	('s', 'Chemical', 'MESH:D013455', (99, 100))	('s', 'Chemical', 'MESH:D013455', (122, 123))	('ERK1/2', 'Gene', (144, 150))	('inhibitor resistant', 'MPA', (374, 393))	('sorafenib', 'Chemical', 'MESH:D000077157', (195, 204))	('ERK1/2', 'Gene', '5595;5594', (144, 150))	('lapatinib', 'Chemical', 'MESH:D000077341', (219, 228))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('s', 'Chemical', 'MESH:D013455', (248, 249))	('PDGFRalpha', 'Gene', (28, 38))	('ERBB', 'Gene', (343, 347))	('s', 'Chemical', 'MESH:D013455', (177, 178))	('s', 'Chemical', 'MESH:D013455', (57, 58))	('ERBB', 'Gene', '1956', (343, 347))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('s', 'Chemical', 'MESH:D013455', (120, 121))	('toxicity', 'Disease', (229, 237))	('s', 'Chemical', 'MESH:D013455', (113, 114))	('enhance', 'PosReg', (211, 218))	('s', 'Chemical', 'MESH:D013455', (17, 18))	('down-regulate', 'NegReg', (74, 87))	('s', 'Chemical', 'MESH:D013455', (334, 335))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('s', 'Chemical', 'MESH:D013455', (253, 254))	('s', 'Chemical', 'MESH:D013455', (119, 120))	('s', 'Chemical', 'MESH:D013455', (6, 7))	('PDGFRalpha', 'Gene', '5156', (28, 38))	('s', 'Chemical', 'MESH:D013455', (357, 358))	('s', 'Chemical', 'MESH:D013455', (388, 389))	('s', 'Chemical', 'MESH:D013455', (244, 245))	('mutations', 'Var', (314, 323))	('ERBB', 'Gene', (277, 281))	('MCL-1', 'Gene', '4170', (88, 93))	('lung cancer', 'Disease', (264, 275))	('s', 'Chemical', 'MESH:D013455', (322, 323))	('ERBB', 'Gene', '1956', (277, 281))	('s', 'Chemical', 'MESH:D013455', (179, 180))	('s', 'Chemical', 'MESH:D013455', (195, 196))
60483	24911215	In addition to receptor effects, Fenton et al suggested that acquired resistance to ERBB1 inhibitors in glioblastoma is mediated by phosphorylation of PTEN at tyrosine 240 which leads to loss of PTEN function, through loss of membrane interaction, and consequent activation of PI3K/AKT pathway; (4) by the sustained up-regulation of pro-survival proteins such as BCL-XL and MCL-1; these proteins are independently targets of sorafenib and lapatinib.	('s', 'Chemical', 'MESH:D013455', (394, 395))	('s', 'Chemical', 'MESH:D013455', (337, 338))	('tyrosine 240', 'Var', (159, 171))	('s', 'Chemical', 'MESH:D013455', (220, 221))	('loss', 'NegReg', (187, 191))	('s', 'Chemical', 'MESH:D013455', (361, 362))	('s', 'Chemical', 'MESH:D013455', (163, 164))	('s', 'Chemical', 'MESH:D013455', (306, 307))	('s', 'Chemical', 'MESH:D013455', (74, 75))	('s', 'Chemical', 'MESH:D013455', (384, 385))	('function', 'MPA', (200, 208))	('PTEN', 'Gene', (195, 199))	('s', 'Chemical', 'MESH:D013455', (99, 100))	('sorafenib', 'Chemical', 'MESH:D000077157', (425, 434))	('s', 'Chemical', 'MESH:D013455', (353, 354))	('MCL-1', 'Gene', (374, 379))	('activation', 'PosReg', (263, 273))	('s', 'Chemical', 'MESH:D013455', (51, 52))	('membrane interaction', 'MPA', (226, 246))	('loss', 'NegReg', (218, 222))	('glioblastoma', 'Disease', 'MESH:D005909', (104, 116))	('lapatinib', 'Chemical', 'MESH:D000077341', (439, 448))	('PTEN', 'Gene', '5728', (195, 199))	('s', 'Chemical', 'MESH:D013455', (255, 256))	('s', 'Chemical', 'MESH:D013455', (111, 112))	('up-regulation', 'PosReg', (316, 329))	('BCL-XL', 'Gene', (363, 369))	('s', 'Chemical', 'MESH:D013455', (135, 136))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('PI3', 'Gene', '5266', (277, 280))	('s', 'Chemical', 'MESH:D013455', (190, 191))	('s', 'Chemical', 'MESH:D013455', (221, 222))	('AKT', 'Gene', (282, 285))	('s', 'Chemical', 'MESH:D013455', (420, 421))	('glioblastoma', 'Disease', (104, 116))	('s', 'Chemical', 'MESH:D013455', (308, 309))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('PTEN', 'Gene', (151, 155))	('s', 'Chemical', 'MESH:D013455', (189, 190))	('s', 'Chemical', 'MESH:D013455', (182, 183))	('tyrosine', 'Chemical', 'MESH:D014443', (159, 167))	('ERBB1', 'Gene', (84, 89))	('s', 'Chemical', 'MESH:D013455', (355, 356))	('s', 'Chemical', 'MESH:D013455', (118, 119))	('PI3', 'Gene', (277, 280))	('s', 'Chemical', 'MESH:D013455', (46, 47))	('s', 'Chemical', 'MESH:D013455', (30, 31))	('BCL-XL', 'Gene', '598', (363, 369))	('ERBB1', 'Gene', '1956', (84, 89))	('s', 'Chemical', 'MESH:D013455', (425, 426))	('MCL-1', 'Gene', '4170', (374, 379))	('AKT', 'Gene', '207', (282, 285))	('PTEN', 'Gene', '5728', (151, 155))
60490	24911215	Elevated levels of NOXA, a toxic BCL-2 family member was observed, as was activation of BAX, and knock down of (BAX+BAK), but surprisingly not (NOXA+PUMA), was protective.	('knock down', 'Var', (97, 107))	('s', 'Chemical', 'MESH:D013455', (132, 133))	('BAK', 'Chemical', '-', (116, 119))	('BCL-2', 'Gene', '596', (33, 38))	('s', 'Chemical', 'MESH:D013455', (68, 69))	('BAX', 'Gene', (88, 91))	('BCL-2', 'Gene', (33, 38))	('BAX', 'Gene', (112, 115))	('BAX', 'Gene', '581', (88, 91))	('BAX', 'Gene', '581', (112, 115))	('activation', 'PosReg', (74, 84))	('s', 'Chemical', 'MESH:D013455', (72, 73))	('NOXA', 'Chemical', 'MESH:C008586', (19, 23))	('s', 'Chemical', 'MESH:D013455', (126, 127))	('s', 'Chemical', 'MESH:D013455', (158, 159))	('s', 'Chemical', 'MESH:D013455', (14, 15))	('s', 'Chemical', 'MESH:D013455', (55, 56))	('NOXA', 'Chemical', 'MESH:C008586', (144, 148))	('s', 'Chemical', 'MESH:D013455', (59, 60))
60492	24911215	Knock down of the death receptor CD95 or of the docking protein FADD reduced cell killing.	('CD95', 'Gene', (33, 37))	('cell killing', 'CPA', (77, 89))	('reduced', 'NegReg', (69, 76))	('CD95', 'Gene', '355', (33, 37))	('Knock down', 'Var', (0, 10))	('FADD', 'Gene', (64, 68))	('FADD', 'Gene', '8772', (64, 68))
60495	24911215	Thus in addition to apoptosis, the induction of autophagy was also investigated through use of LC3-GFP vesicle formation, western blots analyses and knock down of ATG5 and Beclin 1.	('s', 'Chemical', 'MESH:D013455', (124, 125))	('ATG5', 'Gene', (163, 167))	('s', 'Chemical', 'MESH:D013455', (60, 61))	('s', 'Chemical', 'MESH:D013455', (3, 4))	('knock down', 'Var', (149, 159))	('LC3', 'Gene', '84557', (95, 98))	('s', 'Chemical', 'MESH:D013455', (105, 106))	('s', 'Chemical', 'MESH:D013455', (26, 27))	('s', 'Chemical', 'MESH:D013455', (89, 90))	('s', 'Chemical', 'MESH:D013455', (71, 72))	('s', 'Chemical', 'MESH:D013455', (64, 65))	('s', 'Chemical', 'MESH:D013455', (134, 135))	('s', 'Chemical', 'MESH:D013455', (143, 144))	('Beclin 1', 'Gene', (172, 180))	('s', 'Chemical', 'MESH:D013455', (141, 142))	('Beclin 1', 'Gene', '8678', (172, 180))	('ATG5', 'Gene', '9474', (163, 167))	('s', 'Chemical', 'MESH:D013455', (28, 29))	('LC3', 'Gene', (95, 98))
60500	24911215	In order to determine the role of autophagy in drug-mediated cell death, ATG5 and Beclin 1 were knocked down individually and inhibition of autophagy reduced drug combination-induced cell death.	('Beclin 1', 'Gene', '8678', (82, 90))	('ATG5', 'Gene', '9474', (73, 77))	('inhibition', 'Var', (126, 136))	('ATG5', 'Gene', (73, 77))	('reduced', 'NegReg', (150, 157))	('Beclin 1', 'Gene', (82, 90))	('knocked', 'Var', (96, 103))	('autophagy', 'CPA', (140, 149))	('reduced drug combination', 'Phenotype', 'HP:0020173', (150, 174))
60517	24911215	We presented data showing that knock down of the PDGFR significantly enhanced lapatinib toxicity in two isolates.	('s', 'Chemical', 'MESH:D013455', (18, 19))	('knock down', 'Var', (31, 41))	('s', 'Chemical', 'MESH:D013455', (111, 112))	('PDGFR', 'Gene', '5159', (49, 54))	('s', 'Chemical', 'MESH:D013455', (55, 56))	('enhanced', 'PosReg', (69, 77))	('lapatinib', 'Chemical', 'MESH:D000077341', (78, 87))	('s', 'Chemical', 'MESH:D013455', (105, 106))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))	('toxicity', 'Disease', (88, 96))	('PDGFR', 'Gene', (49, 54))	('s', 'Chemical', 'MESH:D013455', (6, 7))
60521	24911215	Inhibition of autophagy reduced combination-mediated cell death suggesting killing can proceed either through cytotoxic autophagy or activation of caspase-dependent pathways.	('autophagy', 'CPA', (14, 23))	('s', 'Chemical', 'MESH:D013455', (172, 173))	('caspase', 'Gene', '841;842', (147, 154))	('s', 'Chemical', 'MESH:D013455', (149, 150))	('s', 'Chemical', 'MESH:D013455', (69, 70))	('combination-mediated cell death', 'CPA', (32, 63))	('s', 'Chemical', 'MESH:D013455', (152, 153))	('caspase', 'Gene', (147, 154))	('Inhibition', 'Var', (0, 10))	('s', 'Chemical', 'MESH:D013455', (64, 65))
60524	23796560	Although the TIC hypothesis remains controversial and the functional assays to define the TIC phenotype are evolving, we and others have demonstrated that TICs may contribute to therapeutic resistance, tumor spread, and angiogenesis.	('TICs', 'Var', (155, 159))	('tumor', 'Disease', (202, 207))	('TIC', 'Phenotype', 'HP:0100033', (155, 158))	('TIC', 'Phenotype', 'HP:0100033', (90, 93))	('contribute', 'Reg', (164, 174))	('angiogenesis', 'CPA', (220, 232))	('TICs', 'Phenotype', 'HP:0100033', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('TIC', 'Phenotype', 'HP:0100033', (13, 16))	('therapeutic resistance', 'CPA', (178, 200))
60532	23796560	We and others have shown that TICs are relatively resistant to conventional cancer therapies (radiotherapy and chemotherapy) and promote tumor growth through angiogenesis.	('tumor', 'Disease', (137, 142))	('promote', 'PosReg', (129, 136))	('TICs', 'Phenotype', 'HP:0100033', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('angiogenesis', 'CPA', (158, 170))	('TICs', 'Var', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('TIC', 'Phenotype', 'HP:0100033', (30, 33))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
60587	23796560	The aptamerhigh cells displayed substantially greater tumor volumes than the aptamerlow cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('aptamerhigh', 'Var', (4, 15))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('greater', 'PosReg', (46, 53))
60588	23796560	These differences translated into survival differences as the survival of mice injected with either A3 or A4 aptamerhigh cells was significantly reduced with decreased mean survival (Fig.	('reduced', 'NegReg', (145, 152))	('decreased', 'NegReg', (158, 167))	('A4 aptamerhigh cells', 'Var', (106, 126))	('survival', 'CPA', (62, 70))	('mice', 'Species', '10090', (74, 78))
60589	23796560	All mice injected with the lower number of aptamerhigh cells (300) developed tumors, whereas 3 of 4 tumors developed with A3 aptamerlow cells and only 2 of 4 tumors developed with A4 aptamerlow cells (Fig.	('tumors', 'Disease', (158, 164))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mice', 'Species', '10090', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('A3 aptamerlow cells', 'Var', (122, 141))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
60612	23796560	Neutralizing antibodies against CCL2 have also demonstrated efficacy in xenografts models as an anti-glioma therapy.	('CCL2', 'Gene', '6347', (32, 36))	('glioma', 'Disease', (101, 107))	('CCL2', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('Neutralizing antibodies', 'Var', (0, 23))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
60616	23796560	Thus, our molecular analysis suggests TICs identified with specific aptamers have gene expression profiles which could promote tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('aptamers', 'Var', (68, 76))	('tumor', 'Disease', (127, 132))	('TICs', 'Phenotype', 'HP:0100033', (38, 42))	('promote', 'PosReg', (119, 126))	('TIC', 'Phenotype', 'HP:0100033', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
60624	23762372	TP53 and IDH1 mutations, CDKN2A deletion, EGFR amplification, chromosome 7 polysomy and EGFRvIII expression) could be associated with distinct prognosis and/or response to the therapy.	('deletion', 'Var', (32, 40))	('EGFR', 'Gene', '1956', (42, 46))	('TP53', 'Gene', (0, 4))	('CDKN2A', 'Gene', (25, 31))	('IDH1', 'Gene', (9, 13))	('TP53', 'Gene', '7157', (0, 4))	('CDKN2A', 'Gene', '1029', (25, 31))	('EGFR', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (9, 13))	('EGFR', 'Gene', '1956', (88, 92))	('associated', 'Reg', (118, 128))	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', (88, 92))
60625	23762372	Moreover, we describe a method which allows for a reliable, as well as time- and cost-effective, screening for EGFR amplification and chromosome 7 polysomy with quantitative Real-Time PCR at DNA level.	('EGFR', 'Gene', '1956', (111, 115))	('EGFR', 'Gene', (111, 115))	('polysomy', 'Var', (147, 155))	('amplification', 'Var', (116, 129))
60628	23762372	Intriguingly, EGFR amplification was associated with a worse outcome in younger patients (HR = 3.75; p<0.01) and in patients treated with radiotherapy (HR = 2.71; p = 0.03).	('EGFR', 'Gene', '1956', (14, 18))	('patients', 'Species', '9606', (80, 88))	('EGFR', 'Gene', (14, 18))	('amplification', 'Var', (19, 32))	('patients', 'Species', '9606', (116, 124))
60630	23762372	Next, EGFR amplification was related to a better prognosis in combination with the homozygous CDKN2A deletion (HR = 0.12; p = 0.01), but to a poorer prognosis in combination with chromosome 7 polysomy (HR = 14.88; p = 0.01).	('CDKN2A', 'Gene', '1029', (94, 100))	('EGFR', 'Gene', (6, 10))	('amplification', 'Var', (11, 24))	('CDKN2A', 'Gene', (94, 100))	('EGFR', 'Gene', '1956', (6, 10))
60642	23762372	TP53 and IDH1 mutations, CDKN2A deletion, EGFR amplification, chromosome 7 polysomy and EGFRvIII expression) in patients treated with a neurosurgical operation and with or without the following therapy (radiotherapy or radio-chemotherapy).	('deletion', 'Var', (32, 40))	('EGFR', 'Gene', '1956', (42, 46))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (0, 4))	('IDH1', 'Gene', (9, 13))	('CDKN2A', 'Gene', '1029', (25, 31))	('EGFR', 'Gene', (42, 46))	('IDH1', 'Gene', '3417', (9, 13))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', '1956', (88, 92))	('CDKN2A', 'Gene', (25, 31))	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', (88, 92))
60663	23762372	The results were interpreted in the following manner: the ratio of EGFR to RNaseP between 1.5 and 5 was considered as resulting from the polysomy, while the ratio of EGFR to RNaseP higher than 5 was considered as resulting from the amplification.	('resulting', 'Reg', (118, 127))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('polysomy', 'Var', (137, 145))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
60664	23762372	In brief, a commercial probe set (Vysis LSI EGFR SpectrumOrange/CEP 7 SpectrumGreen; Abbott Molecular, US) was used to simultaneously detect the copy numbers of the EGFR gene and of chromosome 7.	('EGFR', 'Gene', (165, 169))	('copy numbers', 'Var', (145, 157))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (165, 169))
60678	23762372	To determine the CDKN2A exon 1 and/or exon 2 deletions quantitative Real-Time PCR reactions were performed as described above.	('CDKN2A', 'Gene', '1029', (17, 23))	('CDKN2A', 'Gene', (17, 23))	('deletions', 'Var', (45, 54))
60679	23762372	CDKN2A exon 1 and/or exon 2 deletion was confirmed by agarose gel electrophoresis using BioRad Quantity One 1-D Analysis Software.	('deletion', 'Var', (28, 36))	('CDKN2A', 'Gene', '1029', (0, 6))	('agarose', 'Chemical', 'MESH:D012685', (54, 61))	('CDKN2A', 'Gene', (0, 6))
60692	23762372	We observed the analysed alterations with the following frequencies: TP53 mutation in 22% (17/79); EGFR amplification in 27% (22/82); chromosome 7 polysomy in 27% (21/79); CDKN2A deletion in 50% (40/80); EGFRvIII expression in 18% (14/80) and IDH1 mutation in 3.9% (3/77).	('EGFR', 'Gene', (99, 103))	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('IDH1', 'Gene', (243, 247))	('EGFR', 'Gene', '1956', (204, 208))	('mutation', 'Var', (248, 256))	('deletion', 'Var', (179, 187))	('IDH1', 'Gene', '3417', (243, 247))	('CDKN2A', 'Gene', (172, 178))	('EGFR', 'Gene', '1956', (99, 103))	('polysomy', 'Var', (147, 155))	('CDKN2A', 'Gene', '1029', (172, 178))	('EGFR', 'Gene', (204, 208))
60693	23762372	We did not observe any difference in the overall survival between the patients with and without TP53 mutations in the direct analysis.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', (96, 100))
60699	23762372	Intriguingly, EGFR amplification appeared to have an opposite effect on survival in both groups.	('amplification', 'Var', (19, 32))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))
60701	23762372	Multivariate analysis confirmed the significance of EGFR amplification only in younger patients (HR = 3.75, p = 0.01) (Table 1, Fig.	('EGFR', 'Gene', (52, 56))	('patients', 'Species', '9606', (87, 95))	('amplification', 'Var', (57, 70))	('EGFR', 'Gene', '1956', (52, 56))
60702	23762372	As mentioned before, homozygous deletions of CDKN2A were suspected to be related with a longer survival.	('CDKN2A', 'Gene', (45, 51))	('homozygous deletions', 'Var', (21, 41))	('CDKN2A', 'Gene', '1029', (45, 51))	('related', 'Reg', (73, 80))
60703	23762372	Thus, it was intriguing to observe that such deletions were associated with an enhanced outcome in patients with EGFR amplification (HR = 0.12; p = 0.01)(Fig.	('amplification', 'Var', (118, 131))	('enhanced', 'PosReg', (79, 87))	('patients', 'Species', '9606', (99, 107))	('deletions', 'Var', (45, 54))	('EGFR', 'Gene', '1956', (113, 117))	('outcome', 'MPA', (88, 95))	('EGFR', 'Gene', (113, 117))
60707	23762372	In patients who did not receive radiotherapy the EGFR amplification did not influence the survival (p = 0.50), while in patients who were treated with radiotherapy it was related to an impaired survival (HR = 2.71; p = 0.03) (Fig.	('EGFR', 'Gene', '1956', (49, 53))	('amplification', 'Var', (54, 67))	('EGFR', 'Gene', (49, 53))	('survival', 'MPA', (194, 202))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (120, 128))	('impaired', 'NegReg', (185, 193))
60708	23762372	Intriguingly, we did not observe any differences between the patients with EGFR amplification treated with radiotherapy and the patients who had not received radiotherapy (irrespective of the EGFR status) (p = 0.20) (Fig.	('amplification', 'Var', (80, 93))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (75, 79))	('patients', 'Species', '9606', (128, 136))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (75, 79))	('EGFR', 'Gene', (192, 196))
60714	23762372	Until now, such an approach for the detection and discrimination between the EGFR amplification and chromosome 7 polysomy with Real-Time PCR at the DNA level was not described.	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('amplification', 'Var', (82, 95))
60718	23762372	In the analysed group, the frequency of IDH1 mutation was in accordance with the analysis by Nobusawa et al.	('mutation', 'Var', (45, 53))	('IDH1', 'Gene', '3417', (40, 44))	('IDH1', 'Gene', (40, 44))
60719	23762372	The analysed group was characterised by an overrepresentation of CDKN2A deletions (50% vs. 31%) in comparison to the analysis by Ohgaki et al.	('overrepresentation', 'PosReg', (43, 61))	('CDKN2A', 'Gene', (65, 71))	('CDKN2A', 'Gene', '1029', (65, 71))	('deletions', 'Var', (72, 81))
60720	23762372	The frequency of TP53 mutation was 23% (vs. 28%), of EGFR amplification 27% (vs. 36%); of EGFRvIII expression 18% (vs. 27% or 31%) and of chromosome 7 polysomy was 27% (vs. 39%).	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (17, 21))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('amplification', 'Var', (58, 71))	('TP53', 'Gene', (17, 21))
60723	23762372	To date, EGFRvIII expression has been associated either with poorer prognosis of glioblastoma (in combination with the amplification) or, most commonly, no association has been observed.	('glioblastoma', 'Disease', (81, 93))	('associated', 'Reg', (38, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('expression', 'Var', (18, 28))
60725	23762372	has shown an association of the EGFRvIII expression with a more favourable prognosis of glioblastoma, which the results presented here support.	('glioblastoma', 'Disease', (88, 100))	('association', 'Interaction', (13, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))	('expression', 'Var', (41, 51))
60726	23762372	The possible prognostic value of EGFR amplification and overexpression has been intensively analysed, in most cases without any significant correlation with the clinical outcome observed.	('amplification', 'Var', (38, 51))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
60729	23762372	suggested that EGFR amplification was associated with poorer prognosis in the entire cohort with an emphasis on younger patients.	('amplification', 'Var', (20, 33))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))
60731	23762372	Our data suggest that EGFR amplification may be related to a worse prognosis in younger patients and in patients treated with radiotherapy, while improving the prognosis in older patients.	('amplification', 'Var', (27, 40))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', '1956', (22, 26))	('patients', 'Species', '9606', (179, 187))	('improving', 'PosReg', (146, 155))	('patients', 'Species', '9606', (104, 112))	('EGFR', 'Gene', (22, 26))
60732	23762372	The analyses of the cumulative group (younger or treated with radiotherapy) and of only younger patients treated with radiotherapy may imply that EGFR amplification may be a negative prognostic factor for patients whose survival is not limited by their overall clinical condition.	('patients', 'Species', '9606', (205, 213))	('EGFR', 'Gene', '1956', (146, 150))	('negative', 'NegReg', (174, 182))	('EGFR', 'Gene', (146, 150))	('patients', 'Species', '9606', (96, 104))	('amplification', 'Var', (151, 164))
60734	23762372	An association between EGFR amplification and the effectiveness of the radiotherapy requires a thorough verification, the more so that it may potentially affect the selection of treatment in future.	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('affect', 'Reg', (154, 160))	('amplification', 'Var', (28, 41))
60737	23762372	Our data suggest that the combination of EGFR amplification and polysomy may be correlated with poor prognosis, which requires further verification.	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', (41, 45))	('polysomy', 'Var', (64, 72))	('amplification', 'Var', (46, 59))
60740	23762372	Homozygous deletion of CDKN2A was associated with an improved outcome in patients with the EGFR amplification, but not in patients without this alteration.	('amplification', 'Var', (96, 109))	('outcome', 'MPA', (62, 69))	('EGFR', 'Gene', (91, 95))	('CDKN2A', 'Gene', (23, 29))	('patients', 'Species', '9606', (122, 130))	('CDKN2A', 'Gene', '1029', (23, 29))	('improved', 'PosReg', (53, 61))	('patients', 'Species', '9606', (73, 81))	('EGFR', 'Gene', '1956', (91, 95))
60741	23762372	The reports analysing TP53 mutations in glioblastoma unanimously recognise its lack of prognostic significance in the general population.	('mutations', 'Var', (27, 36))	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('glioblastoma', 'Disease', (40, 52))
60742	23762372	proposed that simultaneous TP53 mutation and EGFR amplification may be related to a poorer prognosis.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('amplification', 'Var', (50, 63))	('EGFR', 'Gene', (45, 49))	('related', 'Reg', (71, 78))	('mutation', 'Var', (32, 40))	('EGFR', 'Gene', '1956', (45, 49))
60743	23762372	the two cases with the concurrent TP53 mutation and EGFR overexpression were characterised by a relatively long survival.	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('TP53', 'Gene', '7157', (34, 38))
60745	23762372	the TP53 mutation was somewhat related to a shorter survival (not significant) in the group of patients without the EGFR amplification.	('mutation', 'Var', (9, 17))	('survival', 'MPA', (52, 60))	('TP53', 'Gene', (4, 8))	('patients', 'Species', '9606', (95, 103))	('EGFR', 'Gene', '1956', (116, 120))	('shorter', 'NegReg', (44, 51))	('EGFR', 'Gene', (116, 120))	('TP53', 'Gene', '7157', (4, 8))
60746	23762372	A positive prognostic significance of the IDH1 mutation has been suggested by several authors due to its relation to the secondary glioblastoma, which are generally characterised by a more favourable outcome, however, we could not perform any reliable analysis due to the low number of such mutations.	('IDH1', 'Gene', '3417', (42, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('mutation', 'Var', (47, 55))	('IDH1', 'Gene', (42, 46))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
60747	23762372	To conclude, the presented method was efficient and reliable in detection and distinction between EGFR amplification and chromosome 7 polysomy.	('EGFR', 'Gene', (98, 102))	('amplification', 'Var', (103, 116))	('EGFR', 'Gene', '1956', (98, 102))
60748	23762372	EGFR amplification was identified as a factor significantly limiting the effectiveness of radiotherapy and the survival of younger patients.	('patients', 'Species', '9606', (131, 139))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('limiting', 'NegReg', (60, 68))	('EGFR', 'Gene', '1956', (0, 4))
60749	23762372	Although the presented data are not sufficient to question the indications for radiotherapy for glioblastoma patients with EGFR amplification and require validation in a larger group of patients, they strongly advocate for the consideration of the patient's molecular status in the putative selection of the therapy, especially in the light of the numerous novel therapeutic possibilities being introduced.	('EGFR', 'Gene', (123, 127))	('amplification', 'Var', (128, 141))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (109, 117))	('glioblastoma', 'Disease', (96, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('EGFR', 'Gene', '1956', (123, 127))	('patient', 'Species', '9606', (248, 255))	('patient', 'Species', '9606', (186, 193))	('patients', 'Species', '9606', (186, 194))
60773	33925295	Although the presence of CTC may lead to disease progression, their detection can provide significant biological information regarding tumor burden and can be useful in clinical diagnostic and monitoring approaches, such as in non-invasive liquid biopsies for personalized cancer care.	('lead to', 'Reg', (33, 40))	('disease progression', 'CPA', (41, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('tumor', 'Disease', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('presence', 'Var', (13, 21))	('CTC', 'Gene', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
60797	33925295	molecularly profiled CTC lines established from breast cancer patients and showed that copy-number gain of a mediator of blood-brain barrier transmigration, SEMA4D and overexpression of MYC may be novel markers for brain metastasis.	('MYC', 'Gene', '4609', (186, 189))	('SEMA4D', 'Gene', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('copy-number', 'Var', (87, 98))	('patients', 'Species', '9606', (62, 70))	('SEMA4D', 'Gene', '10507', (157, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('MYC', 'Gene', (186, 189))	('brain metastasis', 'CPA', (215, 231))	('overexpression', 'PosReg', (168, 182))	('gain', 'PosReg', (99, 103))
60807	33925295	Current main approaches to diagnose, prognosticate, identify therapeutic targets within and monitor treatment response/recurrence of CNS tumors using ctDNA include the identification of genomic alterations and epigenetic signatures.	('CNS tumor', 'Phenotype', 'HP:0100006', (133, 142))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('CNS tumors', 'Disease', 'MESH:D016543', (133, 143))	('CNS tumors', 'Disease', (133, 143))	('epigenetic signatures', 'Var', (210, 231))	('genomic alterations', 'Var', (186, 205))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
60812	33925295	ddPCR has been shown to accurately detect alterations of intertest in non-CNS tumor blood/plasma samples including BRAF V600E alterations in melanomas and EGFR mutations in non-small cell lung cancer, both have targeted treatments available.	('mutations', 'Var', (160, 169))	('tumor blood', 'Disease', (78, 89))	('EGFR', 'Gene', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (173, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (177, 199))	('CNS tumor', 'Phenotype', 'HP:0100006', (74, 83))	('CNS tumor', 'Disease', (74, 83))	('EGFR', 'Gene', '1956', (155, 159))	('alterations', 'Var', (42, 53))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('BRAF', 'Gene', '673', (115, 119))	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('BRAF', 'Gene', (115, 119))	('small cell lung cancer', 'Disease', (177, 199))	('small cell lung cancer', 'Disease', 'MESH:D055752', (177, 199))	('melanomas', 'Disease', (141, 150))	('CNS tumor', 'Disease', 'MESH:D016543', (74, 83))	('alterations', 'Var', (126, 137))	('tumor blood', 'Disease', 'MESH:D007022', (78, 89))
60818	33925295	in metastatic malignant melanomas used ddPCR mutation assays to quantify BRAF and NRAS ctDNA alterations present in order to prognosticate 50 patients and predict response to treatment.	('NRAS', 'Gene', '4893', (82, 86))	('BRAF', 'Gene', '673', (73, 77))	('malignant melanomas', 'Phenotype', 'HP:0002861', (14, 33))	('malignant melanomas', 'Disease', 'MESH:D008545', (14, 33))	('alterations', 'Var', (93, 104))	('malignant melanomas', 'Disease', (14, 33))	('NRAS', 'Gene', (82, 86))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('prognosticate', 'Reg', (125, 138))	('BRAF', 'Gene', (73, 77))	('patients', 'Species', '9606', (142, 150))
60822	33925295	examining TERT promoter mutations in plasma samples from 157 adult glioma patients showed a much higher utility of ddPCR to detect these alterations, with a sensitivity of 62.5% and a specificity of 90%.	('glioma', 'Disease', (67, 73))	('patients', 'Species', '9606', (74, 82))	('TERT', 'Gene', (10, 14))	('TERT', 'Gene', '7015', (10, 14))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('mutations', 'Var', (24, 33))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))
60823	33925295	Notably, during longitudinal monitoring of 5 of these patients, those with tumor recurrence had increased mutant allele frequencies compared to those without recurrence suggesting that ddPCR may have a future role for detecting disease progression.	('increased', 'PosReg', (96, 105))	('mutant', 'Var', (106, 112))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
60827	33925295	Methylation signatures identified in tumor samples are highly tissue-specific and useful for CNS tumor diagnosis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('CNS tumor', 'Disease', 'MESH:D016543', (93, 102))	('CNS tumor', 'Phenotype', 'HP:0100006', (93, 102))	('CNS tumor', 'Disease', (93, 102))
60836	33925295	Specific mean AUROCs per tumor type were 0.82 (95% CI = 0.66-0.98) for IDH mutant gliomas, 0.71 (95% CI = 0.53-0.90) for IDH wildtype gliomas, 0.89 (95% CI = 0.8-0.97) for meningiomas, 0.95 (95% CI = 0.73-1.00) for hemangiopericytomas and 0.93 (95% CI = 0.8-1.0) for low grade glioneuronal tumors.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('glioneuronal tumors', 'Disease', 'MESH:D009369', (277, 296))	('meningiomas', 'Phenotype', 'HP:0002858', (172, 183))	('IDH', 'Gene', (121, 124))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('IDH', 'Gene', (71, 74))	('meningiomas', 'Disease', (172, 183))	('glioneuronal tumors', 'Phenotype', 'HP:0025170', (277, 296))	('glioneuronal tumors', 'Disease', (277, 296))	('tumor', 'Disease', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('IDH', 'Gene', '3417', (121, 124))	('gliomas', 'Disease', (82, 89))	('IDH', 'Gene', '3417', (71, 74))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Disease', (25, 30))	('gliomas', 'Disease', (134, 141))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('hemangiopericytomas', 'Disease', 'MESH:D006393', (215, 234))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('hemangiopericytomas', 'Disease', (215, 234))	('mutant', 'Var', (75, 81))	('meningioma', 'Phenotype', 'HP:0002858', (172, 182))	('meningiomas', 'Disease', 'MESH:D008577', (172, 183))
60837	33925295	While this study demonstrated the ability to differentiate IDH mutant from IDH wildtype gliomas, unfortunately further molecular subtyping of diffuse gliomas, including 1p19q codeletion status was not included as independent groups.	('IDH', 'Gene', (59, 62))	('mutant', 'Var', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('IDH', 'Gene', '3417', (59, 62))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('gliomas', 'Disease', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('gliomas', 'Disease', (150, 157))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
60844	33925295	ddPCR has shown high specificity for genomic alterations in CNS tumors and approaches to improve its sensitivity are currently being assessed including approaches to optimize results in plasma samples as well as the utilization of CSF as the ctDNA source.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CNS tumor', 'Phenotype', 'HP:0100006', (60, 69))	('CNS tumors', 'Disease', 'MESH:D016543', (60, 70))	('CNS tumors', 'Disease', (60, 70))	('genomic alterations', 'Var', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
60848	33925295	Thus, deregulation of miRNA expression plays a role in cancer initiation and progression.	('deregulation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('miRNA expression', 'Protein', (22, 38))	('cancer', 'Disease', (55, 61))
60849	33925295	Furthermore, miRNAs can function either as a tumor suppressor or oncogenic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('miRNAs', 'Var', (13, 19))
60850	33925295	Therefore, changes in a single or small subset of miRNAs can modulate several cellular processes and lead to tumorigenesis.	('miRNAs', 'Protein', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('modulate', 'Reg', (61, 69))	('changes', 'Var', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('lead to', 'Reg', (101, 108))
60855	33925295	showed that levels of miR-21 are significantly upregulated, while miR-128 and miR-342-3p are down-regulated, in the serum of patients with GBM patients compared to healthy controls.	('miR-128', 'Var', (66, 73))	('upregulated', 'PosReg', (47, 58))	('miR-21', 'Gene', '406991', (22, 28))	('levels', 'MPA', (12, 18))	('patients', 'Species', '9606', (143, 151))	('miR-21', 'Gene', (22, 28))	('miR-128', 'Chemical', '-', (66, 73))	('miR-342-3p', 'Var', (78, 88))	('down-regulated', 'NegReg', (93, 107))	('patients', 'Species', '9606', (125, 133))
60859	33925295	also observed that the expression of miR-128 and miR-342-3p positively correlated with glioma grade.	('miR-342-3p', 'Var', (49, 59))	('glioma', 'Disease', (87, 93))	('miR-128', 'Chemical', '-', (37, 44))	('correlated', 'Reg', (71, 81))	('miR-128', 'Var', (37, 44))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('expression', 'MPA', (23, 33))
60860	33925295	In addition to gliomas, Zhi and colleagues reported that upregulated serum levels of miR-20a, miR-106a, and miR-181b are associated with advanced clinical stage of astrocytoma.	('miR-106a', 'Gene', '406899', (94, 102))	('astrocytoma', 'Phenotype', 'HP:0009592', (164, 175))	('miR-106a', 'Gene', (94, 102))	('serum levels', 'MPA', (69, 81))	('astrocytoma', 'Disease', 'MESH:D001254', (164, 175))	('miR-20a', 'Gene', '406982', (85, 92))	('gliomas', 'Phenotype', 'HP:0009733', (15, 22))	('gliomas', 'Disease', (15, 22))	('gliomas', 'Disease', 'MESH:D005910', (15, 22))	('miR-181b', 'Var', (108, 116))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('astrocytoma', 'Disease', (164, 175))	('miR-20a', 'Gene', (85, 92))	('upregulated', 'PosReg', (57, 68))
60861	33925295	Another study found that lower serum levels of miR-497 and miR-125b and miR-29, can be used to distinguish high grade from low-grade gliomas.	('serum levels', 'MPA', (31, 43))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('miR-497', 'Gene', (47, 54))	('miR-497', 'Gene', '574456', (47, 54))	('lower', 'NegReg', (25, 30))	('miR-125b', 'Var', (59, 67))	('gliomas', 'Disease', 'MESH:D005910', (133, 140))	('miR-29', 'Var', (72, 78))	('gliomas', 'Phenotype', 'HP:0009733', (133, 140))	('gliomas', 'Disease', (133, 140))	('high grade', 'Disease', (107, 117))
60929	33925295	Lastly, the sensitivity and specificity of exosomal DNA have been found to be greater than for ctDNA in terms of detecting mutational frequency and potentially also in prognosticating patients.	('detecting', 'Reg', (113, 122))	('exosomal DNA', 'Var', (43, 55))	('mutational frequency', 'Var', (123, 143))	('patients', 'Species', '9606', (184, 192))
60933	33925295	They were able to identify the prognostically important mutant IDH1 mRNA in CSF-derived EVs from five of eight patients with IDH1-mutant tumors, but not in their matched serum-derived EVs.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('IDH1', 'Gene', '3417', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutant', 'Var', (56, 62))	('IDH1', 'Gene', '3417', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('IDH1', 'Gene', (63, 67))	('IDH1', 'Gene', (125, 129))	('patients', 'Species', '9606', (111, 119))
60934	33925295	Additionally, they were able to quantify the number of mutant IDH1 transcripts, which directly correlated with tumor burden.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('IDH1', 'Gene', '3417', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutant', 'Var', (55, 61))	('tumor', 'Disease', (111, 116))	('correlated', 'Reg', (95, 105))	('IDH1', 'Gene', (62, 66))
60935	33925295	Up to one-third of all GBMs harbor the epidermal growth factor receptor (EGFR) vIII mutation resulting in a constitutively active EGFR that does not bind its ligand, but rather, promotes tumor proliferation through downstream events.	('EGFR', 'Gene', '1956', (130, 134))	('vIII', 'Gene', '1351', (79, 83))	('EGFR', 'Gene', '1956', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('epidermal growth factor receptor', 'Gene', '1956', (39, 71))	('promotes', 'PosReg', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('constitutively', 'MPA', (108, 122))	('EGFR', 'Gene', (73, 77))	('tumor', 'Disease', (187, 192))	('epidermal growth factor receptor', 'Gene', (39, 71))	('vIII', 'Gene', (79, 83))	('EGFR', 'Gene', (130, 134))	('mutation', 'Var', (84, 92))
60937	33925295	However, this was only seen in five of 14 patients with biopsies positive for the EGFRvIII mutation, suggesting either suboptimal sensitivity of serum EVs and/or sampling error in the original tumor biopsies due to heterogeneity.	('mutation', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('EGFRvIII', 'Gene', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('patients', 'Species', '9606', (42, 50))
60938	33925295	Interestingly, on longitudinal serum analysis in those five patients with the EGFRvIII mutation seen in serum EVs, EGFRvIII was undetectable after tumor resection, again suggesting a role for serum EVs in monitoring treatment outcome and disease burden.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('patients', 'Species', '9606', (60, 68))	('EGFRvIII', 'Gene', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutation', 'Var', (87, 95))
60939	33925295	was also able to detect the EGFRvIII mutation in the EV of 14 of 23 GBM patients, albeit in the CSF this time with 60% sensitivity and 98% specificity, compared to the gold standard qPCR detection in tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('mutation', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('patients', 'Species', '9606', (72, 80))	('tumor', 'Disease', (200, 205))	('detect', 'Reg', (17, 23))	('EGFRvIII', 'Gene', (28, 36))
60940	33925295	The microRNA miR-21 has been implicated in GBM pathogenesis through its effect on a variety of pathways including IGFBP3, RECK and TIMP3 that mediate a number of oncogenic functions such as suppression of apoptosis, growth proliferation, and DNA repair.	('growth proliferation', 'CPA', (216, 236))	('apoptosis', 'CPA', (205, 214))	('miR-21', 'Gene', (13, 19))	('TIMP3', 'Gene', '7078', (131, 136))	('effect', 'Reg', (72, 78))	('implicated', 'Reg', (29, 39))	('RECK', 'Gene', (122, 126))	('IGFBP3', 'Gene', (114, 120))	('suppression', 'NegReg', (190, 201))	('DNA repair', 'CPA', (242, 252))	('miR-21', 'Gene', '406991', (13, 19))	('microRNA', 'Var', (4, 12))	('RECK', 'Gene', '8434', (122, 126))	('GBM', 'Disease', (43, 46))	('TIMP3', 'Gene', (131, 136))	('IGFBP3', 'Gene', '3486', (114, 120))
60960	33449801	Temozolamide resulted in an increase of 0.59 (0.53-0.66) LY and 0.33 (0.29-0.40) QALY per person at an incremental cost of $75,120 in Indian national rupee (INR) (59,337-93,960).	('QALY', 'MPA', (81, 85))	('increase', 'PosReg', (28, 36))	('Temozolamide', 'Chemical', '-', (0, 12))	('Temozolamide', 'Var', (0, 12))	('0.33', 'Var', (64, 68))
61078	32599788	Particularly, as cytosolic Ca2+ begins to rise, Ca2+ activates various downstream partners such as calmodulin, calcineurin and protein kinase C (PKC) which, in turn, modulate important cellular processes and functions, including transcriptional regulation, intracellular protein trafficking, differentiation, proliferation, adhesion and invasion.	('differentiation', 'CPA', (292, 307))	('transcriptional regulation', 'MPA', (229, 255))	('calcineurin', 'Enzyme', (111, 122))	('cellular processes', 'CPA', (185, 203))	('intracellular protein trafficking', 'MPA', (257, 290))	('protein kinase C', 'Gene', (127, 143))	('PKC', 'Gene', (145, 148))	('calmodulin', 'Gene', (99, 109))	('Ca2+', 'Var', (48, 52))	('modulate', 'Reg', (166, 174))	('proliferation', 'CPA', (309, 322))	('calmodulin', 'Gene', '801', (99, 109))	('Ca2+', 'Chemical', 'MESH:D000069285', (27, 31))	('Ca2+', 'Chemical', 'MESH:D000069285', (48, 52))	('PKC', 'Gene', '112476', (145, 148))	('adhesion', 'CPA', (324, 332))	('protein kinase C', 'Gene', '112476', (127, 143))	('invasion', 'CPA', (337, 345))
61083	32599788	However, during prolonged stimulation and despite serving as the receptor's co-agonist along with IP3, Ca2+ can trigger IP3R ubiquitination and subsequent degradation as a preventative measure against toxic buildup of cytosolic Ca2+.	('IP3', 'Gene', (98, 101))	('Ca2+', 'Var', (103, 107))	('IP3', 'Gene', (120, 123))	('IP3R', 'Gene', '3710', (120, 124))	('ubiquitination', 'MPA', (125, 139))	('Ca2+', 'Chemical', 'MESH:D000069285', (103, 107))	('IP3R', 'Gene', (120, 124))	('IP3', 'Gene', '3710', (120, 123))	('IP3', 'Gene', '3710', (98, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (228, 232))	('degradation', 'MPA', (155, 166))
61093	32599788	As a result, the IP3Rs-mediated increase in the resting cytosolic Ca2+ concentration paves the way for RyRs to reach their maximum functional capacity.	('IP3Rs-mediated', 'Var', (17, 31))	('IP3Rs', 'Chemical', '-', (17, 22))	('increase', 'PosReg', (32, 40))	('Ca2+', 'Chemical', 'MESH:D000069285', (66, 70))	('resting cytosolic Ca2+ concentration', 'MPA', (48, 84))	('RyR', 'Gene', (103, 106))	('RyR', 'Gene', '6262', (103, 106))
61098	32599788	In cardiac myocytes, the opening of voltage-gated L-type Ca2+ channels caused by membrane depolarization increases intracellular Ca2+ level, triggering the opening of RyR2 and subsequent Ca2+ sparks, an essential element in maintaining excitation-contraction coupling in healthy cardiac functions.	('opening', 'MPA', (156, 163))	('RyR2', 'Gene', '6262', (167, 171))	('Ca2+ sparks', 'MPA', (187, 198))	('RyR2', 'Gene', (167, 171))	('Ca2+', 'Chemical', 'MESH:D000069285', (187, 191))	('increases intracellular Ca2+ level', 'Phenotype', 'HP:0003575', (105, 139))	('depolarization', 'Var', (90, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (129, 133))	('intracellular Ca2+ level', 'MPA', (115, 139))	('triggering', 'Reg', (141, 151))	('increases', 'PosReg', (105, 114))	('Ca2+', 'Chemical', 'MESH:D000069285', (57, 61))
61115	32599788	To prevent excessive Ca2+ entry, STIM2.1, a naturally occurring STIM2 variant, hinders STIM-Orai cross-linking and decreases clustering of CRAC channels at the plasma membrane.	('STIM2', 'Gene', (33, 38))	('Ca2+', 'Chemical', 'MESH:D000069285', (21, 25))	('STIM2', 'Gene', '57620', (64, 69))	('Ca2+ entry', 'MPA', (21, 31))	('clustering', 'MPA', (125, 135))	('STIM2', 'Gene', (64, 69))	('decreases', 'NegReg', (115, 124))	('variant', 'Var', (70, 77))	('STIM-Orai cross-linking', 'MPA', (87, 110))	('hinders', 'NegReg', (79, 86))	('STIM2', 'Gene', '57620', (33, 38))
61121	32599788	Post-transcriptional modifications, mainly alternative splicing, generate at least 14 SERCA variants with diverse species-dependent cellular and tissue distributions throughout various stages of development.	('Post', 'Gene', (0, 4))	('alternative splicing', 'Var', (43, 63))	('SERCA', 'Gene', '489', (86, 91))	('SERCA', 'Gene', (86, 91))	('Post', 'Gene', '159371', (0, 4))
61124	32599788	SERCA3 variants are often found co-expressed with the SERCA2b variant in a wide variety of tissues and cells, such as the salivary glands, lymphoid tissues, pancreatic cells and cerebellar Purkinje neurons.	('SERCA3', 'Gene', '489', (0, 6))	('SERCA2', 'Gene', (54, 60))	('variants', 'Var', (7, 15))	('SERCA3', 'Gene', (0, 6))	('SERCA2', 'Gene', '488', (54, 60))	('variant', 'Var', (62, 69))
61126	32599788	As there seems to be notable differences in Ca2+-binding affinities across SERCA isoforms and amongst variants within the same SERCA isoform, the tissue-specific expression equilibrium of SERCA variants transmits differential Ca2+ rhythms required for the survival and function of that specific tissue.	('Ca2+', 'Chemical', 'MESH:D000069285', (226, 230))	('SERCA', 'Gene', '489', (75, 80))	('SERCA', 'Gene', (75, 80))	('SERCA', 'Gene', '489', (188, 193))	('SERCA', 'Gene', (188, 193))	('SERCA', 'Gene', (127, 132))	('transmits differential Ca2+ rhythms', 'MPA', (203, 238))	('Ca2+-binding', 'Protein', (44, 56))	('variants', 'Var', (194, 202))	('SERCA', 'Gene', '489', (127, 132))	('Ca2+', 'Chemical', 'MESH:D000069285', (44, 48))
61127	32599788	Considering the crucial role of SERCA pumps in maintaining ER Ca2+ homeostasis, the intricate modulatory mechanisms and existence of various SERCA variants allow for a tight control of the molecular dynamics and kinetic behavior of this pump.	('variants', 'Var', (147, 155))	('SERCA', 'Gene', '489', (32, 37))	('SERCA', 'Gene', (32, 37))	('Ca2+', 'Chemical', 'MESH:D000069285', (62, 66))	('SERCA', 'Gene', '489', (141, 146))	('SERCA', 'Gene', (141, 146))	('ER Ca2+ homeostasis', 'MPA', (59, 78))
61158	32599788	Furthermore, in colorectal cancer cell lines, abrogation of oncogenic K-Ras unleashed IP3R3 activity, enhancing IP3R3-mediated Ca2+ release and inducing cellular sensitization to apoptosis.	('cellular sensitization to apoptosis', 'CPA', (153, 188))	('inducing', 'Reg', (144, 152))	('IP3R3', 'Gene', '3710', (112, 117))	('K-Ras', 'Gene', (70, 75))	('enhancing', 'PosReg', (102, 111))	('IP3R3', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('abrogation', 'Var', (46, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('IP3R3', 'Gene', '3710', (86, 91))	('K-Ras', 'Gene', '3845', (70, 75))	('IP3R3', 'Gene', (86, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))	('Ca2+', 'Chemical', 'MESH:D000069285', (127, 131))
61173	32599788	Collectively, rampant manipulations of the IP3R expression profile throughout cancer development epitomize the notion that many malignancies have harbored the increasingly diversifying capacity to sabotage IP3R-mediated Ca2+ transients and therefore, global Ca2+ signaling to stimulate oncogenesis at the genetic level.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('IP3R', 'Gene', '3710', (43, 47))	('Ca2+', 'Chemical', 'MESH:D000069285', (220, 224))	('Ca2+', 'Chemical', 'MESH:D000069285', (258, 262))	('cancer', 'Disease', (78, 84))	('manipulations', 'Var', (22, 35))	('IP3R', 'Gene', (43, 47))	('sabotage', 'NegReg', (197, 205))	('global', 'MPA', (251, 257))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('IP3R', 'Gene', '3710', (206, 210))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('IP3R', 'Gene', (206, 210))	('oncogenesis', 'CPA', (286, 297))	('malignancies', 'Disease', (128, 140))	('stimulate', 'PosReg', (276, 285))
61182	32599788	Besides aberrant RyR2 expression levels in giving rise to malignancy, several mutations of RyR2s have been linked to lung cancer.	('malignancy', 'Disease', 'MESH:D009369', (58, 68))	('linked', 'Reg', (107, 113))	('malignancy', 'Disease', (58, 68))	('RyR2', 'Gene', (91, 95))	('RyR2', 'Gene', '6262', (17, 21))	('lung cancer', 'Disease', (117, 128))	('RyR2', 'Gene', (17, 21))	('mutations', 'Var', (78, 87))	('RyR2', 'Gene', '6262', (91, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
61192	32599788	The activity of these oncogenic pathways is often dictated by pathological modifications of Ca2+ release and influx channels, in particular, at the level of store operated Ca2+ entry (SOCE).	('oncogenic', 'CPA', (22, 31))	('Ca2+ release', 'MPA', (92, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (172, 176))	('modifications', 'Var', (75, 88))	('dictated by', 'Reg', (50, 61))	('activity', 'MPA', (4, 12))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))
61195	32599788	In glioblastoma multiforme, STIM1 and Orai1 knockdown decreased cancer cell invasion and proliferation, respectively.	('proliferation', 'CPA', (89, 102))	('STIM1', 'Gene', '6786', (28, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('glioblastoma multiforme', 'Disease', (3, 26))	('Orai1', 'Gene', (38, 43))	('decreased', 'NegReg', (54, 63))	('knockdown', 'Var', (44, 53))	('Orai1', 'Gene', '84876', (38, 43))	('STIM1', 'Gene', (28, 33))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (3, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
61200	32599788	To corroborate this, McAndrew further demonstrated that Orai1 siRNA knockdown not only attenuated cytosolic Ca2+ influx in breast cancer MDA-MB-231 and MCF-7 cell lines in the presence of invasive stimulus PAR-2, but also reduced their viability.	('PAR-2', 'Gene', '2150', (206, 211))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (137, 147))	('Orai1', 'Gene', '84876', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('attenuated', 'NegReg', (87, 97))	('breast cancer', 'Disease', (123, 136))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('MCF-7', 'CellLine', 'CVCL:0031', (152, 157))	('knockdown', 'Var', (68, 77))	('Orai1', 'Gene', (56, 61))	('PAR-2', 'Gene', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('reduced', 'NegReg', (222, 229))	('cytosolic Ca2+ influx', 'MPA', (98, 119))
61208	32599788	Conversely, Orai3 knockdown led to decreased ERalpha+ MCF7 cell proliferation and invasion.	('knockdown', 'Var', (18, 27))	('Orai3', 'Gene', (12, 17))	('ERalpha', 'Gene', (45, 52))	('invasion', 'CPA', (82, 90))	('ERalpha', 'Gene', '2099', (45, 52))	('decreased', 'NegReg', (35, 44))	('MCF7', 'CellLine', 'CVCL:0031', (54, 58))	('Orai3', 'Gene', '93129', (12, 17))
61209	32599788	Another independent study led by Faouzi also demonstrated that Orai3 knockdown impaired breast cancer MCF-7 cell proliferation and arrested cell cycle progression at the G1 phase without affecting the proliferation and survival of wild-type mammary MCF-10A cells.	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('impaired breast cancer', 'Disease', (79, 101))	('Orai3', 'Gene', '93129', (63, 68))	('MCF-7', 'CellLine', 'CVCL:0031', (102, 107))	('cell cycle progression at the G1 phase', 'CPA', (140, 178))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Orai3', 'Gene', (63, 68))	('MCF-10A', 'CellLine', 'CVCL:0598', (249, 256))	('arrested', 'NegReg', (131, 139))	('knockdown', 'Var', (69, 78))	('impaired breast cancer', 'Disease', 'MESH:D001943', (79, 101))
61220	32599788	Additionally, highlighting the interplay between SERCA2 deficiency to malignancy came the finding of Prasad et al.	('SERCA2', 'Gene', (49, 55))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('malignancy', 'Disease', (70, 80))	('SERCA2', 'Gene', '488', (49, 55))	('deficiency', 'Var', (56, 66))
61234	32599788	Moreover, SERCA2b is found over-expressed in epithelial prostate cancer cells and that knockdown of SERCA2b decreases prostate cancer proliferation.	('epithelial prostate cancer', 'Disease', 'MESH:D011471', (45, 71))	('decreases prostate', 'Phenotype', 'HP:0008687', (108, 126))	('SERCA2', 'Gene', '488', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SERCA2', 'Gene', '488', (100, 106))	('epithelial prostate cancer', 'Disease', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('decreases prostate cancer', 'Disease', (108, 133))	('decreases prostate cancer', 'Disease', 'MESH:D011471', (108, 133))	('SERCA2', 'Gene', (10, 16))	('SERCA2', 'Gene', (100, 106))	('knockdown', 'Var', (87, 96))
61249	32599788	This depletion of the ER Ca2+ store, in and of itself, induces ER stress, and causes elevated cytoplasmic Ca2+ that can activate intrinsic apoptotic pathways through calmodulin/calcineurin-mediated signal transduction.	('Ca2+', 'Chemical', 'MESH:D000069285', (106, 110))	('depletion', 'Var', (5, 14))	('stress', 'Disease', 'MESH:D000079225', (66, 72))	('activate', 'PosReg', (120, 128))	('calmodulin', 'Gene', '801', (166, 176))	('Ca2+', 'Chemical', 'MESH:D000069285', (25, 29))	('stress', 'Disease', (66, 72))	('induces', 'Reg', (55, 62))	('elevated', 'PosReg', (85, 93))	('cytoplasmic Ca2+', 'MPA', (94, 110))	('intrinsic apoptotic pathways', 'Pathway', (129, 157))	('calmodulin', 'Gene', (166, 176))
61256	32599788	Through the use of in-silico models, such as molecular dynamic simulations and structure-based virtual screening, Sampath and Sankaranarayanan identified SB01990, SPB06836, and KM06293 as drug leads capable of disrupting Ca2+ binding to the active sites of Orai1, inhibiting ORAI-mediated Ca2+ influx with relatively ideal pharmacokinetics.	('SPB06836', 'Var', (163, 171))	('binding', 'Interaction', (226, 233))	('SB01990', 'Var', (154, 161))	('Ca2+', 'Chemical', 'MESH:D000069285', (289, 293))	('Ca2+', 'Protein', (221, 225))	('inhibiting', 'NegReg', (264, 274))	('ORAI-mediated Ca2+ influx', 'MPA', (275, 300))	('KM06293', 'Chemical', '-', (177, 184))	('Ca2+', 'Chemical', 'MESH:D000069285', (221, 225))	('disrupting', 'NegReg', (210, 220))	('SB01990', 'Chemical', '-', (154, 161))	('Orai1', 'Gene', (257, 262))	('Orai1', 'Gene', '84876', (257, 262))	('KM06293', 'Var', (177, 184))
61260	32599788	Indeed, loss-of-function mutations in human ORAI1 or STIM1 lead to increased susceptibility of developing tumors.	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('STIM1', 'Gene', (53, 58))	('human', 'Species', '9606', (38, 43))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('ORAI1', 'Gene', '84876', (44, 49))	('ORAI1', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('STIM1', 'Gene', '6786', (53, 58))	('loss-of-function', 'NegReg', (8, 24))
61283	32117422	What's more, in the network of SFs and ASEs, CELF5 significantly regulated GSG1L 35696 AP and GSG1L 35698 AP (P < 0.001, R = 0.511 and = -0.492).	('CELF5', 'Gene', '60680', (45, 50))	('35696 AP', 'Var', (81, 89))	('GSG1L', 'Gene', (75, 80))	('ASEs', 'Chemical', '-', (39, 43))	('CELF5', 'Gene', (45, 50))	('GSG1L', 'Gene', '146395', (75, 80))	('GSG1L', 'Gene', '146395', (94, 99))	('GSG1L', 'Gene', (94, 99))	('regulated', 'Reg', (65, 74))
61287	32117422	Based on the comprehensive bioinformatics analysis, we proposed that aberrant splicing factor CUGBP Elav-like family member 5 (CELF5) significantly, positively and negatively, regulated ASE of GSG1L, and the primary bile acid synthesis pathway might play an important role in tumorigenesis and prognosis of GBM.	('CUGBP Elav-like family member 5', 'Gene', '60680', (94, 125))	('ASE', 'Gene', '415', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('bile acid', 'Chemical', 'MESH:D001647', (216, 225))	('GSG1L', 'Gene', (193, 198))	('CELF5', 'Gene', (127, 132))	('primary bile acid synthesis pathway', 'Pathway', (208, 243))	('aberrant', 'Var', (69, 77))	('CUGBP Elav-like family member 5', 'Gene', (94, 125))	('regulated', 'MPA', (176, 185))	('tumor', 'Disease', (276, 281))	('ASE', 'Gene', (186, 189))	('GSG1L', 'Gene', '146395', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('GBM', 'Disease', (307, 310))	('play', 'Reg', (250, 254))	('GBM', 'Disease', 'MESH:D005909', (307, 310))	('CELF5', 'Gene', '60680', (127, 132))	('negatively', 'NegReg', (164, 174))
61290	32117422	Abnormal splicing can improve tumor development by changing metabolism.	('improve', 'PosReg', (22, 29))	('Abnormal splicing', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('metabolism', 'MPA', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('changing', 'Reg', (51, 59))	('tumor', 'Disease', (30, 35))
61307	32117422	Then, an UpSet plot was developed to demonstrate genes processed by splicing events and patterns of splicing events in GBM.	('GBM', 'Disease', (119, 122))	('rat', 'Species', '10116', (44, 47))	('GBM', 'Disease', 'MESH:D005909', (119, 122))	('splicing events', 'Var', (68, 83))
61345	32117422	Moreover, DST 76557 AT, CD3D 18990 ES, TTC13 10258 ME, SV2B 32540 RI, MAP3K13 68008 AA, ZNF302 48996 AD, and SPOCD1 1507 AP were the most significant of the top 20 OS-SEs in each splicing pattern in each bubble plot (Figures 3B-H).	('MAP3K13', 'Gene', '9175', (70, 77))	('TTC13', 'Gene', (39, 44))	('OS-SEs', 'Chemical', '-', (164, 170))	('SPOCD1', 'Gene', (109, 115))	('CD3D', 'Gene', '915', (24, 28))	('ZNF302', 'Gene', '55900', (88, 94))	('ES', 'Chemical', '-', (35, 37))	('DST 76557 AT', 'Var', (10, 22))	('ZNF302', 'Gene', (88, 94))	('TTC13', 'Gene', '79573', (39, 44))	('MAP3K13', 'Gene', (70, 77))	('CD3D', 'Gene', (24, 28))	('SPOCD1', 'Gene', '90853', (109, 115))
61357	32117422	Besides, ST3GAL4 19394 AP was related to cancer status (P < 0.001), PLD3 49891 ES was related to cancer status (P = 0.003), GSG1L 35696 AP was related to cancer status (P = 0.006), GSG1L 35698 AP was related to cancer status (P = 0.007), MUTYH 2651 ES was related to cancer status (P = 0.016), ST3GAL4 19391 AP was related to cancer status (P = 0.020), and TBC1D5 63663 ES was related to cancer status (P = 0.026) (Figures 6C-I).	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('GSG1L', 'Gene', '146395', (181, 186))	('ES', 'Chemical', '-', (79, 81))	('cancer', 'Disease', (41, 47))	('MUTYH', 'Gene', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('TBC1D5', 'Gene', '9779', (357, 363))	('ES', 'Chemical', '-', (370, 372))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ST3GAL4', 'Gene', '6484', (9, 16))	('cancer', 'Disease', (326, 332))	('related', 'Reg', (377, 384))	('cancer', 'Disease', (388, 394))	('GSG1L', 'Gene', '146395', (124, 129))	('ST3GAL4', 'Gene', '6484', (294, 301))	('MUTYH', 'Gene', '4595', (238, 243))	('cancer', 'Disease', (267, 273))	('PLD3 49891', 'Var', (68, 78))	('TBC1D5', 'Gene', (357, 363))	('GSG1L', 'Gene', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('ES', 'Chemical', '-', (249, 251))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('ST3GAL4', 'Gene', (9, 16))	('GSG1L', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ST3GAL4', 'Gene', (294, 301))
61372	32117422	CELF5 (P = 0.007) and GSG1L (P = 0.006) were significantly related to prognosis in two different datasets of SurvExpres (GSE13041 OS P = 0.002; GSE16011 OS P < 0.001; TCGA GBM OS P = 0.281; TCGA GBM 2016 OS P = 0.002) (Figure S5).	('GBM', 'Disease', (195, 198))	('CELF5', 'Gene', (0, 5))	('GSG1L', 'Gene', (22, 27))	('GBM', 'Disease', 'MESH:D005909', (172, 175))	('GBM', 'Disease', 'MESH:D005909', (195, 198))	('GSE13041', 'Var', (121, 129))	('CELF5', 'Gene', '60680', (0, 5))	('related', 'Reg', (59, 66))	('GSG1L', 'Gene', '146395', (22, 27))	('GBM', 'Disease', (172, 175))
61409	32117422	Based on the comprehensive bioinformatics analysis, we proposed that aberrant splicing factor CUGBP Elav-like family member 5 (CELF5) positively and negatively regulated ASE of GSG1L and the primary bile acid synthesis pathway might play an important role in tumorigenesis and prognosis of GBM.	('GBM', 'Disease', 'MESH:D005909', (290, 293))	('CUGBP Elav-like family member 5', 'Gene', '60680', (94, 125))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('ASE', 'Gene', '415', (170, 173))	('regulated', 'Reg', (160, 169))	('GSG1L', 'Gene', (177, 182))	('CELF5', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('bile acid', 'Chemical', 'MESH:D001647', (199, 208))	('aberrant', 'Var', (69, 77))	('CUGBP Elav-like family member 5', 'Gene', (94, 125))	('ASE', 'Gene', (170, 173))	('GSG1L', 'Gene', '146395', (177, 182))	('primary bile acid synthesis pathway', 'Pathway', (191, 226))	('negatively', 'NegReg', (149, 159))	('GBM', 'Disease', (290, 293))	('tumor', 'Disease', (259, 264))	('play', 'Reg', (233, 237))	('CELF5', 'Gene', '60680', (127, 132))
61417	31600301	Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity Cyclin-dependent kinases 4 and 6 (CDK4/6) play critical roles in the G1 to S checkpoint of the cell cycle and have been shown to be overactive in several human cancers.	('ribociclib', 'Var', (28, 38))	('Cyclin-dependent kinases 4 and 6', 'Gene', '1019;1021', (107, 139))	('inhibitors ribociclib', 'Var', (17, 38))	('CDK4/6', 'Gene', '1019;1021', (10, 16))	('CDK4/6', 'Gene', '1019;1021', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('cytotoxicity', 'Disease', 'MESH:D064420', (94, 106))	('human', 'Species', '9606', (261, 266))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancers', 'Disease', (267, 274))	('CDK4/6', 'Gene', (10, 16))	('CDK4/6', 'Gene', (141, 147))	('overactive', 'PosReg', (239, 249))	('cytotoxicity', 'Disease', (94, 106))
61419	31600301	Since CDK4/6 inhibition is thought to induce cell cycle arrest at the G1/S checkpoint, much interest has been focused on combining CDK4/6 inhibitors with cytotoxic agents active against the S or M phase of the cell cycle to enhance therapeutic efficacy.	('CDK4/6', 'Gene', (131, 137))	('cell cycle arrest', 'CPA', (45, 62))	('enhance', 'PosReg', (224, 231))	('inhibition', 'Var', (13, 23))	('CDK4/6', 'Gene', '1019;1021', (6, 12))	('CDK4/6', 'Gene', '1019;1021', (131, 137))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (45, 62))	('CDK4/6', 'Gene', (6, 12))
61420	31600301	Here, we test various combinations of highly selective and potent CDK4/6 inhibitors with commonly used cytotoxic drugs in several cancer cell lines derived from lung, breast and brain cancers, for their cell-killing effects as compared to monotherapy.	('cancer', 'Disease', (184, 190))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('CDK4/6', 'Gene', '1019;1021', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast and brain cancers', 'Disease', 'MESH:D001943', (167, 191))	('cell-killing', 'CPA', (203, 215))	('CDK4/6', 'Gene', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('inhibitors', 'Var', (73, 83))	('combinations', 'Interaction', (22, 34))
61435	31600301	Although single-agent activity has been reported for CDK4/6 inhibitors, combinations with other drugs has demonstrated enhanced anti-cancer efficacy, including combination of ribociclib with an aromatase inhibitor as approved as a first-line treatment for postmenopausal women with metastatic HR+/HER2- breast cancer.	('cancer', 'Disease', (310, 316))	('CDK4/6', 'Gene', (53, 59))	('combination', 'Interaction', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HER2', 'Gene', (297, 301))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('breast cancer', 'Disease', (303, 316))	('cancer', 'Disease', (133, 139))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('HER2', 'Gene', '2064', (297, 301))	('combinations', 'Var', (72, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('HR', 'Gene', '3164', (293, 295))	('CDK4/6', 'Gene', '1019;1021', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('enhanced', 'PosReg', (119, 127))	('women', 'Species', '9606', (271, 276))
61445	31600301	LN428 and LN308 were previously established from human GBM samples.	('GBM', 'Disease', (55, 58))	('human', 'Species', '9606', (49, 54))	('GBM', 'Disease', 'MESH:D005909', (55, 58))	('LN308', 'Var', (10, 15))	('LN428', 'Var', (0, 5))
61448	31600301	Clinical grade ribociclib (LEE011) was obtained from Novartis, Inc. Carmustine (C0400), carboplatin (C2538), temozolomide (T2577), etoposide (E1383), irinotecan (I1406) were from Sigma-Aldrich; paclitaxel or taxol (S1150) and palbociclib (S1116) were from Selleck Chemicals.	('Carmustine', 'Chemical', 'MESH:D002330', (68, 78))	('E1383', 'Var', (142, 147))	('etoposide', 'Chemical', 'MESH:D005047', (131, 140))	('C2538', 'Var', (101, 106))	('paclitaxel', 'Chemical', 'MESH:D017239', (194, 204))	('temozolomide', 'Chemical', 'MESH:C047246', (109, 121))	('S1116', 'Var', (239, 244))	('I1406', 'Chemical', 'MESH:D010638', (162, 167))	('C2538', 'Chemical', 'MESH:D002244', (101, 106))	('taxol', 'Chemical', 'MESH:D017239', (208, 213))	('irinotecan', 'Chemical', 'MESH:C051890', (150, 160))	('C0400', 'Var', (80, 85))	('T2577', 'Var', (123, 128))	('S1116', 'Chemical', 'MESH:C122063', (239, 244))	('C0400', 'Chemical', 'MESH:C541376', (80, 85))	('carboplatin', 'Chemical', 'MESH:D016190', (88, 99))
61455	31600301	CDK4/6 inhibitors are expected to have cytostatic effects by causing cell cycle arrest at the G1/S checkpoint.	('cell cycle arrest at the G1/S checkpoint', 'CPA', (69, 109))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (69, 86))	('CDK4/6', 'Gene', (0, 6))	('causing', 'Reg', (61, 68))
61466	31600301	Although concurrent combinations of ribociclib with etoposide and paclitaxel showed an additive effect in LN308 (S1I Fig) and A549 cells (Fig 1F), respectively, compared to cytotoxic drug or ribociclib alone, this additive effect was not observed in other cell lines or other cytotoxic drugs (Fig 1C-1F and S1H-S1J Fig).	('LN308', 'Var', (106, 111))	('paclitaxel', 'Chemical', 'MESH:D017239', (66, 76))	('etoposide', 'Chemical', 'MESH:D005047', (52, 61))	('combinations', 'Interaction', (20, 32))
61468	31600301	Importantly, in some cases, when ribociclib treatment preceded a cytotoxic drug, reduced cytotoxicity was observed as compared to two-day treatment with the same cytotoxic drug alone (Fig 1C-1F and S1H-S1J Fig).	('reduced cytotoxicity', 'Disease', (81, 101))	('ribociclib', 'Var', (33, 43))	('reduced cytotoxicity', 'Disease', 'MESH:D006987', (81, 101))
61473	31600301	Taken together, these results indicate that the lack of cooperativity, and, in certain sequential combinations, detriment in cancer cell killing when CDK4/6 inhibitors are combined with cytotoxic drugs are likely a class effect of CDK4/6 inhibitors.	('CDK4/6', 'Gene', '1019;1021', (150, 156))	('combined', 'Interaction', (172, 180))	('detriment', 'NegReg', (112, 121))	('CDK4/6', 'Gene', (150, 156))	('CDK4/6', 'Gene', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('inhibitors', 'Var', (157, 167))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('CDK4/6', 'Gene', '1019;1021', (231, 237))
61476	31600301	Although this observation may suggest that ribociclib enhances cytotoxicity when given after a cytotoxic drug, it is more likely that the addition of ribociclib did not add to cytotoxicity and 2 days of treatment with a cytotoxic was sufficient at achieving maximal cytotoxicity since 2- and 4-day treatment with a cytotoxic drug alone had similar cytotoxicity (Fig 1C-1F).	('cytotoxicity', 'Disease', (266, 278))	('enhances', 'PosReg', (54, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (348, 360))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('cytotoxicity', 'Disease', (63, 75))	('cytotoxicity', 'Disease', 'MESH:D064420', (266, 278))	('ribociclib', 'Var', (43, 53))	('cytotoxicity', 'Disease', (348, 360))	('cytotoxicity', 'Disease', (176, 188))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))
61480	31600301	Twenty-four hours of exposure to ribociclib was sufficient to achieve maximal arrest at the G1/S checkpoint as demonstrated by the G1 fraction increasing from 48-62.5% before treatment to 87-97% after treatment in these four cell lines (Fig 3B and 3C and S4B and S4C Fig).	('ribociclib', 'Var', (33, 43))	('S4B', 'Chemical', 'MESH:D013455', (255, 258))	('increasing', 'PosReg', (143, 153))
61489	31600301	However, as demonstrated above (Fig 3B and 3C and S4B and S4C Fig), prolonged treatment with ribociclib led, not to maximal G1/S synchronization, but instead to gradual escape from arrest.	('ribociclib', 'Var', (93, 103))	('arrest', 'MPA', (181, 187))	('S4B', 'Chemical', 'MESH:D013455', (50, 53))	('escape', 'MPA', (169, 175))
61500	31600301	Hence, inhibition of CDK4/6 has emerged as an attractive therapeutic strategy against cancer.	('CDK4/6', 'Gene', '1019;1021', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('inhibition', 'Var', (7, 17))	('CDK4/6', 'Gene', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
61501	31600301	Based on the mechanism of action, CDK4/6 inhibitors are predicted to have cytostatic property.	('cytostatic', 'MPA', (74, 84))	('CDK4/6', 'Gene', '1019;1021', (34, 40))	('CDK4/6', 'Gene', (34, 40))	('inhibitors', 'Var', (41, 51))
61502	31600301	Therefore, the greatest therapeutic potential of CDK4/6 inhibitors lies in their combinations with other therapies.	('combinations', 'Interaction', (81, 93))	('CDK4/6', 'Gene', '1019;1021', (49, 55))	('inhibitors', 'Var', (56, 66))	('CDK4/6', 'Gene', (49, 55))
61514	31600301	The mechanism underlying the antagonism of CDK4/6 inhibitors pre-treatment against cytotoxic drugs, but not when they are given concurrently or after cytotoxic drugs is unclear and could be due to the observation that CDK4/6 inhibitors shifted the burden of E2F-induced DNA repair from homologous recombination to non-homologous end joining, leading to antagonism with cytotoxic agents and contribute to increased growth.	('CDK4/6', 'Gene', (218, 224))	('CDK4/6', 'Gene', (43, 49))	('increased', 'PosReg', (404, 413))	('antagonism', 'MPA', (353, 363))	('E2F-induced', 'Var', (258, 269))	('growth', 'MPA', (414, 420))	('CDK4/6', 'Gene', '1019;1021', (218, 224))	('CDK4/6', 'Gene', '1019;1021', (43, 49))
61515	31600301	Alternatively, cell cycle arrest at G0/G1 transition caused by CDK4/6 inhibitors may nullify cell division dependent cytotoxicity of cytotoxic agents.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (15, 32))	('cytotoxicity of cytotoxic', 'Disease', (117, 142))	('CDK4/6', 'Gene', '1019;1021', (63, 69))	('cytotoxicity of cytotoxic', 'Disease', 'MESH:D064420', (117, 142))	('inhibitors', 'Var', (70, 80))	('nullify', 'NegReg', (85, 92))	('cell cycle arrest at G0/G1 transition', 'CPA', (15, 52))	('CDK4/6', 'Gene', (63, 69))
61516	31600301	Recently, senescence induced by CDK4/6 inhibition has also been shown to promote the development of cancer stem-like cells, leading to attenuated response to cytotoxic agents and tumor recurrence.	('inhibition', 'Var', (39, 49))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('response to cytotoxic agents', 'MPA', (146, 174))	('CDK4/6', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('attenuated', 'NegReg', (135, 145))	('senescence', 'Disease', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('promote', 'PosReg', (73, 80))	('CDK4/6', 'Gene', '1019;1021', (32, 38))	('tumor', 'Disease', (179, 184))
61575	31598150	By silencing the gene on the epigenetic level, MGMT methylation decreased tumors' DNA repair capacity, increasing temozolomide susceptibility.	('silencing', 'Var', (3, 12))	('methyl', 'Chemical', 'MESH:C031105', (52, 58))	('temozolomide susceptibility', 'MPA', (114, 141))	('decreased tumors', 'Disease', 'None', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MGMT', 'Gene', (47, 51))	('increasing', 'PosReg', (103, 113))	('methylation', 'Var', (52, 63))	('MGMT', 'Gene', '4255', (47, 51))	('temozolomide', 'Chemical', 'MESH:C047246', (114, 126))	('decreased tumors', 'Disease', (64, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
61576	31598150	For patients without MGMT promoter methylation, O6-benzylguanine, another inhibitor of MGMT, and RNA interference-mediated MGMT silencing offer promising avenues to increase TMZ efficacy.	('increase', 'PosReg', (165, 173))	('MGMT', 'Gene', (87, 91))	('TMZ', 'Chemical', 'MESH:C047246', (174, 177))	('methyl', 'Chemical', 'MESH:C031105', (35, 41))	('MGMT', 'Gene', '4255', (87, 91))	('silencing', 'NegReg', (128, 137))	('RN', 'Disease', 'MESH:C536267', (97, 99))	('MGMT', 'Gene', (123, 127))	('O6-benzylguanine', 'Var', (48, 64))	('patients', 'Species', '9606', (4, 12))	('MGMT', 'Gene', '4255', (123, 127))	('MGMT', 'Gene', '4255', (21, 25))	('MGMT', 'Gene', (21, 25))	('O6-benzylguanine', 'Chemical', 'MESH:C064976', (48, 64))
61593	31598150	One recent research suggested that CPA improves survival in orthotopic GL261 GBM in mice by metronomic administration (every 6 days), and similar results were then described by several other studies.	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('improves', 'PosReg', (39, 47))	('survival', 'CPA', (48, 56))	('GBM', 'Disease', (77, 80))	('CPA', 'Chemical', 'MESH:D003520', (35, 38))	('CPA', 'Var', (35, 38))	('GBM', 'Disease', 'MESH:D005909', (77, 80))	('mice', 'Species', '10090', (84, 88))
61596	31598150	Despite the infiltrative nature of GBM, partial-brain radiation, recommended in the guideline, leads to no worse survival than whole-brain radiotherapy.	('GBM', 'Disease', 'MESH:D005909', (35, 38))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('GBM', 'Disease', (35, 38))	('partial-brain radiation', 'Var', (40, 63))
61616	31598150	In theory, if we use boron compound to deliver boron-10 precisely to tumor cells, this reaction can lead a selective tumor cell killing without damaging adjacent healthy cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('boron-10', 'Var', (47, 55))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (117, 122))	('boron', 'Chemical', 'MESH:D001895', (47, 52))	('lead', 'Reg', (100, 104))	('boron', 'Chemical', 'MESH:D001895', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
61631	31598150	Nimotuzumab, Nimotuzumab is a humanized monoclonal antibody that binds to epidermal growth factor receptor (EGFR) and alters cell division.	('cell division', 'CPA', (125, 138))	('binds', 'Interaction', (65, 70))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('epidermal growth factor receptor', 'Gene', '1956', (74, 106))	('Nimotuzumab', 'Var', (13, 24))	('epidermal growth factor receptor', 'Gene', (74, 106))	('alters', 'Reg', (118, 124))
61632	31598150	EGFR belongs to the ErbB family, which is related to many downstream pathways whose mutation or activation would facilitate angiogenesis and GBM growth (Fig.	('GBM', 'Disease', (141, 144))	('EGFR', 'Gene', (0, 4))	('GBM', 'Disease', 'MESH:D005909', (141, 144))	('ErbB', 'Gene', (20, 24))	('ErbB', 'Gene', '1956', (20, 24))	('GBM', 'Phenotype', 'HP:0012174', (141, 144))	('angiogenesis', 'CPA', (124, 136))	('facilitate', 'PosReg', (113, 123))	('EGFR', 'Gene', '1956', (0, 4))	('activation', 'PosReg', (96, 106))	('mutation', 'Var', (84, 92))
61640	31598150	Further studies are ongoing to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).	('NCT02573324', 'Var', (73, 84))	('NCT02343406', 'Var', (114, 125))	('glioblastoma', 'Disease', (100, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (100, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))
61678	31598150	G47Delta, developed by Todo et al., is a promising third generation oncolytic HSV-1 to be tested in patients with recurrent or residual GBM in a phase II study (UMIN000015995) started in 2015 Japan.	('GBM', 'Disease', 'MESH:D005909', (136, 139))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('HSV-1', 'Species', '10298', (78, 83))	('G47Delta', 'Var', (0, 8))	('patients', 'Species', '9606', (100, 108))	('GBM', 'Disease', (136, 139))
61733	31099446	Most cancers, including gliomas, activate telomerase to evade this process.13 The promoter mutations of TERT occur at 2 hotspots (-124C > T or -146C > T) in a mutually exclusive manner.	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('-124C > T', 'SUBSTITUTION', 'None', (130, 139))	('cancers', 'Disease', (5, 12))	('-146C > T', 'Var', (143, 152))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('-146C > T', 'SUBSTITUTION', 'None', (143, 152))	('TERT', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('-124C > T', 'Var', (130, 139))	('gliomas', 'Disease', (24, 31))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
61734	31099446	Either of these mutations creates a de novo binding site for GABPA, which activates the promoter and upregulates TERT expression.14, 15 The introduction of TERT promoter mutation in induced pluripotent stem cells abrogates telomerase silencing upon differentiation, and these cells overcome replicative senescence and infinitely multiply upon acquisition of proliferating mutations.16 Thus, it appears that TERT promoter mutations are the most common driver oncogenic event in GBM, making it an attractive therapeutic target.	('GABPA', 'Gene', '14390', (61, 66))	('GABPA', 'Gene', (61, 66))	('mutations', 'Var', (421, 430))	('GBM', 'Phenotype', 'HP:0012174', (477, 480))	('TERT promoter', 'Gene', (407, 420))
61743	31099446	To establish a mouse brain tumor xenograft, U87MG, U87MG-Fluc2, GSC23, GS-Y03 (1 x 105 cells in 2 muL PBS) or LN229 (5 x 105 cells in 2 muL PBS) cells were stereotactically inoculated into the right cerebral hemisphere of immunodeficient mice by using a Hamilton syringe and stereotactic micro-injector (Narishige, Tokyo, Japan).	('GS-Y03', 'Disease', 'MESH:D011125', (71, 77))	('U87MG', 'CellLine', 'CVCL:0022', (44, 49))	('PBS', 'Chemical', 'MESH:D007854', (140, 143))	('mouse', 'Species', '10090', (15, 20))	('U87MG', 'CellLine', 'CVCL:0022', (51, 56))	('immunodeficient', 'Disease', 'MESH:D007153', (222, 237))	('immunodeficient', 'Disease', (222, 237))	('GS', 'Disease', 'MESH:D011125', (71, 73))	('GS-Y03', 'Disease', (71, 77))	('U87MG', 'Var', (44, 49))	('GS', 'Disease', 'MESH:D011125', (64, 66))	('U87MG-Fluc2', 'Var', (51, 62))	('LN229', 'CellLine', 'CVCL:0393', (110, 115))	('brain tumor', 'Phenotype', 'HP:0030692', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('PBS', 'Chemical', 'MESH:D007854', (102, 105))	('brain tumor', 'Disease', (21, 32))	('brain tumor', 'Disease', 'MESH:D001932', (21, 32))	('mice', 'Species', '10090', (238, 242))
61751	31099446	For in vivo bioluminescence study, eribulin or saline was injected into mice harboring U87MG-Fluc2 intracerebral tumors until the first mouse of the control group died.	('saline', 'Chemical', 'MESH:D012965', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('U87MG', 'CellLine', 'CVCL:0022', (87, 92))	('intracerebral tumors', 'Disease', 'MESH:D002543', (99, 119))	('eribulin', 'Chemical', 'MESH:C490954', (35, 43))	('U87MG-Fluc2', 'Var', (87, 98))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mouse', 'Species', '10090', (136, 141))	('intracerebral tumors', 'Disease', (99, 119))
61752	31099446	For in vivo survival study, eribulin or saline was intraperitoneally injected into mice harboring intracranial U87MG, LN229, GSC23 or GS-Y03 tumors.	('U87MG', 'CellLine', 'CVCL:0022', (111, 116))	('saline', 'Chemical', 'MESH:D012965', (40, 46))	('U87MG', 'Var', (111, 116))	('GS-Y03 tumors', 'Disease', 'MESH:D011125', (134, 147))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('GS', 'Disease', 'MESH:D011125', (134, 136))	('mice', 'Species', '10090', (83, 87))	('LN229', 'CellLine', 'CVCL:0393', (118, 123))	('GS-Y03 tumors', 'Disease', (134, 147))	('eribulin', 'Chemical', 'MESH:C490954', (28, 36))	('GS', 'Disease', 'MESH:D011125', (125, 127))
61769	31099446	The cytotoxic effect of eribulin on the TERT-mutated GBM cell lines U87MG, U251MG, U118MG and LN229 and patient-derived sphere-cultured cells GSC23 and GS-Y03 was examined in vitro using the WST assay (Figure 1).	('GS-Y03', 'Disease', 'MESH:D011125', (152, 158))	('U251MG', 'CellLine', 'CVCL:0021', (75, 81))	('U251MG', 'Var', (75, 81))	('GS', 'Disease', 'MESH:D011125', (142, 144))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('GS-Y03', 'Disease', (152, 158))	('GS', 'Disease', 'MESH:D011125', (152, 154))	('LN229', 'CellLine', 'CVCL:0393', (94, 99))	('U118MG', 'Var', (83, 89))	('U87MG', 'CellLine', 'CVCL:0022', (68, 73))	('eribulin', 'Chemical', 'MESH:C490954', (24, 32))	('patient', 'Species', '9606', (104, 111))
61771	31099446	The IC50 values of the TERT-mutated cells U87MG, U251MG, U118MG, LN 229, GSC23 and GS-Y03 (mean 0.32, 0.15, 0.36, 2.12, 0.21 and 1.10 nmol/L, respectively) were significantly lower than those of TERT-wild-type ES-2 (17.16 nmol/L) and TOV-21G (IC50 not reached) cells (P < 0.001) (Figure 1B).	('GS', 'Disease', 'MESH:D011125', (73, 75))	('IC50', 'MPA', (4, 8))	('GS-Y03', 'Disease', (83, 89))	('GS', 'Disease', 'MESH:D011125', (83, 85))	('lower', 'NegReg', (175, 180))	('U251MG', 'CellLine', 'CVCL:0021', (49, 55))	('U87MG', 'CellLine', 'CVCL:0022', (42, 47))	('U251MG', 'Var', (49, 55))	('U118MG', 'Var', (57, 63))	('U87MG', 'Var', (42, 47))	('GS-Y03', 'Disease', 'MESH:D011125', (83, 89))
61772	31099446	Thus, GBM cell lines that harbored TERT promoter mutations appeared to be more susceptible to eribulin than TERT-wild-type ES-2 and TOV-21G cells.	('eribulin', 'Chemical', 'MESH:C490954', (94, 102))	('mutations', 'Var', (49, 58))	('GBM', 'Phenotype', 'HP:0012174', (6, 9))	('susceptible to eribulin', 'MPA', (79, 102))	('TERT promoter', 'Gene', (35, 48))
61782	31099446	U87MG, GSC23 or GS-Y03 cells (105 cells/mouse) were stereotactically implanted into the brain of BALB/c nu/nu athymic mice on day 0.	('GS-Y03', 'Disease', 'MESH:D011125', (16, 22))	('GS', 'Disease', 'MESH:D011125', (16, 18))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('GS-Y03', 'Disease', (16, 22))	('GS', 'Disease', 'MESH:D011125', (7, 9))	('mouse', 'Species', '10090', (40, 45))	('mice', 'Species', '10090', (118, 122))	('U87MG', 'Var', (0, 5))
61791	31099446	In contrast, the concentration of eribulin in U87MG brain tumor was equivalent to that in the plasma (127 nmol/L at 0.25 hours after injection) and remained high even after 24 hours of injection (91.7 nmol/L, Figure 4A, red line).	('brain tumor', 'Phenotype', 'HP:0030692', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('U87MG', 'Var', (46, 51))	('eribulin', 'Chemical', 'MESH:C490954', (34, 42))	('brain tumor', 'Disease', (52, 63))	('brain tumor', 'Disease', 'MESH:D001932', (52, 63))	('U87MG', 'CellLine', 'CVCL:0022', (46, 51))
61804	31099446	When the tumors reached an average size of 5 mm in diameter, eribulin (0.125, 0.25 or 0.5 mg/kg) or saline was injected intraperitoneally 3 times per week for 2 weeks (days 8, 11, 13, 15, 18 and 20), and the sizes of the subcutaneous tumors were measured.	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (221, 239))	('eribulin', 'Chemical', 'MESH:C490954', (61, 69))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (221, 240))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('0.125', 'Var', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('saline', 'Chemical', 'MESH:D012965', (100, 106))	('tumors', 'Disease', (9, 15))	('subcutaneous tumors', 'Disease', (221, 240))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (221, 240))
61813	31099446	The results of in vitro growth inhibition assay showed that the growth of all 4 glioma cell lines tested was strongly suppressed by eribulin, with most of the IC50 values being below 1 nM (Figure 1).	('glioma', 'Disease', (80, 86))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('eribulin', 'Var', (132, 140))	('eribulin', 'Chemical', 'MESH:C490954', (132, 140))	('growth', 'CPA', (64, 70))	('suppressed', 'NegReg', (118, 128))
61825	31099446	In support of this, it has been reported that eribulin reduced the size of metastatic brain tumors developed from breast cancers, suggesting that eribulin penetrated intracerebral tumors in these cases.36, 37, 38  The most intriguing finding in our study was that the concentration of eribulin in the U87MG brain xenograft remained high even 24 hours after the injection (91.7 +- 35.0 nM), although its concentration in the plasma decreased below the detectable level (Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast cancers', 'Disease', 'MESH:D001943', (114, 128))	('eribulin', 'Chemical', 'MESH:C490954', (146, 154))	('breast cancers', 'Disease', (114, 128))	('brain tumor', 'Phenotype', 'HP:0030692', (86, 97))	('U87MG', 'CellLine', 'CVCL:0022', (301, 306))	('intracerebral tumors', 'Disease', 'MESH:D002543', (166, 186))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('intracerebral tumors', 'Disease', (166, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('brain tumors', 'Phenotype', 'HP:0030692', (86, 98))	('brain tumors', 'Disease', 'MESH:D001932', (86, 98))	('concentration', 'MPA', (268, 281))	('U87MG', 'Var', (301, 306))	('eribulin', 'Chemical', 'MESH:C490954', (285, 293))	('eribulin', 'Chemical', 'MESH:C490954', (46, 54))	('brain tumors', 'Disease', (86, 98))
61835	31099446	In addition, it remains unclear whether eribulin impairs self-renewal ability in sphere-forming glioblastoma cells.	('eribulin', 'Chemical', 'MESH:C490954', (40, 48))	('glioblastoma', 'Disease', (96, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('impairs', 'NegReg', (49, 56))	('self-renewal ability', 'CPA', (57, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('eribulin', 'Var', (40, 48))
61886	31064137	FAK causes focal contact disassembly once phosphorylated by AKT1.	('FAK', 'Var', (0, 3))	('focal contact disassembly', 'Disease', (11, 36))	('causes', 'Reg', (4, 10))	('AKT1', 'Gene', '207', (60, 64))	('AKT1', 'Gene', (60, 64))
61919	31064137	Loss of E-cadherin may affect the beta-catenin/WNT signaling pathway, resulting in upregulation of genes involved in growth and metastasis.	('E-cadherin', 'Gene', (8, 18))	('genes', 'MPA', (99, 104))	('E-cadherin', 'Gene', '999', (8, 18))	('upregulation', 'PosReg', (83, 95))	('beta-catenin', 'Gene', '1499', (34, 46))	('affect', 'Reg', (23, 29))	('Loss', 'Var', (0, 4))	('beta-catenin', 'Gene', (34, 46))
61923	31064137	Indeed, the silencing of integrin alphav/beta3 in B16 melanoma cells reduces their migratory capacity in vitro and metastatic potential in vivo.	('metastatic potential in vivo', 'CPA', (115, 143))	('migratory capacity in vitro', 'CPA', (83, 110))	('integrin alphav/beta3', 'Protein', (25, 46))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('reduces', 'NegReg', (69, 76))	('silencing', 'Var', (12, 21))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('B16', 'CellLine', 'CVCL:N540', (50, 53))
61931	31064137	Besides, NEDD9 overexpression leads to increased phosphorylation of beta3-integrin on Tyr785 in the cytoplasmic domain promoting the assembly of a signaling complex containing beta3-integrin, SRC, FAK and NEDD9.	('NEDD9', 'Gene', '4739', (9, 14))	('NEDD9', 'Gene', (9, 14))	('beta3-integrin', 'Protein', (68, 82))	('NEDD9', 'Gene', (205, 210))	('NEDD9', 'Gene', '4739', (205, 210))	('Tyr785', 'Var', (86, 92))	('overexpression', 'Var', (15, 29))	('beta3-integrin', 'Protein', (176, 190))	('increased', 'PosReg', (39, 48))	('phosphorylation', 'MPA', (49, 64))	('Tyr785', 'Chemical', '-', (86, 92))	('promoting', 'PosReg', (119, 128))	('assembly', 'MPA', (133, 141))
61966	31064137	Under ER stress, GRP78 dissociation and disulfide bond modification mediated by the protein disulfide isomerase PDIA5 stabilize ATF6 and promotes its export to the Golgi apparatus.	('GRP78', 'Gene', (17, 22))	('export to the Golgi apparatus', 'MPA', (150, 179))	('promotes', 'PosReg', (137, 145))	('GRP78', 'Gene', '3309', (17, 22))	('ATF6', 'Gene', (128, 132))	('disulfide bond modification', 'MPA', (40, 67))	('PDIA5', 'Gene', (112, 117))	('stabilize', 'MPA', (118, 127))	('disulfide', 'Chemical', 'MESH:D004220', (92, 101))	('disulfide', 'Chemical', 'MESH:D004220', (40, 49))	('PDIA5', 'Gene', '10954', (112, 117))	('dissociation', 'Var', (23, 35))	('ATF6', 'Gene', '22926', (128, 132))
61977	31064137	Phosphorylation of eIF2alpha leads to the attenuation of the global translation, reducing the folding demand on the ER.	('reducing', 'NegReg', (81, 89))	('folding demand', 'MPA', (94, 108))	('global translation', 'MPA', (61, 79))	('Phosphorylation', 'Var', (0, 15))	('eIF2alpha', 'Gene', (19, 28))	('attenuation', 'NegReg', (42, 53))	('eIF2alpha', 'Gene', '83939', (19, 28))
61982	31064137	GADD34 is activated downstream of CHOP and its expression results in a negative feedback loop for PERK signaling pathway.	('GADD34', 'Gene', (0, 6))	('PERK', 'Gene', '9451', (98, 102))	('CHOP', 'Gene', '1649', (34, 38))	('expression', 'Var', (47, 57))	('negative feedback loop', 'MPA', (71, 93))	('results in', 'Reg', (58, 68))	('PERK', 'Gene', (98, 102))	('CHOP', 'Gene', (34, 38))	('GADD34', 'Gene', '23645', (0, 6))
61989	31064137	High GRP78 expression is associated with metastasis and poor prognosis in breast, colon, esophageal, lung and skin cancers.	('skin cancers', 'Disease', 'MESH:D012878', (110, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('High', 'Var', (0, 4))	('associated', 'Reg', (25, 35))	('esophageal', 'Disease', (89, 99))	('expression', 'MPA', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('skin cancer', 'Phenotype', 'HP:0008069', (110, 121))	('GRP78', 'Gene', '3309', (5, 10))	('lung', 'Disease', (101, 105))	('GRP78', 'Gene', (5, 10))	('skin cancers', 'Disease', (110, 122))	('skin cancers', 'Phenotype', 'HP:0008069', (110, 122))	('breast', 'Disease', (74, 80))	('metastasis', 'CPA', (41, 51))	('colon', 'Disease', (82, 87))
61990	31064137	Moreover, ablation of the UPR sensors leads to a significant reduction in tumor growth in different types of cancers like colon, pancreatic, breast cancer and GBM.	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('GBM', 'Disease', (159, 162))	('colon', 'Disease', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('reduction', 'NegReg', (61, 70))	('cancers', 'Disease', (109, 116))	('pancreatic', 'Disease', 'MESH:D010195', (129, 139))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('GBM', 'Phenotype', 'HP:0012174', (159, 162))	('tumor', 'Disease', (74, 79))	('ablation', 'Var', (10, 18))	('breast cancer', 'Disease', (141, 154))	('pancreatic', 'Disease', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
61997	31064137	The three sensors of the UPR have been recently linked to tumor cell migration/invasion processes such as ECM and actin cytoskeleton remodeling and cytoskeleton reorganization, modification of cellular adhesion, activation of signaling pathways associated with cell mobility, and EMT.	('signaling pathways', 'Pathway', (226, 244))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('modification', 'Var', (177, 189))	('cytoskeleton reorganization', 'CPA', (148, 175))	('ECM', 'CPA', (106, 109))	('EMT', 'CPA', (280, 283))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cellular', 'Protein', (193, 201))	('activation', 'PosReg', (212, 222))	('linked', 'Reg', (48, 54))
62031	31064137	For instance, in GBM, the inhibition of IRE1 decreases the expression of proangiogenic factors such as VEGFA, IL1beta, IL6, and CXCL8 (also named IL8) and leads to a reduction of angiogenesis.	('IL8', 'Gene', (146, 149))	('VEGFA', 'Gene', (103, 108))	('reduction', 'NegReg', (166, 175))	('IL6', 'Gene', (119, 122))	('IL8', 'Gene', '3576', (146, 149))	('inhibition', 'Var', (26, 36))	('decreases', 'NegReg', (45, 54))	('IL1beta', 'Gene', (110, 117))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('CXCL8', 'Gene', '3576', (128, 133))	('angiogenesis', 'CPA', (179, 191))	('expression', 'MPA', (59, 69))	('VEGFA', 'Gene', '7422', (103, 108))	('IL1beta', 'Gene', '3553', (110, 117))	('IRE1', 'Gene', (40, 44))	('CXCL8', 'Gene', (128, 133))	('IL6', 'Gene', '3569', (119, 122))
62033	31064137	Selective impairment of IRE1 RNase increase invasion, vessel co-option capacity and mesenchymal features in U87 glioma cells.	('increase', 'PosReg', (35, 43))	('IRE1 RNase', 'Protein', (24, 34))	('invasion', 'CPA', (44, 52))	('impairment', 'Var', (10, 20))	('U87', 'CellLine', 'CVCL:0022', (108, 111))	('glioma', 'Disease', (112, 118))	('mesenchymal features', 'CPA', (84, 104))	('vessel co-option capacity', 'CPA', (54, 79))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))
62034	31064137	Interestingly, in colorectal cancers high XBP1s expression is associated with metastatic tumors in patients and with cancer cell invasion in vitro by controlling VEGFR2 expression.	('tumors', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('XBP1s', 'Gene', (42, 47))	('expression', 'MPA', (169, 179))	('VEGFR2', 'Gene', (162, 168))	('associated', 'Reg', (62, 72))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('controlling', 'Reg', (150, 161))	('VEGFR2', 'Gene', '3791', (162, 168))	('colorectal cancers', 'Disease', 'MESH:D015179', (18, 36))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('high', 'Var', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('colorectal cancers', 'Disease', (18, 36))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
62046	31064137	However, other studies indicate that XBP1s increases the metastatic potential of tumor cells by the induction of the expression of several EMT transcription factors, including SNAI1, SNAI2, ZEB2 and TCF3.	('SNAI1', 'Gene', (176, 181))	('TCF3', 'Gene', '6929', (199, 203))	('ZEB2', 'Gene', (190, 194))	('XBP1s', 'Var', (37, 42))	('expression', 'MPA', (117, 127))	('TCF3', 'Gene', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('increases', 'PosReg', (43, 52))	('ZEB2', 'Gene', '9839', (190, 194))	('SNAI2', 'Gene', '6591', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SNAI1', 'Gene', '6615', (176, 181))	('SNAI2', 'Gene', (183, 188))	('tumor', 'Disease', (81, 86))
62052	31064137	Remarkably, the regulation of cytoskeleton dynamics by IRE1 is independent of its canonical RNase activity, but instead IRE1 serves as a scaffold that recruits FLNA, scaffolding to PKCalpha, to increase FLNA phosphorylation.	('FLNA', 'Protein', (203, 207))	('increase', 'PosReg', (194, 202))	('FLNA', 'Protein', (160, 164))	('IRE1', 'Var', (120, 124))	('PKCalpha', 'Gene', (181, 189))	('PKCalpha', 'Gene', '5578', (181, 189))
62054	31064137	In addition, using a panel of tumor cell lines, IRE1 silencing decreased tumor cell migration.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('IRE1', 'Gene', (48, 52))	('decreased', 'NegReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (73, 78))	('silencing', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
62059	31064137	Furthermore, silencing of XBP1 decreased the formation of lung metastases in an orthotopic TNBC xenograft mouse model (Figure 2, (2)).	('XBP1', 'Gene', (26, 30))	('decreased', 'NegReg', (31, 40))	('lung metastases', 'Disease', (58, 73))	('lung metastases', 'Disease', 'MESH:D009362', (58, 73))	('silencing', 'Var', (13, 22))	('mouse', 'Species', '10090', (106, 111))
62063	31064137	Using a bioinformatic approach that integrates gene mutations and DNA methylation changes, CREB3L1 was identified as an important regulatory driver in prostate cancer.	('mutations', 'Var', (52, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('CREB3L1', 'Gene', (91, 98))	('CREB3L1', 'Gene', '90993', (91, 98))	('prostate cancer', 'Disease', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))
62065	31064137	Surprisingly, CREB3L1 is lost in metastatic cells from breast and bladder tumors due to the methylation of its gene (in the promoter region and the first intronic region) leading to an epigenetic silencing.	('CREB3L1', 'Gene', '90993', (14, 21))	('bladder tumors', 'Disease', (66, 80))	('methylation', 'Var', (92, 103))	('bladder tumors', 'Phenotype', 'HP:0009725', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast', 'Disease', (55, 61))	('bladder tumors', 'Disease', 'MESH:D001749', (66, 80))	('epigenetic silencing', 'MPA', (185, 205))	('CREB3L1', 'Gene', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
62070	31064137	CREB3L1 inhibition also reduces FAK activation, an important kinase that regulates cell/ECM interaction via its impact on ECM (Figure 1, (2)).	('reduces', 'NegReg', (24, 31))	('CREB3L1', 'Gene', (0, 7))	('inhibition', 'Var', (8, 18))	('FAK activation', 'MPA', (32, 46))	('CREB3L1', 'Gene', '90993', (0, 7))
62072	31064137	PERK-mediated eIF2alpha phosphorylation also induces LAMP3-dependent cervix cancer cell migration under hypoxia.	('PERK', 'Gene', (0, 4))	('cervix cancer', 'Disease', (69, 82))	('eIF2alpha', 'Gene', (14, 23))	('PERK', 'Gene', '9451', (0, 4))	('induces', 'Reg', (45, 52))	('eIF2alpha', 'Gene', '83939', (14, 23))	('LAMP3', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('hypoxia', 'Disease', (104, 111))	('cervix cancer', 'Disease', 'MESH:D002583', (69, 82))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('cervix cancer', 'Phenotype', 'HP:0030079', (69, 82))	('phosphorylation', 'Var', (24, 39))	('LAMP3', 'Gene', '27074', (53, 58))
62073	31064137	Importantly, LAMP3 expression is also associated with metastasis and poor prognostic in breast, cervix and colorectal cancers and head and neck squamous carcinomas.	('cervix', 'Disease', (96, 102))	('associated', 'Reg', (38, 48))	('LAMP3', 'Gene', '27074', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('expression', 'Var', (19, 29))	('neck squamous carcinomas', 'Disease', 'MESH:D000077195', (139, 163))	('colorectal cancers', 'Disease', 'MESH:D015179', (107, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('head and neck squamous carcinomas', 'Phenotype', 'HP:0012288', (130, 163))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (144, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('breast', 'Disease', (88, 94))	('neck squamous carcinomas', 'Disease', (139, 163))	('metastasis', 'CPA', (54, 64))	('colorectal cancers', 'Disease', (107, 125))	('LAMP3', 'Gene', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
62079	31064137	Interestingly, several inhibitors of the ER stress sensors have been reported to affect tumor migration.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibitors', 'Var', (23, 33))	('affect', 'Reg', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
62083	31064137	IRE1 inhibitors such as quercetin and sunitinib also inhibit tumor migration by modulating the same molecular actors of the ECM remodeling and intracellular signaling pathways, i.e., metalloproteinases and kinases, but again, these effects were not yet proven to occur through the inhibition of IRE1.	('IRE1', 'Gene', (0, 4))	('sunitinib', 'Chemical', 'MESH:D000077210', (38, 47))	('inhibit', 'NegReg', (53, 60))	('inhibitors', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('modulating', 'Reg', (80, 90))	('metalloproteinases', 'Pathway', (183, 201))	('quercetin', 'Chemical', 'MESH:D011794', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('kinases', 'Pathway', (206, 213))	('tumor', 'Disease', (61, 66))
62085	31064137	The PERK inhibitor GSK2606414 blocks brain tumor cell migration, but this inhibitor is also known to target RIPK1 and c-KIT.	('GSK2606414', 'Chemical', 'MESH:C576403', (19, 29))	('blocks', 'NegReg', (30, 36))	('RIPK1', 'Gene', '8737', (108, 113))	('GSK2606414', 'Var', (19, 29))	('brain tumor', 'Disease', (37, 48))	('brain tumor', 'Disease', 'MESH:D001932', (37, 48))	('PERK', 'Gene', '9451', (4, 8))	('brain tumor', 'Phenotype', 'HP:0030692', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('c-KIT', 'Gene', (118, 123))	('RIPK1', 'Gene', (108, 113))	('c-KIT', 'Gene', '3815', (118, 123))	('PERK', 'Gene', (4, 8))
62089	31064137	; and FONDECYT 1140549, FONDAP program 15150012, Millennium Institute P09-015-F, Michael J Fox Foundation for Parkinson's Research, Target Validation grant 9277, FONDEF ID16I10223, FONDEF D11E1007, US Office of Naval Research-Global N62909-16-1-2003, US Air Force Office of Scientific Research FA9550-16-1-0384, ALSRP Therapeutic Idea Award AL150111, Muscular Dystrophy Association 382453, Seed grant Leading House for the Latin American Region, Switzerland, and CONICYT-Brazil 441921/2016-7 to C.H.	('Muscular Dystrophy', 'Disease', (351, 369))	('Muscular Dystrophy', 'Phenotype', 'HP:0003560', (351, 369))	('Muscular Dystrophy', 'Disease', 'MESH:D009136', (351, 369))	("Parkinson'", 'Disease', 'MESH:D010302', (110, 120))	("Parkinson'", 'Disease', (110, 120))	('AL150111', 'Var', (341, 349))
62111	30867233	Finally, we discuss how pharmacological activation of the proteasome could produce novel therapeutics to treat neurodegenerative disease.	('neurodegenerative disease', 'Disease', (111, 136))	('pharmacological', 'Var', (24, 39))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (111, 136))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (111, 136))
62117	30867233	Interestingly, deletion of the first eight alpha3 residues (alpha3 N-20S) sufficiently destabilizes the closed-gate conformation and accelerates the entry and degradation of peptides.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('destabilizes', 'NegReg', (87, 99))	('entry', 'MPA', (149, 154))	('closed-gate conformation', 'MPA', (104, 128))	('deletion', 'Var', (15, 23))	('accelerates', 'PosReg', (133, 144))	('degradation of peptides', 'MPA', (159, 182))
62119	30867233	Wild-type 20S proteasome activity is similarly accelerated when bound to a proteasome activator (e.g., 19S/PA700, 11S/PA28, Blm10/PA200).	('accelerated', 'PosReg', (47, 58))	('20S', 'MPA', (10, 13))	('Blm10/PA200', 'Var', (124, 135))	('Blm10', 'Chemical', '-', (124, 129))	('bound', 'Interaction', (64, 69))
62124	30867233	As expected, mutation to a serine residue retains significant activity, whereas mutation to an alanine residue completely abolishes activity.	('activity', 'MPA', (62, 70))	('activity', 'MPA', (132, 140))	('mutation', 'Var', (13, 21))	('serine', 'Chemical', 'MESH:D012694', (27, 33))	('abolishes', 'NegReg', (122, 131))	('alanine', 'Chemical', 'MESH:D000409', (95, 102))
62130	30867233	Tyrosine pore loops inside the ATPases "grip" the substrate and this tight association enables the processive process of substrate unfolding and translocation into the 20S core.	('Tyrosine', 'Var', (0, 8))	('ATP', 'Chemical', 'MESH:D000255', (31, 34))	('translocation', 'MPA', (145, 158))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))
62142	30867233	PA200/Blm10-containing proteasomes specifically catalyze the acetylation-dependent, but not polyubiquitination-dependent, core histone degradation during somatic DNA damage response and spermatogenesis.	('PA200/Blm10-containing', 'Var', (0, 22))	('catalyze', 'Reg', (48, 56))	('acetylation-dependent', 'MPA', (61, 82))	('Blm10', 'Chemical', '-', (6, 11))	('core histone degradation', 'MPA', (122, 146))	('N', 'Chemical', 'MESH:D009584', (163, 164))
62144	30867233	The proteasome degrades many cell cycle regulatory proteins that typically have short half-lives (e.g., cyclin B1, p21, p27) and tumor suppressors (e.g., p53) promoting cycle progression.	('p21', 'Var', (115, 118))	('degrades', 'NegReg', (15, 23))	('cyclin B1', 'Protein', (104, 113))	('p27', 'Var', (120, 123))	('cycle progression', 'CPA', (169, 186))	('p53', 'Var', (154, 157))	('promoting', 'PosReg', (159, 168))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cell cycle', 'Protein', (29, 39))	('tumor', 'Disease', (129, 134))
62165	30867233	Multiple physiologic conditions also lead to accumulation of misfolded proteins in the ER and subsequent UPR activation, including hypoxia, glucose deprivation, oxidative stress, and mutations in certain secretory proteins.	('hypoxia', 'Disease', (131, 138))	('mutations', 'Var', (183, 192))	('glucose deprivation', 'Disease', 'MESH:D012892', (140, 159))	('accumulation', 'PosReg', (45, 57))	('UPR activation', 'PosReg', (105, 119))	('oxidative stress', 'Phenotype', 'HP:0025464', (161, 177))	('glucose deprivation', 'Disease', (140, 159))	('hypoxia', 'Disease', 'MESH:D000860', (131, 138))	('misfolded proteins', 'MPA', (61, 79))
62190	30867233	Second, as with other peptide aldehydes, MG-132 also inhibits (albeit with much lower affinity) calpains and cathepsins; therefore, it is necessary to perform control experiments to confirm that the observed effects are due to proteasome inhibition.	('MG-132', 'Var', (41, 47))	('peptide aldehydes', 'Chemical', '-', (22, 39))	('MG-132', 'Chemical', 'MESH:C072553', (41, 47))	('pain', 'Phenotype', 'HP:0012531', (99, 103))	('cathepsins', 'Protein', (109, 119))	('inhibits', 'NegReg', (53, 61))	('pain', 'Disease', 'MESH:D010146', (99, 103))	('pain', 'Disease', (99, 103))
62220	30867233	Due to solvent exposure in the P2 position, P2 can accommodate a range of moieties without affecting proteasome binding and is often the site for modifications aimed at improving inhibitor solubility and stability.	('improving', 'PosReg', (169, 178))	('P2', 'Chemical', 'MESH:C020845', (31, 33))	('modifications', 'Var', (146, 159))	('inhibitor solubility', 'MPA', (179, 199))	('stability', 'MPA', (204, 213))	('P2', 'Chemical', 'MESH:C020845', (44, 46))
62223	30867233	Discordant data in the yeast 20S proteasome structure in complex with ALLN showed that the inhibitor bound to all six proteasome active sites, but the biochemical data indicated that the ALLN proteasome inhibitor preferentially inhibited the beta5 site (with very low activity against beta1 and beta2) unless used at extremely high concentrations.	('N', 'Chemical', 'MESH:D009584', (190, 191))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('inhibited', 'NegReg', (228, 237))	('beta5', 'Protein', (242, 247))	('preferentially', 'PosReg', (213, 227))	('ALLN', 'Var', (187, 191))
62225	30867233	Exploiting beta5c/beta5i residue differences near the S1 pocket improved PKS21187 (AsnEDA-based inhibitor) affinity for beta5i down to 15 nM (from 58 nM) and successfully improved selectivity (20-fold) over beta5c (Santos et al., 2017).	('AsnEDA', 'Chemical', '-', (83, 89))	('PKS21187', 'Gene', (73, 81))	('differences', 'Var', (33, 44))	('selectivity', 'MPA', (180, 191))	('improved', 'PosReg', (64, 72))	('improved', 'PosReg', (171, 179))	('affinity', 'MPA', (107, 115))
62229	30867233	Epoxyketone warhead replacement with vinyl sulfone moieties in beta5 inhibitors further improves beta5 site (but not beta5i site) selectivity.	('improves', 'PosReg', (88, 96))	('beta5 site', 'MPA', (97, 107))	('Epoxyketone', 'Chemical', '-', (0, 11))	('replacement', 'Var', (20, 31))	('vinyl sulfone', 'Chemical', 'MESH:C009873', (37, 50))
62263	30867233	Unlike ubiquitin-R-GFP, the reporter UbG76V-GFP cannot be deubiquitinated (thereby bypassing the N-end rule pathway) and is a model substrate for the in vivo ubiquitin fusion degradation (UFD) pathway.	('UbG76V-GFP', 'Var', (37, 47))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('N-end rule pathway', 'Pathway', (97, 115))
62269	30867233	First, proteasome inhibition stabilizes the NF-kappaB complex in the cytoplasm and reduces NF-kappaB-dependent gene expression.	('stabilizes', 'Reg', (29, 39))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('reduces', 'NegReg', (83, 90))	('NF-kappaB-dependent', 'Gene', (91, 110))	('NF-kappaB complex', 'Protein', (44, 61))	('inhibition', 'Var', (18, 28))	('proteasome', 'Protein', (7, 17))
62274	30867233	Third, proteasome inhibition stabilizes various tumor suppressor proteins (e.g., p27, p53) and prevents cell cycle progression.	('p27', 'Var', (81, 84))	('prevents', 'NegReg', (95, 103))	('tumor', 'Disease', (48, 53))	('stabilizes', 'NegReg', (29, 39))	('cell cycle progression', 'CPA', (104, 126))	('inhibition', 'Var', (18, 28))	('p53', 'Protein', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('proteasome', 'Protein', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
62278	30867233	In addition, mutations in the beta5 bortezomib binding pocket are associated with bortezomib resistance in MM cell lines.	('bortezomib', 'Chemical', 'MESH:D000069286', (36, 46))	('bortezomib', 'Chemical', 'MESH:D000069286', (82, 92))	('associated', 'Reg', (66, 76))	('bortezomib resistance', 'MPA', (82, 103))	('mutations', 'Var', (13, 22))
62284	30867233	Bone marrow stem cells (BMSCs) isolated from patients with bortezomib-resistance MM have different cytokine profiles than BMSCs from patients with bortezomib-sensitive MM.	('bortezomib-resistance', 'Var', (59, 80))	('bortezomib', 'Chemical', 'MESH:D000069286', (147, 157))	('bortezomib', 'Chemical', 'MESH:D000069286', (59, 69))	('cytokine profiles', 'MPA', (99, 116))	('different', 'Reg', (89, 98))
62297	30867233	Many in vivo mouse studies and in vitro DRG explant studies of bortezomib-induced PN demonstrate accumulation of ubiquitinated proteins in DRG soma, defects in mitochondrial calcium homeostasis, disrupted mitochondrial axonal transport, alterations in tubulin polymerization and localization, and defects in fast axonal transport due to blockage of axonal protein turnover.	('tubulin polymerization', 'MPA', (252, 274))	('blockage', 'NegReg', (337, 345))	('localization', 'MPA', (279, 291))	('defects', 'Var', (149, 156))	('defects', 'NegReg', (297, 304))	('fast axonal transport', 'MPA', (308, 329))	('axonal protein turnover', 'MPA', (349, 372))	('ubiquitinated proteins', 'MPA', (113, 135))	('disrupted', 'NegReg', (195, 204))	('accumulation', 'PosReg', (97, 109))	('mitochondrial calcium homeostasis', 'MPA', (160, 193))	('bortezomib', 'Chemical', 'MESH:D000069286', (63, 73))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('calcium', 'Chemical', 'MESH:D002118', (174, 181))	('mitochondrial axonal transport', 'MPA', (205, 235))	('alterations', 'Reg', (237, 248))
62322	30867233	Carfilzomib has a tripeptide backbone containing phenylalanine, leucine, and homophenylalanine with a terminal epoxyketone group that forms an irreversible covalently bond with the proteasome catalytic threonine.	('leucine', 'Chemical', 'MESH:D007930', (64, 71))	('threonine', 'Chemical', 'MESH:D013912', (202, 211))	('epoxyketone', 'Chemical', '-', (111, 122))	('homophenylalanine', 'Chemical', 'MESH:C014328', (77, 94))	('phenylalanine', 'Chemical', 'MESH:D010649', (49, 62))	('Carfilzomib', 'Chemical', 'MESH:C524865', (0, 11))	('leucine', 'Var', (64, 71))	('phenylalanine', 'Chemical', 'MESH:D010649', (81, 94))	('tripeptide', 'Chemical', '-', (18, 28))	('phenylalanine', 'Var', (49, 62))
62386	30867233	Mutations in Rpn11 that disrupt its catalytic activity stall ubiquitin substrate degradation and eventually lead to cell death.	('catalytic activity', 'MPA', (36, 54))	('ubiquitin substrate degradation', 'MPA', (61, 92))	('Mutations', 'Var', (0, 9))	('lead to', 'Reg', (108, 115))	('death', 'Disease', 'MESH:D003643', (121, 126))	('death', 'Disease', (121, 126))	('stall', 'NegReg', (55, 60))	('Rpn11', 'Gene', (13, 18))
62390	30867233	This antitumor activity suggests that Rpn11 inhibition may be an effective alternative to active site inhibition for treating malignancies.	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('Rpn11', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('inhibition', 'Var', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('malignancies', 'Disease', (126, 138))	('tumor', 'Disease', (9, 14))
62391	30867233	Enhancing proteasome function has the potential to treat protein misfolding disorders, such as neurodegenerative diseases, and Usp14 inhibition may promote ubiquitin-dependent protein degradation.	('Enhancing', 'PosReg', (0, 9))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (95, 121))	('Usp14', 'Gene', (127, 132))	('proteasome', 'Protein', (10, 20))	('protein misfolding disorders', 'Disease', (57, 85))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (95, 121))	('inhibition', 'Var', (133, 143))	('ubiquitin-dependent protein degradation', 'MPA', (156, 195))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (95, 120))	('neurodegenerative diseases', 'Disease', (95, 121))	('promote', 'PosReg', (148, 155))
62394	30867233	Impaired proteasome function has been implicated, as a primary cause or a secondary consequence, in the pathogenesis of many neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington diseases.	('neurodegenerative diseases', 'Disease', (125, 151))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (125, 150))	('proteasome', 'Protein', (9, 19))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (125, 151))	('Huntington diseases', 'Disease', (189, 208))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (125, 151))	('Alzheimer, Parkinson', 'Disease', 'MESH:D000544', (163, 183))	('Huntington diseases', 'Disease', 'MESH:D006816', (189, 208))	('Impaired', 'Var', (0, 8))
62398	30867233	generated an HEK293 cell line with a stable transfection of a mutant 20S alpha subunit (alpha3 N) that induces 20S gate opening.	('mutant', 'Var', (62, 68))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('HEK293', 'CellLine', 'CVCL:0045', (13, 19))	('20S gate opening', 'MPA', (111, 127))	('induces', 'Reg', (103, 110))
62399	30867233	They showed that HEK293-alpha3 N cells had increased degradation of proteasome substrates (including tau protein) and increased resistance to oxidative stress compared with the wild type.	('HEK293', 'CellLine', 'CVCL:0045', (17, 23))	('increased', 'PosReg', (118, 127))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('oxidative stress', 'Phenotype', 'HP:0025464', (142, 158))	('increased', 'PosReg', (43, 52))	('HEK293-alpha3', 'Var', (17, 30))	('resistance to oxidative stress', 'MPA', (128, 158))
62402	30867233	Fine-tuning the pharmacological properties of proteasome inhibitors may improve their efficacy for use in solid tumors.	('solid tumors', 'Disease', (106, 118))	('proteasome', 'Protein', (46, 56))	('improve', 'PosReg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('Fine-tuning', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('efficacy', 'MPA', (86, 94))
62404	30867233	ABP activity-based probe amc amino-4-methylcoumarin AsnEDA asparagine-ethylenediamine BMSC bone marrow stem cell CNS central nervous system DRG dorsal root ganglion DUB deubiquitinase E-64 (2S,3S)-3-[[(2S)-1-[4-(diaminomethylideneamino)butylamino]-4-methyl-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid EM electron microscopy ER endoplasmic reticulum ERAD endoplasmic reticulum-associated protein degradation FDA U.S. Food and Drug Administration GBM glioblastoma GFP green fluorescent protein GST glutathione S-transferase HbYX hydrophobic-tyrosine-any residue HEK293 human embryonic kidney 293 IFN interferon IKK IkappaB kinase KZR-616 (2S,3R)-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide LU-102 N-[1-[4-(aminomethyl)-3-methylsulfonylphenyl]but-3-en-2-yl]-5-[[(2S)-2-azido-3-phenylpropanoyl]amino]-2-(2-methylpropyl)-4-oxooctanamide MG-132 carbobenzyl-Leu-Leu-Leu-aldehyde MHC-I major histocompatibility complex class I MLN2238 ([(1R)-1-[[2-[(2 5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid MLN9708 4-(carboxymethyl)-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid MM multiple myeloma NF-kappaB nuclear factor-kappaB NPI-0052 (1S,2R,5R)-2-(2-chloroethyl)-5-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-1-methyl-7-oxa-4-azabicyclo[3.2.0]heptane-3,6-dione ODC ornithine decarboxylase ONX-0912 (or PR-047) N-[(2S)-3-methoxy-1-[[(2S)-3-methoxy-1-[[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide ONX-0914 (or PR-957) (2S)-3-(4-methoxyphenyl)-N-[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide PN peripheral neuropathy PNS peripheral nervous system PS-341 Pyz-Phe-boroLeu RRMM relapsed/refractory multiple myeloma Suc-LLVY succinyl-leucine-leucine-valine-tyrosine TPP-II tripeptidyl-protease II UBL ubiquitin-like UFD ubiquitin fusion degradation pathway UPR unfolded protein response UPS ubiquitin proteasome system Wrote or contributed to the writing of the manuscript: Thibaudeau, Smith.	('5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid', 'Chemical', '-', (1072, 1136))	('methyl-', 'Chemical', '-', (250, 257))	('glioblastoma', 'Disease', 'MESH:D005909', (458, 470))	('N', 'Chemical', 'MESH:D009584', (1909, 1910))	('asparagine-ethylenediamine', 'Chemical', '-', (59, 85))	('N', 'Chemical', 'MESH:D009584', (1298, 1299))	('[(1R)-1-[[2-[(', 'Chemical', '-', (1165, 1179))	('embryonic kidney', 'Disease', (582, 598))	('N', 'Chemical', 'MESH:D009584', (823, 824))	('N', 'Chemical', 'MESH:D009584', (1497, 1498))	('N', 'Chemical', 'MESH:D009584', (1330, 1331))	('ONX-0912', 'Chemical', 'MESH:C554738', (1496, 1504))	('TPP-II', 'Chemical', '-', (2053, 2059))	('leucine', 'Chemical', 'MESH:D007930', (2021, 2028))	('multiple myeloma', 'Phenotype', 'HP:0006775', (1281, 1297))	('glioblastoma', 'Disease', (458, 470))	('N', 'Chemical', 'MESH:D009584', (1749, 1750))	('AsnEDA', 'Chemical', '-', (52, 58))	('leucine', 'Chemical', 'MESH:D007930', (2029, 2036))	('Leu-Leu-Leu-aldehyde', 'Disease', (979, 999))	('N', 'Chemical', 'MESH:D009584', (1884, 1885))	('glioblastoma', 'Phenotype', 'HP:0012174', (458, 470))	('Pyz-Phe-boroLeu', 'Chemical', '-', (1945, 1960))	('N', 'Chemical', 'MESH:D009584', (1139, 1140))	('amino-4-methylcoumarin', 'Chemical', '-', (29, 51))	('multiple myeloma', 'Phenotype', 'HP:0006775', (1986, 2002))	('ONX-0914', 'Chemical', 'MESH:C542291', (1703, 1711))	('methyl-', 'Chemical', '-', (1669, 1676))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (1886, 1907))	('N', 'Chemical', 'MESH:D009584', (653, 654))	('peripheral neuropathy', 'Disease', (1886, 1907))	('N', 'Chemical', 'MESH:D009584', (605, 606))	('multiple myeloma', 'Disease', 'MESH:D009101', (1281, 1297))	('N', 'Chemical', 'MESH:D009584', (1049, 1050))	('embryonic kidney', 'Disease', 'MESH:D007674', (582, 598))	('N', 'Chemical', 'MESH:D009584', (114, 115))	('chloroethyl', 'Chemical', '-', (1355, 1366))	('HEK293', 'CellLine', 'CVCL:0045', (569, 575))	('tyrosine', 'Chemical', 'MESH:D014443', (2044, 2052))	('PS-341', 'Chemical', 'MESH:D000069286', (1938, 1944))	('MG-132', 'Chemical', 'MESH:C072553', (960, 966))	('multiple myeloma', 'Disease', 'MESH:D009101', (1986, 2002))	('N', 'Chemical', 'MESH:D009584', (1517, 1518))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (1886, 1907))	('amc', 'Chemical', 'MESH:C028743', (25, 28))	('multiple myeloma', 'Disease', (1281, 1297))	('E-64', 'Chemical', 'MESH:C024974', (184, 188))	('Leu-Leu-Leu-aldehyde', 'Disease', 'MESH:D016111', (979, 999))	('methyl-', 'Chemical', '-', (1418, 1425))	('glutathione', 'Chemical', 'MESH:D005978', (505, 516))	('multiple myeloma', 'Disease', (1986, 2002))	('LU-102', 'Chemical', 'MESH:C000602005', (816, 822))	('MLN2238', 'Var', (1047, 1054))	('tyrosine', 'Chemical', 'MESH:D014443', (548, 556))	('[(1R)-1-[[2-[(', 'Chemical', '-', (1056, 1070))	('Suc-LLVY', 'Chemical', '-', (2003, 2011))	('N', 'Chemical', 'MESH:D009584', (1704, 1705))
62405	30283731	Lessons learned from rindopepimut treatment in patients with EGFRvIII-expressing glioblastoma EGFRvIII is the most common mutation of EGFR and results in the creation of a tumor-specific antigen that is detectable in 23-33% of human glioblastoma (GBM).	('tumor', 'Disease', (172, 177))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('EGFR', 'Gene', '1956', (134, 138))	('EGFR', 'Gene', '1956', (94, 98))	('mutation', 'Var', (122, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (233, 245))	('EGFR', 'Gene', '1956', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('GBM', 'Phenotype', 'HP:0012174', (247, 250))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('glioblastoma', 'Disease', (233, 245))	('results in', 'Reg', (143, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (233, 245))	('glioblastoma', 'Disease', (81, 93))	('EGFR', 'Gene', (134, 138))	('human', 'Species', '9606', (227, 232))	('EGFR', 'Gene', (94, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('EGFR', 'Gene', (61, 65))
62406	30283731	EGFRvIII arises due to the deletion of EGFR exons 2-7, which generates a truncated extracellular domain capable of constitutive EGFR activation.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('deletion', 'Var', (27, 35))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('EGFR', 'Gene', '1956', (0, 4))
62422	30283731	Surprisingly, there was suggestion toward improved survival of patients treated with rindopepimut in the exploratory analysis of patients with significant residual disease, although this effect was less pronounced when tumor burden was defined by each investigator rather than central review.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('rindopepimut', 'Var', (85, 97))	('improved', 'PosReg', (42, 50))	('tumor', 'Disease', (219, 224))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('survival', 'MPA', (51, 59))
62423	30283731	The study confirmed findings of earlier phase clinical trials showing that, rindopepimut induces a moderate to rapid EGFRvIII-specific antibody response in the majority of patients, which suggests that failure to generate an immune response was not a primary reason for the lack of improved survival.	('failure', 'Disease', (202, 209))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('rindopepimut', 'Var', (76, 88))	('patients', 'Species', '9606', (172, 180))	('failure', 'Disease', 'MESH:D017093', (202, 209))
62462	29644006	Thus, HOTAIR can act as modular scaffold, with different binding sites for harboring demethylase (LSD1, that mediates the enzymatic demethylation of histone H3 dimethyl lysine 4, H3K4me2) and methylase (PRC2 and the histone H3 lysine 27 - H3K27 - methylase EZH2) complexes, resulting in the transcriptional inhibition of the HOXD locus on chromosome 2 by epigenetic control of the chromatin structure.	('HOXD', 'Gene', '3230', (325, 329))	('demethylase', 'Gene', (85, 96))	('demethylase', 'Gene', '8932', (85, 96))	('H3', 'Chemical', 'MESH:C012616', (179, 181))	('lysine', 'Chemical', 'MESH:D008239', (227, 233))	('histone H3 dimethyl lysine 4', 'Chemical', '-', (149, 177))	('transcriptional', 'MPA', (291, 306))	('H3', 'Chemical', 'MESH:C012616', (224, 226))	('lysine', 'Chemical', 'MESH:D008239', (169, 175))	('H3', 'Chemical', 'MESH:C012616', (239, 241))	('LSD1', 'Gene', (98, 102))	('LSD1', 'Gene', '23028', (98, 102))	('epigenetic', 'Var', (355, 365))	('HOTAIR', 'Gene', '100124700', (6, 12))	('EZH2', 'Gene', '2146', (257, 261))	('EZH2', 'Gene', (257, 261))	('HOXD', 'Gene', (325, 329))	('H3', 'Chemical', 'MESH:C012616', (157, 159))	('HOTAIR', 'Gene', (6, 12))
62475	29644006	In 250 IDH-wt GBMs analyzed for gene copy number, HOTAIR amplification and deletion (either focal or chromosomal) were found in 0.8% (2/250) and in 3.2% of the samples (8/250; Figure 1B), respectively, while no amplifications or deletions were found in 20 IDH-mut GBMs (Figure 1B).	('IDH', 'Gene', (7, 10))	('IDH', 'Gene', '3417', (7, 10))	('HOTAIR', 'Gene', (50, 56))	('deletion', 'Var', (75, 83))	('HOTAIR', 'Gene', '100124700', (50, 56))	('IDH', 'Gene', (256, 259))	('IDH', 'Gene', '3417', (256, 259))
62476	29644006	While HOTAIR levels were high in 3 of the 5 HOTAIR-amplified tumors, it was also present in 1 tumor with gene deletion and in 116 without copy number aberrations (Figure 1B).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('HOTAIR', 'Gene', '100124700', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('HOTAIR', 'Gene', (44, 50))	('gene deletion', 'Var', (105, 118))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('HOTAIR', 'Gene', (6, 12))	('HOTAIR', 'Gene', '100124700', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))
62477	29644006	These data show HOTAIR copy number aberrations are rare in GBM, and unlikely associated with its increased expression levels (p = 0.182).	('copy number aberrations', 'Var', (23, 46))	('HOTAIR', 'Gene', '100124700', (16, 22))	('HOTAIR', 'Gene', (16, 22))
62480	29644006	In a subset of 70 GBMs (66 IDH-wt and 4 IDH-mut) for which both gene expression and methylation data were available, we found the methylation levels of 3 probes located in the intragenic region of HOTAIR (cg00079219, cg18824990 and cg24895871) to be significantly inversely correlated with HOTAIR expression levels (r = -0.36, p = 0.002; r = -0.43, p = 0.0002; and r = -0.35, p = 0.003, respectively; Figure 1D).	('methylation levels', 'MPA', (130, 148))	('IDH', 'Gene', (27, 30))	('cg24895871', 'Var', (232, 242))	('IDH', 'Gene', '3417', (27, 30))	('HOTAIR', 'Gene', (197, 203))	('IDH', 'Gene', (40, 43))	('HOTAIR', 'Gene', (290, 296))	('HOTAIR', 'Gene', '100124700', (197, 203))	('HOTAIR', 'Gene', '100124700', (290, 296))	('inversely', 'NegReg', (264, 273))	('cg18824990', 'Var', (217, 227))	('IDH', 'Gene', '3417', (40, 43))	('cg00079219', 'Var', (205, 215))
62481	29644006	Of note, performing the same analysis exclusively for the IDH-wt GBMs showed that the methylation levels of the probes cg00079219 and cg18824990 were inversely correlated with HOTAIR expression (r = -0.39, p = 0.0002; r = -0.39, p = 0.0014), while methylation levels at the probe cg24895871 lost their association with expression (r = -0.26, p = 0.167).	('HOTAIR', 'Gene', (176, 182))	('IDH', 'Gene', '3417', (58, 61))	('inversely', 'NegReg', (150, 159))	('HOTAIR', 'Gene', '100124700', (176, 182))	('cg00079219', 'Var', (119, 129))	('cg18824990', 'Var', (134, 144))	('methylation levels', 'MPA', (86, 104))	('correlated', 'Interaction', (160, 170))	('IDH', 'Gene', (58, 61))
62482	29644006	We further corroborated the relevance of these associations in IDH-wt GBM patients in the French dataset as the 3 intragenic methylation probes were also found to inversely correlate with HOTAIR expression (cg00079219 r = -0.53, p = 0.016; cg18824990 r = -0.523, p = 0.017; cg24895871 r = -0.521, p = 0.018), and in the combination of IDH-wt glioma grade III and IDH-wt GBM patients (cg00079219 r = -0.43, p = 0.004; cg18824990 r = -0.453, p = 0.002; cg24895871 r = -0.431, p = 0.004).	('cg18824990 r', 'Var', (240, 252))	('cg00079219', 'Var', (207, 217))	('cg18824990', 'Var', (417, 427))	('IDH', 'Gene', '3417', (363, 366))	('cg00079219', 'Var', (384, 394))	('IDH', 'Gene', (63, 66))	('IDH', 'Gene', '3417', (335, 338))	('patients', 'Species', '9606', (74, 82))	('IDH', 'Gene', '3417', (63, 66))	('IDH', 'Gene', (335, 338))	('cg24895871', 'Var', (274, 284))	('cg24895871', 'Var', (451, 461))	('HOTAIR', 'Gene', (188, 194))	('patients', 'Species', '9606', (374, 382))	('IDH', 'Gene', (363, 366))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('HOTAIR', 'Gene', '100124700', (188, 194))	('IDH-wt glioma grade III and IDH', 'Gene', '3417', (335, 366))
62486	29644006	Together, our data suggest an association between methylation and HOTAIR's expression in GBM patients and glioma cell lines, but other mechanisms may be crucial in reactivating HOTAIR in these tumors.	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('HOTAIR', 'Gene', '100124700', (66, 72))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('HOTAIR', 'Gene', (177, 183))	('expression', 'MPA', (75, 85))	('methylation', 'Var', (50, 61))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('HOTAIR', 'Gene', '100124700', (177, 183))	('glioma', 'Disease', (106, 112))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('patients', 'Species', '9606', (93, 101))	('HOTAIR', 'Gene', (66, 72))	('association', 'Interaction', (30, 41))
62488	29644006	Specifically, GBM cell lines with overexpression or silencing of HOXA9 presented increased or reduced expression of HOTAIR, respectively; raising the hypothesis that HOXA9 may directly regulate HOTAIR expression.	('HOTAIR', 'Gene', (194, 200))	('HOXA9', 'Gene', '3205', (65, 70))	('silencing', 'Var', (52, 61))	('reduced', 'NegReg', (94, 101))	('expression', 'MPA', (102, 112))	('HOXA9', 'Gene', '3205', (166, 171))	('HOTAIR', 'Gene', '100124700', (194, 200))	('HOXA9', 'Gene', (65, 70))	('overexpression', 'PosReg', (34, 48))	('HOTAIR', 'Gene', (116, 122))	('HOTAIR', 'Gene', '100124700', (116, 122))	('regulate', 'Reg', (185, 193))	('HOXA9', 'Gene', (166, 171))	('expression', 'MPA', (201, 211))
62493	29644006	In both U251 and U87MG-HOXA9, ChIP-qPCR revealed significantly increased HOXA9 occupancy of the promoter region of HOTAIR in comparison to their respective controls (Figure 2D and 2E; p < 0.0002 for U251; p = 0.0148 for U87MG-HOXA9), confirming that HOXA9 directly interacts with the promoter region of HOTAIR.	('HOTAIR', 'Gene', (115, 121))	('HOXA9', 'Gene', (23, 28))	('HOTAIR', 'Gene', (303, 309))	('increased', 'PosReg', (63, 72))	('HOXA9', 'Gene', (250, 255))	('HOXA9', 'Gene', (226, 231))	('U87MG-HOXA9', 'CellLine', 'CVCL:0022', (17, 28))	('HOTAIR', 'Gene', '100124700', (115, 121))	('U251', 'Var', (8, 12))	('occupancy', 'MPA', (79, 88))	('HOTAIR', 'Gene', '100124700', (303, 309))	('HOXA9', 'Gene', '3205', (73, 78))	('U87MG-HOXA9', 'CellLine', 'CVCL:0022', (220, 231))	('HOXA9', 'Gene', '3205', (23, 28))	('HOXA9', 'Gene', '3205', (250, 255))	('HOXA9', 'Gene', (73, 78))	('HOXA9', 'Gene', '3205', (226, 231))
62515	29644006	Finally, we found that high HOTAIR expression is also associated with shorter overall survival in grade II (n = 226) and grade III (n = 240) glioma patients in the RNA-seq data from the larger TCGA dataset (Supplementary Tables 5 and 6; p = 0.020 and p < 0.0001, respectively; Log-rank test), and independently of patient age, gender, and molecular subtype (IDH and 1p/19q status) in the case of grade II gliomas (p = 0.032; Cox regression model), but not for grade III gliomas (p = 0.395; Cox regression model), in which high HOTAIR levels were highly correlated with wild-type IDH.	('gliomas', 'Phenotype', 'HP:0009733', (470, 477))	('IDH', 'Gene', (358, 361))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('HOTAIR', 'Gene', (527, 533))	('III gliomas', 'Disease', (466, 477))	('IDH', 'Gene', (579, 582))	('overall survival', 'CPA', (78, 94))	('gliomas', 'Phenotype', 'HP:0009733', (405, 412))	('patients', 'Species', '9606', (148, 156))	('high', 'Var', (23, 27))	('II gliomas', 'Disease', (402, 412))	('IDH', 'Gene', '3417', (358, 361))	('glioma', 'Disease', (405, 411))	('IDH', 'Gene', '3417', (579, 582))	('II gliomas', 'Disease', 'MESH:D005910', (467, 477))	('glioma', 'Disease', (470, 476))	('glioma', 'Disease', 'MESH:D005910', (405, 411))	('glioma', 'Disease', 'MESH:D005910', (470, 476))	('patient', 'Species', '9606', (148, 155))	('II gliomas', 'Disease', 'MESH:D005910', (402, 412))	('glioma', 'Disease', (141, 147))	('HOTAIR', 'Gene', '100124700', (28, 34))	('glioma', 'Phenotype', 'HP:0009733', (405, 411))	('III gliomas', 'Disease', 'MESH:D005910', (466, 477))	('shorter', 'NegReg', (70, 77))	('glioma', 'Phenotype', 'HP:0009733', (470, 476))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('HOTAIR', 'Gene', '100124700', (527, 533))	('HOTAIR', 'Gene', (28, 34))	('patient', 'Species', '9606', (314, 321))
62527	29644006	Copy number alterations in HOTAIR locus were rare and did not associate with its expression levels, suggesting this is not a prominent underlying mechanism in GBM.	('HOTAIR', 'Gene', '100124700', (27, 33))	('HOTAIR', 'Gene', (27, 33))	('expression', 'MPA', (81, 91))	('Copy number alterations', 'Var', (0, 23))
62528	29644006	Contrarily, modulation of DNA methylation levels in GBM cell lines by the demethylating agent 5-Aza indicated that intragenic CpGs in HOTAIR locus affected its transcriptional levels in a cell line-dependent manner (globally, most cell lines increased HOTAIR levels upon demethylation, while U87MG did not, possibly attributable to different kinetics of 5-Aza response and/or lack of expression of all necessary HOTAIR transcriptional regulators).	('HOTAIR', 'Gene', '100124700', (412, 418))	('HOTAIR', 'Gene', (252, 258))	('affected', 'Reg', (147, 155))	('5-Aza', 'Chemical', 'MESH:D001374', (94, 99))	('transcriptional levels', 'MPA', (160, 182))	('5-Aza', 'Chemical', 'MESH:D001374', (354, 359))	('demethylation', 'Var', (271, 284))	('increased', 'PosReg', (242, 251))	('HOTAIR', 'Gene', (134, 140))	('HOTAIR', 'Gene', '100124700', (252, 258))	('HOTAIR', 'Gene', '100124700', (134, 140))	('HOTAIR', 'Gene', (412, 418))	('U87MG', 'CellLine', 'CVCL:0022', (292, 297))
62529	29644006	Moreover, methylation probes covering CpG islands in HOTAIR locus showed significant inverse correlations between HOTAIR's intragenic DNA methylation and expression levels in GBM specimens.	('intragenic DNA methylation', 'MPA', (123, 149))	('HOTAIR', 'Gene', (114, 120))	('inverse', 'NegReg', (85, 92))	('HOTAIR', 'Gene', (53, 59))	('HOTAIR', 'Gene', '100124700', (53, 59))	('HOTAIR', 'Gene', '100124700', (114, 120))	('methylation', 'Var', (10, 21))	('expression levels', 'MPA', (154, 171))
62542	29644006	For example, the CT variant of the functional single nucleotide polymorphism rs12826786 in HOTAIR locus was associated with its higher intratumoral expression in glioma, and would require further addressing.	('glioma', 'Disease', (162, 168))	('rs12826786', 'Var', (77, 87))	('HOTAIR', 'Gene', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('HOTAIR', 'Gene', '100124700', (91, 97))	('rs12826786', 'Mutation', 'rs12826786', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('higher', 'PosReg', (128, 134))	('tumor', 'Disease', (140, 145))
62549	29644006	While drugs directly interfering with HOTAIR function are currently being studied but still not clinically used in glioma, it may be interesting to test pharmacological approaches that act upstream of HOTAIR activation, namely PI3K inhibitors (e.g., PI-103 and LY294002) that have been shown to silence HOXA9 transcription, and might thus result in HOTAIR downregulation.	('glioma', 'Disease', (115, 121))	('LY294002', 'Var', (261, 269))	('HOTAIR', 'Gene', (201, 207))	('transcription', 'MPA', (309, 322))	('downregulation', 'NegReg', (356, 370))	('silence', 'NegReg', (295, 302))	('HOTAIR', 'Gene', '100124700', (201, 207))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('LY294002', 'Chemical', 'MESH:C085911', (261, 269))	('HOTAIR', 'Gene', (349, 355))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('HOTAIR', 'Gene', (38, 44))	('HOTAIR', 'Gene', '100124700', (349, 355))	('PI-103', 'Var', (250, 256))	('HOXA9', 'Gene', '3205', (303, 308))	('PI-103', 'Chemical', 'MESH:C522973', (250, 256))	('HOXA9', 'Gene', (303, 308))	('HOTAIR', 'Gene', '100124700', (38, 44))
62555	29644006	Tumor tissues were snap-frozen in dry ice or isopentane cooled in liquid nitrogen directly from the operating room, and stored at -80  C. In the French dataset, 57% of the samples were IDH1 genotyped by EpigenDx (Worcester, MA) using pyrosequencing (assays ADS1703 and ADS1704), while the other 43% by analyzing the most frequent IDH1 mutations in exon 4 (codon 132) using RFLP.	('IDH1', 'Gene', (330, 334))	('IDH1', 'Gene', '3417', (330, 334))	('IDH1', 'Gene', '3417', (185, 189))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('isopentane', 'Chemical', 'MESH:C067038', (45, 55))	('mutations', 'Var', (335, 344))	('nitrogen', 'Chemical', 'MESH:D009584', (73, 81))	('IDH1', 'Gene', (185, 189))
62562	29644006	TCGA Agilent's G4502A 244K gene expression profiles from 572 GBMs, 27 grades II and III gliomas (Supplementary Table 1), and 10 unmatched normal samples were analyzed, and "level 3" values of HOTAIR (probe A_32_P168442) and HOXA9 (probe A_23_P500998) were used.	('III gliomas', 'Disease', 'MESH:D005910', (84, 95))	('HOXA9', 'Gene', '3205', (224, 229))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('G4502A', 'Var', (15, 21))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('HOXA9', 'Gene', (224, 229))	('III gliomas', 'Disease', (84, 95))	('HOTAIR', 'Gene', (192, 198))	('HOTAIR', 'Gene', '100124700', (192, 198))	('G4502A', 'SUBSTITUTION', 'None', (15, 21))
62565	29644006	Cases were classified based on WHO malignancy grade and considering genetic information according to latest WHO recommendations to: IDH-wt; IDH-mut (without 1p/19q codeletion), and IDH-mut and 1p/19q codeleted.	('IDH', 'Gene', (181, 184))	('IDH', 'Gene', '3417', (140, 143))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('IDH', 'Gene', '3417', (181, 184))	('IDH', 'Gene', (132, 135))	('malignancy', 'Disease', (35, 45))	('IDH', 'Gene', '3417', (132, 135))	('1p/19q codeleted', 'Var', (193, 209))	('IDH', 'Gene', (140, 143))
62570	29644006	The human cancer microarray database Oncomine (www.oncomine.com; Oncomine , Compendia Bioscience, Ann Arbor, MI) was used for analysis and visualization of HOTAIR expression (probe 239153_at) in 45 WHO grade II, 98 WHO grade III, and 296 primary WHO grade IV gliomas (Supplementary Table 1).	('Compendia Bioscience', 'Disease', 'None', (76, 96))	('human', 'Species', '9606', (4, 9))	('probe 239153_at', 'Var', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('HOTAIR', 'Gene', (156, 162))	('HOTAIR', 'Gene', '100124700', (156, 162))	('gliomas', 'Phenotype', 'HP:0009733', (259, 266))	('IV gliomas', 'Disease', (256, 266))	('IV gliomas', 'Disease', 'MESH:D005910', (256, 266))	('Compendia Bioscience', 'Disease', (76, 96))	('Oncomine', 'Chemical', '-', (37, 45))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('Oncomine', 'Chemical', '-', (65, 73))
62608	29644006	5-Aza 5-Aza-2'-deoxycytidine ChIP Chromatin-immunoprecipitation FBS fetal bovine Serum GBM glioblastoma HR Hazard Ratio H3K27 histone H3 lysine 27 H3K4me2 histone H3 dimethyl lysine 4 HOTAIR HOX transcript antisense intergenic RNA IDH isocitrate dehydrogenase IgG Immunoglobulin G lncRNA long non-coding RNAs KPS Karnofsky Performance Score LSD1/CoREST/REST lysine specific demethylase 1/REST corepressor 1/RE1-silencing transcription factor MSCV murine stem cell virus MSP methylation-specific PCR mut mutant OS overall survival Pen-Strep penicillin-streptomycin PRC2 polycomb repressor complex 2 qPCR quantitative PCR REMBRANDT Repository of Molecular Brain Neoplasia Data RT-PCR reverse transcription-PCR TCGA The Cancer Genome Atlas WHO World Health Organization wt wildtype	('5-Aza', 'Chemical', 'MESH:D001374', (0, 5))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('H3', 'Chemical', 'MESH:C012616', (163, 165))	('HOTAIR', 'Gene', '100124700', (184, 190))	('LSD1', 'Gene', '23028', (341, 345))	('Cancer Genome Atlas', 'Disease', (717, 736))	('LSD1', 'Gene', (341, 345))	('IDH', 'Gene', (231, 234))	('OS', 'Chemical', '-', (510, 512))	('H3', 'Chemical', 'MESH:C012616', (147, 149))	('glioblastoma', 'Disease', (91, 103))	('CoREST', 'Gene', (346, 352))	('HOTAIR', 'Gene', (184, 190))	('penicillin', 'Chemical', 'MESH:D010406', (540, 550))	('5-Aza', 'Chemical', 'MESH:D001374', (6, 11))	('bovine', 'Species', '9913', (74, 80))	('streptomycin', 'Chemical', 'MESH:D013307', (551, 563))	('Cancer', 'Phenotype', 'HP:0002664', (717, 723))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('IDH', 'Gene', '3417', (231, 234))	('FBS', 'Disease', (64, 67))	('histone H3 dimethyl lysine 4', 'Chemical', '-', (155, 183))	('Pen', 'Gene', (530, 533))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (6, 28))	('FBS', 'Disease', 'MESH:D005198', (64, 67))	('Molecular Brain Neoplasia Data', 'Disease', (644, 674))	('demethylase', 'Gene', (374, 385))	('H3', 'Chemical', 'MESH:C012616', (134, 136))	('lysine', 'Chemical', 'MESH:D008239', (175, 181))	('demethylase', 'Gene', '8932', (374, 385))	('Brain Neoplasia', 'Phenotype', 'HP:0030692', (654, 669))	('Neoplasia', 'Phenotype', 'HP:0002664', (660, 669))	('lysine', 'Chemical', 'MESH:D008239', (137, 143))	('REST corepressor 1', 'Gene', (388, 406))	('lysine', 'Chemical', 'MESH:D008239', (358, 364))	('Pen', 'Gene', '27344', (530, 533))	('murine stem cell virus', 'Species', '258023', (447, 469))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (717, 736))	('Molecular Brain Neoplasia Data', 'Disease', 'MESH:D009369', (644, 674))	('mutant', 'Var', (503, 509))	('MSCV', 'Species', '258023', (442, 446))	('REST corepressor 1', 'Gene', '23186', (388, 406))	('CoREST', 'Gene', '23186', (346, 352))
62615	29383189	Moreover, it was revealed that the expression of HOXD4 have a significant impact on the OS of Grade IV glioma with IDH wild-type and 1p/19q intact according to TCGA data.	('HOXD4', 'Gene', (49, 54))	('impact', 'Reg', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('HOXD4', 'Gene', '3233', (49, 54))	('IDH', 'Gene', (115, 118))	('IDH', 'Gene', '3417', (115, 118))	('glioma', 'Disease', (103, 109))	('expression', 'Var', (35, 45))
62663	29383189	Univariate analysis demonstrated that group with low HOXD4 expression had a considerably better OS than group of high HOXD4 expression in total glioma patients (Figure 3E p<0.001) and WHO II (Figure 3F p<0.001), III (Figure 3G p=0.012).	('better', 'PosReg', (89, 95))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('HOXD4', 'Gene', (53, 58))	('HOXD4', 'Gene', (118, 123))	('patients', 'Species', '9606', (151, 159))	('glioma', 'Disease', (144, 150))	('HOXD4', 'Gene', '3233', (118, 123))	('HOXD4', 'Gene', '3233', (53, 58))	('low', 'Var', (49, 52))
62665	29383189	In a further investigation of TCGA data, we also seek the gene mutation and chromosome gene copy number variation of glioma cohort, and then acquired IDH mutations and 1p19q co-deletion in these samples.	('1p19q', 'Var', (168, 173))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma cohort', 'Disease', 'MESH:D005910', (117, 130))	('IDH', 'Gene', (150, 153))	('mutations', 'Var', (154, 163))	('glioma cohort', 'Disease', (117, 130))	('IDH', 'Gene', '3417', (150, 153))
62685	29383189	In recent years, discovery of IDH mutations is one of the most important findings in glioma genomics.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', (85, 91))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (30, 33))	('mutations', 'Var', (34, 43))
62686	29383189	IDH mutations have a definite relationship with the survival of glioma patients, which has been widely recognized.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('IDH', 'Gene', (0, 3))	('patients', 'Species', '9606', (71, 79))	('IDH', 'Gene', '3417', (0, 3))	('relationship', 'Reg', (30, 42))	('glioma', 'Disease', (64, 70))	('mutations', 'Var', (4, 13))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
62778	28347118	In contrast to other EGFRs, the mutant form EGFRvIII is tumor-specific; it is not expressed in normal tissues.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('mutant', 'Var', (32, 38))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
62782	28347118	Thus, the application of epidermal growth factor (EGF), which is one of several natural ligands for EGFR, could help cover all of the subsets of tumor cells that express wild-type EGFR, as well as its mutant forms.	('EGFR', 'Gene', '1956', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('EGFR', 'Gene', (100, 104))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('mutant', 'Var', (201, 207))	('tumor', 'Disease', (145, 150))
62800	28347118	This is because ANG-PF127-PAAIO has dual targeting capacity due to its recognition of the LDL receptor-related protein, which is overexpressed in both BBB and glioblastoma cells and the clathrin-mediated receptor on the U87 surface.	('PAAIO', 'Chemical', '-', (26, 31))	('U87', 'CellLine', 'CVCL:0022', (220, 223))	('LDL receptor', 'Gene', '3949', (90, 102))	('LDL receptor', 'Gene', (90, 102))	('glioblastoma', 'Disease', (159, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('PF127', 'Chemical', '-', (20, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))	('ANG-PF127-PAAIO', 'Var', (16, 31))
62808	28347118	In vivo, the particles can penetrate the BBB of both the Tg2576 Alzheimer's disease (AD) model and non-transgenic mice.	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (64, 83))	("Alzheimer's disease", 'Disease', (64, 83))	('transgenic mice', 'Species', '10090', (103, 118))	('Tg2576', 'Var', (57, 63))	('rat', 'Species', '10116', (32, 35))	('AD', 'Disease', 'MESH:D000544', (85, 87))	('AD', 'Disease', (85, 87))	('AD', 'Phenotype', 'HP:0002511', (85, 87))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (64, 83))
62896	27905892	EGFR amplification is one of the most common gene changes happening in tumorigenesis of GBM.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('EGFR', 'Gene', '1956', (0, 4))
62908	27905892	This study indicates that miR-491 may serve as a potential diagnostic marker of GBM and restoration of miR-491 together with other combined treatments, may develop into an effective method for the treatment of gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (210, 217))	('gliomas', 'Disease', (210, 217))	('miR-491', 'Gene', (26, 33))	('miR-491', 'Gene', '574444', (26, 33))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('restoration', 'Var', (88, 99))	('miR-491', 'Gene', '574444', (103, 110))	('develop', 'Reg', (156, 163))	('miR-491', 'Gene', (103, 110))	('gliomas', 'Disease', 'MESH:D005910', (210, 217))
62923	27905892	To determine sequence specificity, we also established the plasmids pGL3-TRIM28-mt in which the conserved targeting sequence of miR-491 was mutated to 5'-GUAAAGA-3'.	('miR-491', 'Gene', '574444', (128, 135))	('pGL3', 'Gene', (68, 72))	('miR-491', 'Gene', (128, 135))	('pGL3', 'Gene', '6391', (68, 72))	('mutated', 'Var', (140, 147))
62934	27905892	BibiServ analysis showed that the free energy (DG) was approximately -29.5 kcal/mol for hybridization of the TRIM28 3'-UTR and miR-491 (Fig.	("TRIM28 3'-UTR", 'Var', (109, 122))	('hybridization', 'MPA', (88, 101))	('miR-491', 'Gene', '574444', (127, 134))	('miR-491', 'Gene', (127, 134))
62940	27905892	miR-491 mimics or scrambled miRNA controls were synthesized to knock down the expression of miR-491 and western-blot assay showed miR-491 mimics markedly suppressed TRIM28 expression at protein level (Fig.	('miR-491', 'Gene', '574444', (92, 99))	('suppressed', 'NegReg', (154, 164))	('TRIM28', 'Gene', (165, 171))	('miR-491', 'Gene', '574444', (0, 7))	('miR-491', 'Gene', (130, 137))	('miR', 'Gene', '220972', (92, 95))	('miR-491', 'Gene', (92, 99))	('miR', 'Gene', (92, 95))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('miR', 'Gene', '220972', (0, 3))	('miR-491', 'Gene', (0, 7))	('expression', 'MPA', (172, 182))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('mimics', 'Var', (138, 144))	('miR-491', 'Gene', '574444', (130, 137))
62952	27905892	Our previous study demonstrated that knockdown of TRIM28 in glioma cells suppressed cell proliferation, which could be partially explained by the negative correlation between TRIM28 and p21 expression in GBM patients.	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('patients', 'Species', '9606', (208, 216))	('knockdown', 'Var', (37, 46))	('glioma', 'Disease', (60, 66))	('TRIM28', 'Gene', (50, 56))	('p21', 'Gene', (186, 189))	('suppressed', 'NegReg', (73, 83))	('p21', 'Gene', '644914', (186, 189))	('cell proliferation', 'CPA', (84, 102))	('TRIM28', 'Gene', (175, 181))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
62958	27905892	TRIM28 protein was obviously up-regulated in U87 and U251 cells after transfection with miR-491, which also confirmed above conclusion.	('TRIM28', 'Gene', (0, 6))	('U87', 'Gene', '641648', (45, 48))	('miR-491', 'Gene', '574444', (88, 95))	('miR-491', 'Gene', (88, 95))	('up-regulated', 'PosReg', (29, 41))	('transfection', 'Var', (70, 82))	('U87', 'Gene', (45, 48))	('U251', 'CellLine', 'CVCL:0021', (53, 57))	('protein', 'Protein', (7, 14))
62960	27905892	Deletion of MIR-491 has been recently reported to modulate the invasion and proliferation of GBM.	('MIR-491', 'Gene', (12, 19))	('MIR-491', 'Gene', '574444', (12, 19))	('modulate', 'Reg', (50, 58))	('Deletion', 'Var', (0, 8))
62963	27905892	Loss of MIR-491 could regulate IGFBP2, CDK6 and EGFR proliferative pathways, by which the propagation of GBM cancer stem cells was inhibited.	('EGFR', 'Gene', '1956', (48, 52))	('CDK6', 'Gene', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('regulate', 'Reg', (22, 30))	('CDK6', 'Gene', '1021', (39, 43))	('propagation of', 'CPA', (90, 104))	('cancer', 'Disease', (109, 115))	('EGFR', 'Gene', (48, 52))	('MIR-491', 'Gene', (8, 15))	('MIR-491', 'Gene', '574444', (8, 15))	('IGFBP2', 'Gene', '3485', (31, 37))	('inhibited', 'NegReg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Loss', 'Var', (0, 4))	('IGFBP2', 'Gene', (31, 37))
62973	27905892	TRIM28 also took part in the acceleration of H3-K9 methylation at the p21 promoter.	('p21', 'Gene', (70, 73))	('TRIM28', 'Var', (0, 6))	('p21', 'Gene', '644914', (70, 73))	('H3-K9', 'Protein', (45, 50))
62977	27905892	As a result, restoration of miR-491 together with other combined treatments may develop into an effective method for the treatment of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('gliomas', 'Disease', (134, 141))	('miR-491', 'Gene', '574444', (28, 35))	('gliomas', 'Disease', 'MESH:D005910', (134, 141))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('miR-491', 'Gene', (28, 35))	('restoration', 'Var', (13, 24))
62981	27845331	Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth.	('abrogation', 'Var', (87, 97))	('impairs tumour growth', 'Disease', 'MESH:D006130', (169, 190))	('patients', 'Species', '9606', (70, 78))	('impairs tumour growth', 'Disease', (169, 190))	('GBM', 'Phenotype', 'HP:0012174', (119, 122))	('shorter', 'NegReg', (43, 50))	('enhances', 'PosReg', (123, 131))	('BRCA1', 'Gene', (7, 12))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('DD', 'Disease', 'MESH:C536170', (148, 150))	('BRCA1', 'Gene', (101, 106))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('RS', 'Chemical', '-', (132, 134))	('glioma', 'Disease', (63, 69))
62982	27845331	Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis.	('RRM2', 'Gene', (165, 169))	('GBM', 'Phenotype', 'HP:0012174', (190, 193))	('BRCA1-mediated', 'Var', (150, 164))	('DD', 'Disease', 'MESH:C536170', (220, 222))	('RS', 'Chemical', '-', (216, 218))	('apoptosis', 'CPA', (227, 236))	('RRM2', 'Gene', '6241', (88, 92))	('RRM2', 'Gene', (88, 92))	('endogenous RS', 'MPA', (205, 218))	('RRM2', 'Gene', '6241', (165, 169))
62996	27845331	DSBs trigger the DNA damage response (DDR) network including checkpoints that provide an intrinsic barrier to carcinogenesis.	('checkpoints', 'MPA', (61, 72))	('DD', 'Disease', 'MESH:C536170', (38, 40))	('trigger', 'Reg', (5, 12))	('DSBs', 'Var', (0, 4))	('DSBs', 'Chemical', '-', (0, 4))	('carcinogenesis', 'Disease', 'MESH:D063646', (110, 124))	('carcinogenesis', 'Disease', (110, 124))
62999	27845331	), and germ-line BRCA1 mutations account for large subsets of hereditary breast and ovarian cancer cases.	('BRCA1', 'Gene', (17, 22))	('mutations', 'Var', (23, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (62, 98))
63011	27845331	GBM cells with BRCA1 knockdown were partially arrested at G2 phase and exhibited only modest reduction (compared with DMSO-treated controls) of G2/M checkpoint delay after nocodazole treatment (Fig.	('G2 phase', 'CPA', (58, 66))	('reduction', 'NegReg', (93, 102))	('DMSO', 'Chemical', 'MESH:D004121', (118, 122))	('G2/M checkpoint delay', 'MPA', (144, 165))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('nocodazole', 'Chemical', 'MESH:D015739', (172, 182))	('BRCA1', 'Gene', (15, 20))	('knockdown', 'Var', (21, 30))
63012	27845331	BRCA1 knockdown in normal human astrocytes (NHA-26 and NHA-DRB) also decreased their viability and caused G1 arrest (Supplementary Fig.	('viability', 'CPA', (85, 94))	('BRCA1', 'Gene', (0, 5))	('G1 arrest', 'CPA', (106, 115))	('decreased', 'NegReg', (69, 78))	('NHA-26', 'CellLine', 'CVCL:8806', (44, 50))	('knockdown', 'Var', (6, 15))	('caused', 'Reg', (99, 105))	('human', 'Species', '9606', (26, 31))
63013	27845331	To investigate whether the effect of BRCA1 knockdown on cell viability is unique to GBM cancer cells, we have tested additional four cancer cell lines.	('GBM', 'Phenotype', 'HP:0012174', (84, 87))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('knockdown', 'Var', (43, 52))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BRCA1', 'Gene', (37, 42))
63017	27845331	In non-malignant control cells (BJ; human foreskin fibroblasts), BRCA1 knockdown reduced their viability and induced G2/M arrest (Supplementary Fig.	('G2/M arrest', 'CPA', (117, 128))	('BJ', 'CellLine', 'CVCL:6573', (32, 34))	('induced', 'Reg', (109, 116))	('BRCA1', 'Gene', (65, 70))	('knockdown', 'Var', (71, 80))	('viability', 'MPA', (95, 104))	('reduced', 'NegReg', (81, 88))	('human', 'Species', '9606', (36, 41))
63019	27845331	BRCA1 knockdown significantly extended survival of the tumour-bearing mice (Fig.	('tumour', 'Disease', (55, 61))	('survival', 'CPA', (39, 47))	('BRCA1', 'Gene', (0, 5))	('extended', 'PosReg', (30, 38))	('mice', 'Species', '10090', (70, 74))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('knockdown', 'Var', (6, 15))
63020	27845331	To understand the cause of S-phase arrest after BRCA1 knockdown in GBM cells, indicative of enhanced RS levels, we employed several methods to evaluate the extent of RS-induced DNA damage and DDR activation.	('RS levels', 'MPA', (101, 110))	('DD', 'Disease', 'MESH:C536170', (192, 194))	('knockdown', 'Var', (54, 63))	('S-phase', 'MPA', (27, 34))	('BRCA1', 'Gene', (48, 53))	('RS', 'Chemical', '-', (101, 103))	('RS', 'Chemical', '-', (166, 168))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))	('enhanced', 'PosReg', (92, 100))
63021	27845331	Microscopy analyses of GBM01 and GBM02 cells confirmed increased p-RPA/Rad51 foci in S phase and 53BP1 body counts in G1 after shRNA-mediated BRCA1 knockdown (shBRCA1-2/-4) compared with control (shCTRL) (Fig.	('GBM', 'Phenotype', 'HP:0012174', (23, 26))	('GBM', 'Phenotype', 'HP:0012174', (33, 36))	('RPA', 'Gene', (67, 70))	('increased', 'PosReg', (55, 64))	('S phase', 'CPA', (85, 92))	('BRCA1', 'Gene', (142, 147))	('Rad51', 'Gene', (71, 76))	('Rad51', 'Gene', '5888', (71, 76))	('53BP1', 'Gene', (97, 102))	('53BP1', 'Gene', '7158', (97, 102))	('RPA', 'Gene', '6117', (67, 70))	('knockdown', 'Var', (148, 157))
63022	27845331	DDR activation is thought to reflect DNA RS (refs) and, consistently, BRCA1 knockdown in GBM cells led to the activation of ATM/Chk2-Chk1/RPA signalling (Fig.	('Chk2', 'Gene', (128, 132))	('DD', 'Disease', 'MESH:C536170', (0, 2))	('activation', 'PosReg', (110, 120))	('knockdown', 'Var', (76, 85))	('Chk1', 'Gene', (133, 137))	('RPA', 'Gene', (138, 141))	('ATM', 'Gene', '472', (124, 127))	('GBM', 'Phenotype', 'HP:0012174', (89, 92))	('Chk1', 'Gene', '1111', (133, 137))	('RS', 'Chemical', '-', (41, 43))	('BRCA1', 'Gene', (70, 75))	('RPA', 'Gene', '6117', (138, 141))	('ATM', 'Gene', (124, 127))	('Chk2', 'Gene', '11200', (128, 132))
63024	27845331	Both, the fraction of PCNA+/gammaH2AX+and p-RPA+/ gammaH2AX+cells were increased after BRCA1 knockdown compared with controls, indicative of replication fork stalling and/or collapse into DSBs (Fig.	('knockdown', 'Var', (93, 102))	('gammaH2AX', 'Chemical', '-', (50, 59))	('PCNA', 'Gene', (22, 26))	('RPA', 'Gene', '6117', (44, 47))	('replication fork stalling', 'CPA', (141, 166))	('DSBs', 'Chemical', '-', (188, 192))	('BRCA1', 'Gene', (87, 92))	('PCNA', 'Gene', '5111', (22, 26))	('gammaH2AX', 'Chemical', '-', (28, 37))	('RPA', 'Gene', (44, 47))	('increased', 'PosReg', (71, 80))
63027	27845331	Notably, the immunoblot analysis of p-RPA in normal human controls (NHA-DRB, BJ) and the four non-GBM cancer cell lines (OVCAR5, Cal51, PC3 and HELA) confirmed elevated p-RPA levels after BRCA1 knockdown (Supplementary Figs 1d and 2c).	('RPA', 'Gene', (38, 41))	('PC3', 'Gene', '3853', (136, 139))	('elevated', 'PosReg', (160, 168))	('BJ', 'CellLine', 'CVCL:6573', (77, 79))	('BRCA1', 'Gene', (188, 193))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('knockdown', 'Var', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('RPA', 'Gene', '6117', (171, 174))	('human', 'Species', '9606', (52, 57))	('cancer', 'Disease', (102, 108))	('PC3', 'Gene', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('RPA', 'Gene', '6117', (38, 41))	('RPA', 'Gene', (171, 174))
63030	27845331	HU treatment resulted in markedly shorter CldU tract length in cells with BRCA1 knockdown compared with control (Fig.	('knockdown', 'Var', (80, 89))	('CldU tract length', 'CPA', (42, 59))	('shorter', 'NegReg', (34, 41))	('CldU', 'Chemical', '-', (42, 46))	('BRCA1', 'Gene', (74, 79))
63031	27845331	The HU-induced CldU tract shortening observed even in the shCTRL-exposed cells indicated that GBM cells are sensitive to dNTP depletion already in the presence of BRCA1 (Table 2 and Supplementary Table 1), and this phenotype was further enhanced on BRCA1 knockdown.	('knockdown', 'Var', (255, 264))	('enhanced', 'PosReg', (237, 245))	('dNTP depletion', 'MPA', (121, 135))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('BRCA1', 'Gene', (249, 254))	('CldU', 'Chemical', '-', (15, 19))	('dNTP', 'Chemical', '-', (121, 125))	('sensitive', 'MPA', (108, 117))
63036	27845331	Notably, both the messengerRNA (mRNA) and protein levels of RRM2 were decreased in GBM cells lacking BRCA1 (Fig.	('lacking', 'Var', (93, 100))	('decreased', 'NegReg', (70, 79))	('BRCA1', 'Gene', (101, 106))	('RRM2', 'Gene', (60, 64))	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('protein levels', 'MPA', (42, 56))	('RRM2', 'Gene', '6241', (60, 64))
63040	27845331	In GBM01 cells with BRCA1 knockdown (shBRCA1-2 & shBRCA1-4), the RRM2 protein levels significantly decreased in all cell cycle phases, while this decrease was more prominent in S-G2/M phases than in G1 phase.	('BRCA1', 'Gene', (20, 25))	('RRM2', 'Gene', '6241', (65, 69))	('RRM2', 'Gene', (65, 69))	('in S-G2/M', 'CPA', (174, 183))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('knockdown', 'Var', (26, 35))	('all cell cycle', 'CPA', (112, 126))	('the', 'Protein', (61, 64))	('significantly', 'NegReg', (85, 98))
63046	27845331	Intriguingly, BRCA1 knockdown did not result in RRM2 protein level changes in either NHA-DRB or BJ cells (Supplementary Fig.	('RRM2', 'Gene', (48, 52))	('BRCA1', 'Gene', (14, 19))	('RRM2', 'Gene', '6241', (48, 52))	('BJ', 'CellLine', 'CVCL:6573', (96, 98))	('knockdown', 'Var', (20, 29))
63051	27845331	siRNA-mediated knockdown of AP-1 and Sp1 did not significantly impair transcriptional activation of RRM2 promoter, whereas the knockdown of E2F1 reduced RRM2 promoter activation to the same extent as BRCA1.	('reduced', 'NegReg', (145, 152))	('RRM2', 'Gene', '6241', (100, 104))	('RRM2', 'Gene', (100, 104))	('knockdown', 'Var', (127, 136))	('impair', 'NegReg', (63, 69))	('RRM2', 'Gene', '6241', (153, 157))	('RRM2', 'Gene', (153, 157))	('AP-1', 'Gene', '3725', (28, 32))	('AP-1', 'Gene', (28, 32))	('E2F1', 'Gene', (140, 144))	('transcriptional activation', 'MPA', (70, 96))
63052	27845331	Interestingly, simultaneous knockdown of BRCA1 and E2F1 had no additional impact on RRM2 transcription when compared with either alone (Fig.	('transcription', 'MPA', (89, 102))	('BRCA1', 'Gene', (41, 46))	('knockdown', 'Var', (28, 37))	('RRM2', 'Gene', '6241', (84, 88))	('RRM2', 'Gene', (84, 88))	('E2F1', 'Gene', (51, 55))
63054	27845331	4d) and its knockdown significantly reduced BRCA1 recruitment to promoter regions amplified by both primer sets (P1 and P2), thereby indicating that BRCA1 binding and transcriptional activation of RRM2 occurs in E2F1-dependent manner (Fig.	('P1 and P2', 'Gene', '1423;4888', (113, 122))	('binding', 'Interaction', (155, 162))	('knockdown', 'Var', (12, 21))	('recruitment to promoter regions', 'MPA', (50, 81))	('RRM2', 'Gene', '6241', (197, 201))	('reduced', 'NegReg', (36, 43))	('transcriptional', 'MPA', (167, 182))	('RRM2', 'Gene', (197, 201))	('BRCA1', 'Gene', (149, 154))	('BRCA1', 'Protein', (44, 49))
63056	27845331	We found that ectopic expression of RRM2 at least in part rescued the BRCA1 knockdown-associated phenotypes of decreased fork progression speed associated with increased phosphorylation of RPA (assessed by immunoblot analysis), as well as the viability of GBM cells (Fig.	('RPA', 'Gene', (189, 192))	('GBM', 'Phenotype', 'HP:0012174', (256, 259))	('increased', 'PosReg', (160, 169))	('decreased', 'NegReg', (111, 120))	('fork', 'MPA', (121, 125))	('RRM2', 'Gene', '6241', (36, 40))	('BRCA1', 'Gene', (70, 75))	('RRM2', 'Gene', (36, 40))	('RPA', 'Gene', '6117', (189, 192))	('ectopic expression', 'Var', (14, 32))	('phosphorylation', 'MPA', (170, 185))
63064	27845331	Supportive of likely favourable therapeutic index, astrocytes (NHA-26) were more resistant to triapine compared with GBM lines, with EC50 of 2.5 muM and no effect on astrocyte viability when treated with EC50-GBM02 or 10 muM triapine (Fig.	('EC50-GBM02', 'Var', (204, 214))	('EC50', 'Var', (133, 137))	('muM', 'Gene', '56925', (145, 148))	('GBM', 'Phenotype', 'HP:0012174', (209, 212))	('triapine', 'Chemical', 'MESH:C078157', (225, 233))	('triapine', 'Chemical', 'MESH:C078157', (94, 102))	('muM', 'Gene', '56925', (221, 224))	('muM', 'Gene', (145, 148))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('muM', 'Gene', (221, 224))	('resistant', 'MPA', (81, 90))	('NHA-26', 'CellLine', 'CVCL:8806', (63, 69))
63072	27845331	The combined administration of triapine (EC50-Tria) and olaparib (EC50-Ola and EC25-Ola) was more efficient at reducing GBM cell viability than either drug alone, a combinational effect not observed in NHA-26 or BJ cells used as non-malignant controls (Supplementary Fig.	('EC25-Ola', 'Var', (79, 87))	('EC50-Tria', 'Disease', 'None', (41, 50))	('GBM cell viability', 'CPA', (120, 138))	('GBM', 'Phenotype', 'HP:0012174', (120, 123))	('BJ', 'CellLine', 'CVCL:6573', (212, 214))	('reducing', 'NegReg', (111, 119))	('rat', 'Species', '10116', (21, 24))	('NHA-26', 'CellLine', 'CVCL:8806', (202, 208))	('olaparib', 'Chemical', 'MESH:C531550', (56, 64))	('Ola', 'Chemical', '-', (71, 74))	('Ola', 'Chemical', '-', (84, 87))	('EC50-Tria', 'Disease', (41, 50))	('triapine', 'Chemical', 'MESH:C078157', (31, 39))
63085	27845331	6c, BRCA1 high patients (>14.5%, median survival=230 days, were 14.5% represents median BRCA1 positivity in our cohort) had significantly shorter overall survival than BRCA1 low patients (<14.5%, median survival not yet available as over 50% of patients were alive at the end of this study) or patients negative for BRCA1 (BRCA1 negat.	('patients', 'Species', '9606', (15, 23))	('overall survival', 'MPA', (146, 162))	('BRCA1', 'Gene', (4, 9))	('patients', 'Species', '9606', (245, 253))	('patients', 'Species', '9606', (294, 302))	('shorter', 'NegReg', (138, 145))	('patients', 'Species', '9606', (178, 186))	('high', 'Var', (10, 14))
63089	27845331	According to multivariate analysis (Supplementary Table 3) both, BRCA1 and RRM2 positivity, correlate with WHO malignancy degree and patient age, but are independent of proliferative index (% of Ki67+ cells).	('rat', 'Species', '10116', (176, 179))	('patient', 'Species', '9606', (133, 140))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('BRCA1', 'Gene', (65, 70))	('malignancy', 'Disease', (111, 121))	('positivity', 'Var', (80, 90))	('RRM2', 'Gene', '6241', (75, 79))	('RRM2', 'Gene', (75, 79))
63098	27845331	Similarly, high RRM2 expression (RRM2 high) analysis was associated with worsen survival of glioma, in general, and GBM patients, in particular (Supplementary Fig.	('worsen', 'NegReg', (73, 79))	('high', 'Var', (11, 15))	('GBM', 'Phenotype', 'HP:0012174', (116, 119))	('survival', 'MPA', (80, 88))	('glioma', 'Disease', (92, 98))	('RRM2', 'Gene', (33, 37))	('patients', 'Species', '9606', (120, 128))	('RRM2', 'Gene', '6241', (33, 37))	('RRM2', 'Gene', (16, 20))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('RRM2', 'Gene', '6241', (16, 20))
63106	27845331	Cells are particularly sensitive during S phase when DNA damage causes replication fork stalling or collapse, collectively referred to as replication stress, one of the emerging hallmarks of cancer.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('DNA', 'Var', (53, 56))	('collapse', 'MPA', (100, 108))	('replication fork stalling', 'CPA', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
63109	27845331	Our present findings provide the first clear evidence that BRCA1 positivity increases with increasing degree of malignancy in human gliomas and serves as a negative prognostic factor for patient survival (Fig.	('human', 'Species', '9606', (126, 131))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('BRCA1', 'Gene', (59, 64))	('positivity', 'Var', (65, 75))	('increases', 'PosReg', (76, 85))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('negative', 'NegReg', (156, 164))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('patient', 'Species', '9606', (187, 194))	('malignancy', 'Disease', (112, 122))
63113	27845331	Our data indicate, that this phenotype is at least in part attributable to down-regulation of RRM2 upon BRCA1 knockdown (Figs 1, 2, 3).	('knockdown', 'Var', (110, 119))	('down-regulation', 'NegReg', (75, 90))	('RRM2', 'Gene', '6241', (94, 98))	('RRM2', 'Gene', (94, 98))	('BRCA1', 'Gene', (104, 109))
63116	27845331	To rule out that the drop in RRM2 levels was not simply a cell cycle effect, because BRCA1 knockdown arrested cells in S-phase in which RRM2 levels are known to be the highest, we have performed cell cycle analysis with nocodazole arrest (Fig.	('BRCA1', 'Gene', (85, 90))	('knockdown', 'Var', (91, 100))	('RRM2', 'Gene', '6241', (29, 33))	('RRM2', 'Gene', (29, 33))	('nocodazole', 'Chemical', 'MESH:D015739', (220, 230))	('RRM2', 'Gene', '6241', (136, 140))	('RRM2', 'Gene', (136, 140))
63117	27845331	In addition, the analysis of RRM2 expression in individual cell cycle (G1-S-G2/M) phases confirmed that after BRCA1 knockdown, RRM2 levels decreased in all cell cycle phases (Fig.	('knockdown', 'Var', (116, 125))	('decreased', 'NegReg', (139, 148))	('BRCA1', 'Gene', (110, 115))	('RRM2', 'Gene', '6241', (29, 33))	('RRM2', 'Gene', (29, 33))	('RRM2', 'Gene', '6241', (127, 131))	('RRM2', 'Gene', (127, 131))
63118	27845331	To evaluate whether this phenotype is unique to GBM or applies to other cell types, we performed BRCA1 knockdown in 4 additional cancer and 3 non-malignant cell lines.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))	('BRCA1', 'Gene', (97, 102))	('knockdown', 'Var', (103, 112))
63119	27845331	Our experiments showed no major impact on growth characteristics of human ovarian (OVCAR5) and breast cancer (Cal51) cell lines upon BRCA1 knockdown.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('human', 'Species', '9606', (68, 73))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('knockdown', 'Var', (139, 148))	('BRCA1', 'Gene', (133, 138))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
63120	27845331	Prostate (PC3) and cervical carcinoma (HELA) cell lines experienced lowered viability and cell cycle arrest at G2/M after BRCA1 knockdown, but continued growing (Supplementary Fig.	('PC3', 'Gene', '3853', (10, 13))	('BRCA1', 'Gene', (122, 127))	('lowered', 'NegReg', (68, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('knockdown', 'Var', (128, 137))	('cell cycle arrest', 'CPA', (90, 107))	('PC3', 'Gene', (10, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('cervical carcinoma', 'Disease', 'MESH:D002575', (19, 37))	('cervical carcinoma', 'Disease', (19, 37))
63132	27845331	Ectopic expression of RRM2 rescued the BRCA1-depletion phenotype (RS/viability), thereby underscoring the importance of this newly identified BRCA1 function.	('BRCA1-depletion phenotype', 'MPA', (39, 64))	('rescued', 'PosReg', (27, 34))	('RS', 'Chemical', '-', (66, 68))	('Ectopic expression', 'Var', (0, 18))	('RRM2', 'Gene', (22, 26))	('RRM2', 'Gene', '6241', (22, 26))
63135	27845331	Supraphysiological levels of RRM2 can lead to genomic instability and tumorigenesis due to imbalanced dNTP pools, underlining its 'proto-oncogenic' role.	('Supraphysiological levels', 'Var', (0, 25))	('imbalanced dNTP pools', 'MPA', (91, 112))	('dNTP', 'Chemical', '-', (102, 106))	('RRM2', 'Gene', '6241', (29, 33))	('lead to', 'Reg', (38, 45))	('RRM2', 'Gene', (29, 33))	('tumorigenesis', 'CPA', (70, 83))	('genomic', 'MPA', (46, 53))
63137	27845331	Importantly, NHA-26 cells were resistant to doses of triapine used to target GBM cells and EC50-NHA26 was significantly higher, consistent with reports suggesting the use of triapine as a neuroprotectant.	('GBM', 'Phenotype', 'HP:0012174', (77, 80))	('EC50-NHA26', 'Var', (91, 101))	('NHA-26', 'Gene', (13, 19))	('triapine', 'Chemical', 'MESH:C078157', (53, 61))	('triapine', 'Chemical', 'MESH:C078157', (174, 182))	('NHA-26', 'CellLine', 'CVCL:8806', (13, 19))
63141	27845331	Impaired fork recovery after BRCA1 knockdown and S-phase arrest coincided with DDR signalling and increased frequency of p-RPA+/gammaH2AX+ GBM cells altogether indicating the conversion of stalled forks into DSBs.	('knockdown', 'Var', (35, 44))	('gammaH2AX', 'Chemical', '-', (128, 137))	('RPA', 'Gene', '6117', (123, 126))	('fork recovery', 'MPA', (9, 22))	('DD', 'Disease', 'MESH:C536170', (79, 81))	('DSBs', 'Chemical', '-', (208, 212))	('increased', 'PosReg', (98, 107))	('RPA', 'Gene', (123, 126))	('BRCA1', 'Gene', (29, 34))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
63143	27845331	We now show that impairment of replication fork restart may potentiate effects of olaparib on triapine treated GBM cells (Supplementary Fig.	('potentiate', 'PosReg', (60, 70))	('olaparib', 'Chemical', 'MESH:C531550', (82, 90))	('impairment', 'Var', (17, 27))	('triapine', 'Chemical', 'MESH:C078157', (94, 102))	('effects', 'MPA', (71, 78))	('replication fork restart', 'CPA', (31, 55))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
63206	27845331	To allow for quantification of mitotic cells and RRM2- or p-RPA/gammaH2AX- or PCNA-gammaH2AX-positive cells, cells were further labelled with anti-H3Ser10, anti-RRM2, anti-p-RPA+anti-gammaH2AX or anti-PCNA+gammaH2AX antibodies, respectively.	('PCNA', 'Gene', '5111', (201, 205))	('PCNA', 'Gene', (78, 82))	('RRM2', 'Gene', '6241', (161, 165))	('gammaH2AX', 'Chemical', '-', (183, 192))	('RPA', 'Gene', '6117', (60, 63))	('RRM2', 'Gene', '6241', (49, 53))	('RRM2', 'Gene', (49, 53))	('anti-H3Ser10', 'Var', (142, 154))	('RPA', 'Gene', '6117', (174, 177))	('gammaH2AX', 'Chemical', '-', (64, 73))	('PCNA', 'Gene', '5111', (78, 82))	('RPA', 'Gene', (60, 63))	('PCNA', 'Gene', (201, 205))	('gammaH2AX', 'Chemical', '-', (83, 92))	('RPA', 'Gene', (174, 177))	('gammaH2AX', 'Chemical', '-', (206, 215))	('RRM2', 'Gene', (161, 165))
63255	26916251	Nineteen of the patients included in the study additionally underwent DSC perfusion MR imaging (SSEPI gradient echo, TR 1500ms, TE 50ms, flip angle 40, dync scans 45, slice thickness 4.4mm, scan time 1:12 minutes).	('TE 50ms', 'Var', (128, 135))	('TR 1500ms', 'Var', (117, 126))	('patients', 'Species', '9606', (16, 24))	('DSC perfusion MR imaging', 'MPA', (70, 94))
63325	26251796	VNS (at age 18 years) led to a 60% reduction of intractable seizures.	('seizures', 'Phenotype', 'HP:0001250', (60, 68))	('seizures', 'Disease', (60, 68))	('seizure', 'Phenotype', 'HP:0001250', (60, 67))	('VNS', 'Var', (0, 3))	('seizures', 'Disease', 'MESH:D012640', (60, 68))	('reduction', 'NegReg', (35, 44))
63341	26251796	In a study of resected hemimegalencephalic hemispheres, Lee et al found de novo somatic mutations in identified genes (phosphatidylinositol 3-kinase [PIK3CA], the protein AKT kinase [AKT3], and a mammalian target of rapamycin [mTOR]) that are known to be associated with malignant tumors (breast and pancreas).	('mTOR', 'Gene', (227, 231))	('mammalian target of rapamycin', 'Gene', '2475', (196, 225))	('associated', 'Reg', (255, 265))	('mutations', 'Var', (88, 97))	('phosphatidylinositol', 'Gene', (119, 139))	('hemimegalencephalic', 'Disease', 'None', (23, 42))	('mTOR', 'Gene', '2475', (227, 231))	('hemimegalencephalic', 'Disease', (23, 42))	('PIK3CA', 'Gene', '5290', (150, 156))	('breast and pancreas', 'Disease', 'MESH:D010190', (289, 308))	('mammalian target of rapamycin', 'Gene', (196, 225))	('malignant tumors', 'Disease', 'MESH:D018198', (271, 287))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('AKT3', 'Gene', '10000', (183, 187))	('malignant tumors', 'Disease', (271, 287))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('PIK3CA', 'Gene', (150, 156))	('AKT3', 'Gene', (183, 187))	('hemimegalencephalic hemisphere', 'Phenotype', 'HP:0007206', (23, 53))
63381	26251796	The mutations affected defined genes (PIK3CA, AKT3, and mTOR) regulating cell signaling in response to insulin and growth factors and influencing cell size, proliferation, differentiation, and apoptosis.	('differentiation', 'CPA', (172, 187))	('cell signaling', 'MPA', (73, 87))	('mTOR', 'Gene', (56, 60))	('apoptosis', 'CPA', (193, 202))	('mTOR', 'Gene', '2475', (56, 60))	('PIK3CA', 'Gene', (38, 44))	('AKT3', 'Gene', (46, 50))	('PIK3CA', 'Gene', '5290', (38, 44))	('affected', 'Reg', (14, 22))	('cell size', 'CPA', (146, 155))	('AKT3', 'Gene', '10000', (46, 50))	('mutations', 'Var', (4, 13))	('influencing', 'Reg', (134, 145))	('proliferation', 'CPA', (157, 170))
63383	26251796	Although the mutations are known to be associated with malignant tumors (breast, pancreas), the presence of other mutations is needed for tumor development and dissemination.	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (39, 49))	('malignant tumors', 'Disease', (55, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (13, 22))	('malignant tumors', 'Disease', 'MESH:D018198', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
63389	26251796	The increased tissue levels of NGF, numerous NGF receptor-positive cells, and NGF affinity for cerebral blood vessels and nerve fibers in the hemimegalencephalic hemisphere were confirmed, and experimental studies proved a slight increase in tumor growth and tumor cell migration after NGF, as well as the role of NGF as a significant promotor of promigratory and proproliferative glioblastoma activities.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('NGF', 'Chemical', '-', (78, 81))	('hemimegalencephalic', 'Disease', 'None', (142, 161))	('NGF', 'Chemical', '-', (45, 48))	('hemimegalencephalic', 'Disease', (142, 161))	('tumor', 'Disease', (242, 247))	('NGF receptor', 'Gene', '4804', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('NGF', 'Var', (286, 289))	('NGF', 'Chemical', '-', (314, 317))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('glioblastoma', 'Disease', 'MESH:D005909', (381, 393))	('hemimegalencephalic hemisphere', 'Phenotype', 'HP:0007206', (142, 172))	('NGF receptor', 'Gene', (45, 57))	('glioblastoma', 'Disease', (381, 393))	('NGF', 'Chemical', '-', (31, 34))	('tumor', 'Disease', (259, 264))	('glioblastoma', 'Phenotype', 'HP:0012174', (381, 393))	('NGF', 'Chemical', '-', (286, 289))	('increase', 'PosReg', (230, 238))
63404	23548312	Moreover, MSCs delivered Cy3-miR-124 mimic to glioma xenografts when administered intracranially.	('glioma xenografts', 'Disease', (46, 63))	('Cy3-miR-124', 'Var', (25, 36))	('MSC', 'Gene', '9242', (10, 13))	('Cy3', 'Chemical', '-', (25, 28))	('MSC', 'Gene', (10, 13))	('glioma xenografts', 'Disease', 'MESH:D005910', (46, 63))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
63417	23548312	Over the past several years, it has become evident that the post-transcriptional regulation of gene expression by miRNAs has major implications in various areas of cell biology and that deregulation of various miRNAs is associated with a variety of pathological conditions including the initiation and progression of human cancer.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', (323, 329))	('associated', 'Reg', (220, 230))	('implications', 'Reg', (131, 143))	('human', 'Species', '9606', (317, 322))	('deregulation', 'Var', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('post-transcriptional', 'MPA', (60, 80))
63418	23548312	Indeed, specific miRNAs such as miR-124 and miR-128 have been reported to be downregulated in GBM and GSCs, whereas the expression of other miRNAs including miR-10b, miR-21 and miR-26a is increased in these tumors as compared to normal brains.	('miR-10b', 'Gene', '406903', (157, 164))	('downregulated', 'NegReg', (77, 90))	('miR-21', 'Gene', '406991', (166, 172))	('expression', 'MPA', (120, 130))	('miR-128', 'Var', (44, 51))	('miR-26a', 'Gene', (177, 184))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('GBM', 'Disease', (94, 97))	('miR-10b', 'Gene', (157, 164))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('GSCs', 'Disease', (102, 106))	('miR-26a', 'Gene', '407015', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('miR-21', 'Gene', (166, 172))	('tumors', 'Disease', (207, 213))	('miR-124', 'Var', (32, 39))	('increased', 'PosReg', (188, 197))
63419	23548312	Therefore, delivery of specific miRNAs or silencing of overexpressed ones appears to be a potential mode of therapy for these tumors.	('silencing', 'Var', (42, 51))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
63422	23548312	Moreover, the delivered miRNA altered gene expression in the recipient glioma cells and impacted their function.	('glioma', 'Disease', (71, 77))	('gene expression', 'MPA', (38, 53))	('function', 'MPA', (103, 111))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('altered', 'Reg', (30, 37))	('impacted', 'Reg', (88, 96))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('miRNA', 'Var', (24, 29))
63430	23548312	The MSCs were transfected with the Cy3-miR-124 or Cy3-miR-145 and co-cultured with the specific glioma cell lines that were labeled with a Green CellTracker.	('miR-145', 'Gene', (54, 61))	('Cy3', 'Chemical', '-', (50, 53))	('Cy3-miR-124', 'Var', (35, 46))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('miR-145', 'Gene', '406937', (54, 61))	('MSC', 'Gene', '9242', (4, 7))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('MSC', 'Gene', (4, 7))	('Cy3', 'Chemical', '-', (35, 38))	('glioma', 'Disease', (96, 102))
63431	23548312	As presented in Figure 1B, Cy3-miR-124 was detected in the majority of the MSCs (red alone) and in most of the A172 cells labeled with the Green CellTracker.	('MSC', 'Gene', '9242', (75, 78))	('MSC', 'Gene', (75, 78))	('Cy3-miR-124', 'Var', (27, 38))	('Cy3', 'Chemical', '-', (27, 30))
63435	23548312	Using FACS analysis, we further documented that the majority of the glioma cells that were labeled with the Green CellTracker, were also positive for Cy3 miR-124 when co-cultured with BM-MSCs that were transfected with the fluorescent miRNA (Figure 1C).	('positive', 'Reg', (137, 145))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('MSC', 'Gene', (187, 190))	('Cy3', 'Chemical', '-', (150, 153))	('Cy3 miR-124', 'Var', (150, 161))	('glioma', 'Disease', (68, 74))	('MSC', 'Gene', '9242', (187, 190))
63440	23548312	The different MSCs expressed similar levels of miR-124 and miR-145 following transfection with the specific miRNA mimics (Supplementary Figure S1).	('miR-124', 'Var', (47, 54))	('MSC', 'Gene', '9242', (14, 17))	('miR-145', 'Gene', (59, 66))	('miR-145', 'Gene', '406937', (59, 66))	('MSC', 'Gene', (14, 17))
63441	23548312	Similar to BM-MSCs, MSCs derived from adipose tissue (AD-MSC), umbilical cord or placenta also efficiently delivered Cy3 miR-124 to glioma cells (Supplementary Figure S2).	('glioma', 'Disease', (132, 138))	('MSC', 'Gene', '9242', (57, 60))	('MSC', 'Gene', '9242', (20, 23))	('Cy3', 'Chemical', '-', (117, 120))	('MSC', 'Gene', (57, 60))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('MSC', 'Gene', '9242', (14, 17))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('MSC', 'Gene', (20, 23))	('Cy3 miR-124', 'Var', (117, 128))	('MSC', 'Gene', (14, 17))
63443	23548312	We then examined if the delivered miR-124 was functional in the recipient glioma cells.	('miR-124', 'Var', (34, 41))	('glioma', 'Disease', (74, 80))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (74, 80))
63459	23548312	qRT-PCR analysis demonstrated increased delivery of miR-124 to the U87 cells that were cultured with miR-124 transfected MSCs in the transwell chamber (Figure 3B) and a decrease of about 30% in the luciferase activity of the SCP-1 reporter gene (Figure 3C).	('decrease', 'NegReg', (169, 177))	('U87', 'Gene', (67, 70))	('delivery', 'MPA', (40, 48))	('luciferase', 'Enzyme', (198, 208))	('SCP-1', 'Gene', '6847', (225, 230))	('SCP-1', 'Gene', (225, 230))	('U87', 'Gene', '641648', (67, 70))	('MSC', 'Gene', '9242', (121, 124))	('miR-124', 'Var', (52, 59))	('transfected', 'Var', (109, 120))	('increased', 'PosReg', (30, 39))	('miR-124 transfected', 'Var', (101, 120))	('MSC', 'Gene', (121, 124))	('activity', 'MPA', (209, 217))
63463	23548312	The merge image presented in Figure 3D, demonstrates co-localization of the Cy3 labeled miR-124 and GFP labeled exosomes in the transfected MSCs.	('Cy3', 'Chemical', '-', (76, 79))	('Cy3', 'Var', (76, 79))	('MSC', 'Gene', '9242', (140, 143))	('co-localization', 'MPA', (53, 68))	('MSC', 'Gene', (140, 143))	('miR-124', 'Gene', (88, 95))
63470	23548312	As presented in Figure 3I, GW4869 significantly decreased the secretion of exosomes as determined by the lower levels of CD81, CD9 and Alix in the exosome preparation of the treated cells.	('lower', 'NegReg', (105, 110))	('GW4869', 'Chemical', 'MESH:C468773', (27, 33))	('Alix', 'Gene', (135, 139))	('CD81', 'Gene', '975', (121, 125))	('decreased', 'NegReg', (48, 57))	('secretion of exosomes', 'MPA', (62, 83))	('GW4869', 'Var', (27, 33))	('CD9', 'Gene', (127, 130))	('CD9', 'Gene', '928', (127, 130))	('Alix', 'Gene', '10015', (135, 139))	('CD81', 'Gene', (121, 125))
63471	23548312	Moreover, treatment with GW4869 abolished the decreased luciferase activity of U87 cells transfected with the SCP1-3'-UTR luciferase reporter plasmid and co-cultured with MSCs expressing a miR-124 mimic, whereas it had no effect on the luciferase activity of U87 cells co-cultured with MSCs expressing a control miR (Figure 3J).	('plasmid', 'Species', '2509', (142, 149))	('MSC', 'Gene', (286, 289))	('SCP1', 'Gene', (110, 114))	('U87', 'Gene', (79, 82))	('MSC', 'Gene', '9242', (286, 289))	('GW4869', 'Chemical', 'MESH:C468773', (25, 31))	('U87', 'Gene', '641648', (79, 82))	('U87', 'Gene', (259, 262))	('MSC', 'Gene', (171, 174))	('SCP1', 'Gene', '6847', (110, 114))	('GW4869', 'Var', (25, 31))	('activity', 'MPA', (67, 75))	('MSC', 'Gene', '9242', (171, 174))	('U87', 'Gene', '641648', (259, 262))	('decreased', 'NegReg', (46, 55))	('luciferase', 'Enzyme', (56, 66))	('abolished', 'NegReg', (32, 41))
63472	23548312	Both carbenoxolone and GW4869 did not exert cytotoxic effect as was evident by measurement of LDH (data not shown).	('GW4869', 'Chemical', 'MESH:C468773', (23, 29))	('carbenoxolone', 'Chemical', 'MESH:D002229', (5, 18))	('LDH', 'MPA', (94, 97))	('GW4869', 'Var', (23, 29))
63475	23548312	Similarly, co-cultures of U87 cells with MSCs transfected with a miR-124 mimic had a significant decreased cell migration as determined by a transwell migration assay as compared with co-cultures of U87 cells with MSCs expressing a control miR (Figures 4A, 4B).	('MSC', 'Gene', '9242', (214, 217))	('U87', 'Gene', (26, 29))	('cell migration', 'CPA', (107, 121))	('MSC', 'Gene', (214, 217))	('miR-124', 'Gene', (65, 72))	('U87', 'Gene', '641648', (26, 29))	('decreased', 'NegReg', (97, 106))	('MSC', 'Gene', '9242', (41, 44))	('U87', 'Gene', '641648', (199, 202))	('U87', 'Gene', (199, 202))	('MSC', 'Gene', (41, 44))	('transwell migration assay', 'CPA', (141, 166))	('mimic', 'Var', (73, 78))
63478	23548312	Similar results were obtained with AD-MSCs and with MSCs expressing a non-fluorescent miR-124 (data not shown).	('MSC', 'Gene', (52, 55))	('MSC', 'Gene', (38, 41))	('miR-124', 'Var', (86, 93))	('MSC', 'Gene', '9242', (52, 55))	('MSC', 'Gene', '9242', (38, 41))	('non-fluorescent miR-124', 'Var', (70, 93))
63480	23548312	We found that BM-MSCs delivered both Cy3 miR-124 and Cy3 miR-145 to the GSCs, as evidenced by localization of the Cy3 fluorescent miR in the green labeled HF2414 GSCs (Figure 5A).	('Cy3', 'Chemical', '-', (53, 56))	('Cy3', 'Chemical', '-', (37, 40))	('miR-145', 'Gene', (57, 64))	('Cy3 miR-124', 'Var', (37, 48))	('miR-145', 'Gene', '406937', (57, 64))	('MSC', 'Gene', '9242', (17, 20))	('HF2414', 'CellLine', 'CVCL:AR02', (155, 161))	('MSC', 'Gene', (17, 20))	('Cy3', 'Chemical', '-', (114, 117))
63481	23548312	Similar to the results observed for the miRNA delivery in the glioma cells, we found that MSCs derived from adipose tissue, umbilical cord and placenta also delivered miR-124 to the HF2414 GSCs (Figure 5B) and the HF2485 GSCs (data not shown).	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('miR-124', 'Var', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('HF2414', 'CellLine', 'CVCL:AR02', (182, 188))	('MSC', 'Gene', '9242', (90, 93))	('HF2485', 'CellLine', 'CVCL:7359', (214, 220))	('glioma', 'Disease', (62, 68))	('MSC', 'Gene', (90, 93))
63482	23548312	The miR-145 mimic decreased the self-renewal of both HF2485 and HF2414 GSCs (Figure 5C).	('HF2485', 'CellLine', 'CVCL:7359', (53, 59))	('decreased', 'NegReg', (18, 27))	('HF2414', 'CellLine', 'CVCL:AR02', (64, 70))	('HF2414', 'Var', (64, 70))	('self-renewal', 'CPA', (32, 44))	('miR-145', 'Gene', (4, 11))	('miR-145', 'Gene', '406937', (4, 11))
63483	23548312	Likewise, GSCs that were co-cultured with BM-MSCs expressing a miR-145 mimic exhibited a significant decrease in their self-renewal compared to GSCs that were co-cultured with MSCs expressing a control miRNA (Figure 5C).	('self-renewal', 'CPA', (119, 131))	('MSC', 'Gene', (176, 179))	('mimic', 'Var', (71, 76))	('miR-145', 'Gene', '406937', (63, 70))	('MSC', 'Gene', '9242', (45, 48))	('miR-145', 'Gene', (63, 70))	('decrease', 'NegReg', (101, 109))	('MSC', 'Gene', '9242', (176, 179))	('MSC', 'Gene', (45, 48))
63486	23548312	In addition, we employed a luciferase reporter plasmid containing the 3'-UTR of Sox2 and found that the miR-145 mimic significantly decreased the luciferase activity of this construct in the HF2414 GSCs (Figure 5F).	('luciferase', 'Enzyme', (146, 156))	('HF2414', 'CellLine', 'CVCL:AR02', (191, 197))	('miR-145', 'Gene', '406937', (104, 111))	('mimic', 'Var', (112, 117))	('Sox2', 'Gene', '6657', (80, 84))	('Sox2', 'Gene', (80, 84))	('plasmid', 'Species', '2509', (47, 54))	('decreased', 'NegReg', (132, 141))	('miR-145', 'Gene', (104, 111))	('activity', 'MPA', (157, 165))
63489	23548312	In addition, GSCs that were co-cultured with BM-MSCs expressing miR-124 (Figure 5H) or AD-MSCs (data not shown) exhibited a significant decrease in self-renewal as compared to GSCs that were co-cultured with MSCs expressing a control miRNA (Figure 5H).	('miR-124', 'Var', (64, 71))	('MSC', 'Gene', '9242', (208, 211))	('decrease', 'NegReg', (136, 144))	('MSC', 'Gene', (208, 211))	('MSC', 'Gene', '9242', (90, 93))	('self-renewal', 'CPA', (148, 160))	('MSC', 'Gene', '9242', (48, 51))	('MSC', 'Gene', (48, 51))	('MSC', 'Gene', (90, 93))
63492	23548312	Twenty-two days post tumor cell implantation, when the xenografts reached about 60% of their maximal volume, BM-MSCs transfected with a Con-miR or Cy3-miR-124 were injected ipsilaterally and the mice were sacrificed 3 days later.	('mice', 'Species', '10090', (195, 199))	('Cy3-miR-124', 'Var', (147, 158))	('tumor', 'Disease', (21, 26))	('MSC', 'Gene', '9242', (112, 115))	('MSC', 'Gene', (112, 115))	('Cy3', 'Chemical', '-', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
63493	23548312	Brain sections were visualized under fluorescent microscopy to analyze the delivery of Cy3-miR-124 by BM-MSCs to the GFP-labeled U87 cells.	('MSC', 'Gene', '9242', (105, 108))	('U87', 'Gene', (129, 132))	('MSC', 'Gene', (105, 108))	('Cy3-miR-124', 'Var', (87, 98))	('U87', 'Gene', '641648', (129, 132))	('Cy3', 'Chemical', '-', (87, 90))
63494	23548312	H&E staining demonstrated the presence of MSCs transfected with Cy3-miR-124 within the xenografts (Figure 6A).	('with', 'Var', (59, 63))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('Cy3', 'Chemical', '-', (64, 67))	('MSC', 'Gene', '9242', (42, 45))	('MSC', 'Gene', (42, 45))
63496	23548312	Merged images demonstrate the co-localization of Cy3-miR-124 in some of the GFP-labeled glioma cells (Figure 6B), suggesting delivery of the fluorescently labeled miRNA by BM-MSCs to the glioma xenografts.	('glioma xenografts', 'Disease', 'MESH:D005910', (187, 204))	('glioma xenografts', 'Disease', (187, 204))	('glioma', 'Disease', (187, 193))	('Cy3-miR-124', 'Var', (49, 60))	('glioma', 'Disease', (88, 94))	('MSC', 'Gene', '9242', (175, 178))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('MSC', 'Gene', (175, 178))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('Cy3', 'Chemical', '-', (49, 52))
63497	23548312	In addition, we measured the expression of miR-124 in sorted GFP positive tumor cells derived from xenografts treated with MSCs transfected with Con miR or with miR-124.	('miR-124', 'Gene', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MSC', 'Gene', '9242', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('miR-124', 'Var', (161, 168))	('MSC', 'Gene', (123, 126))	('tumor', 'Disease', (74, 79))	('expression', 'MPA', (29, 39))
63498	23548312	As presented in Figure 6C, the expression of miR-124 was significantly higher in GFP positive tumor cells derived from mice treated with MSCs transfected with miR-124 compared with tumor cells derived from mice treated with MSCs transfecetd with a Con miR.	('higher', 'PosReg', (71, 77))	('MSC', 'Gene', (224, 227))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mice', 'Species', '10090', (206, 210))	('tumor', 'Disease', (94, 99))	('transfected', 'Var', (142, 153))	('miR-124', 'Gene', (45, 52))	('expression', 'MPA', (31, 41))	('MSC', 'Gene', '9242', (224, 227))	('MSC', 'Gene', '9242', (137, 140))	('miR-124', 'Var', (159, 166))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('MSC', 'Gene', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('GFP', 'Gene', (81, 84))
63504	23548312	We focused on the delivery of miR-124 and miR-145 since these miRNAs are expressed in low levels in glioma cells and GSCs and therefore can serve as potential candidates for miRNA replacement therapy in GBM.	('miR-124', 'Var', (30, 37))	('miR-145', 'Gene', '406937', (42, 49))	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('GBM', 'Phenotype', 'HP:0012174', (203, 206))	('miR-145', 'Gene', (42, 49))
63513	23548312	In addition to the miRNA delivery in vitro, we also found that BM-MSCs that were administered ipsilaterally were able to peripherally penetrate the U87-derived xenografts, deliver the Cy3-miR-124 to nearby glioma cells and downregulate the expression of the miR-124 target gene, CDK6.	('U87', 'Gene', (148, 151))	('U87', 'Gene', '641648', (148, 151))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('Cy3', 'Chemical', '-', (184, 187))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('expression', 'MPA', (240, 250))	('MSC', 'Gene', '9242', (66, 69))	('Cy3-miR-124', 'Var', (184, 195))	('deliver', 'Reg', (172, 179))	('CDK6', 'Gene', (279, 283))	('downregulate', 'NegReg', (223, 235))	('CDK6', 'Gene', '1021', (279, 283))	('MSC', 'Gene', (66, 69))	('glioma', 'Disease', (206, 212))
63522	23548312	Collectively, these results indicate that MSCs may deliver miRNA mimics efficiently and functionally to both adjacent and remote tumor cells.	('miRNA', 'Var', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('MSC', 'Gene', '9242', (42, 45))	('tumor', 'Disease', (129, 134))	('MSC', 'Gene', (42, 45))
63546	23548312	Using FACS analysis the cells were found to be positive for CD73, CD90 and CD105 but negative for the hematopoietic markers CD14, CD34, CD80 and CD45.	('CD90', 'Gene', '7070', (66, 70))	('CD80', 'Gene', (136, 140))	('CD45', 'Gene', '5788', (145, 149))	('CD73', 'Gene', (60, 64))	('positive', 'Reg', (47, 55))	('CD90', 'Gene', (66, 70))	('CD80', 'Gene', '941', (136, 140))	('CD45', 'Gene', (145, 149))	('CD34', 'Gene', (130, 134))	('CD34', 'Gene', '947', (130, 134))	('CD14', 'Gene', (124, 128))	('CD105', 'Var', (75, 80))	('CD14', 'Gene', '929', (124, 128))	('CD73', 'Gene', '4907', (60, 64))
63562	23548312	MSCs were transfected with Cy3 labeled miRNAs and the cells were washed thoroughly to remove residual transfection solution 24 h later.	('MSC', 'Gene', (0, 3))	('MSC', 'Gene', '9242', (0, 3))	('Cy3', 'Var', (27, 30))	('Cy3', 'Chemical', '-', (27, 30))
63606	23548312	The delivery of the Cy3-labeled miR-124 by the MSCs was examined in the GFP-labeled glioma cells using a fluorescence microscope.	('glioma', 'Disease', (84, 90))	('Cy3', 'Chemical', '-', (20, 23))	('MSC', 'Gene', '9242', (47, 50))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('MSC', 'Gene', (47, 50))	('miR-124', 'Var', (32, 39))	('glioma', 'Disease', 'MESH:D005910', (84, 90))
63612	33374813	Nine proteins, i.e., tubulin 2B chain, CD59, far upstream element-binding, CD44, histone H1.4, caldesmon, osteopontin, tropomyosin chain and metallothionein-2, marked the core of newly diagnosed glioblastoma with respect to tumor periphery.	('metallothionein-2', 'Gene', (141, 158))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('CD44', 'Var', (75, 79))	('glioblastoma', 'Disease', (195, 207))	('caldesmon', 'Gene', (95, 104))	('CD59', 'Gene', (39, 43))	('caldesmon', 'Gene', '800', (95, 104))	('tumor', 'Disease', (224, 229))	('histone H1.4', 'Gene', '3008', (81, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (195, 207))	('osteopontin', 'Gene', '6696', (106, 117))	('metallothionein-2', 'Gene', '4502', (141, 158))	('histone H1.4', 'Gene', (81, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (195, 207))	('osteopontin', 'Gene', (106, 117))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
63641	33374813	The gene-ontology overrepresentation analysis by PANTHER tool resulted in five pathways overrepresented (p value < 0.05), namely, in decreasing order of fold enrichment, serine glycine biosynthesis (P02776), pentose phosphate pathway (P02762), 5-hydroxytryptamine degredation (P04372), de novo purine biosynthesis (P02738), and huntington disease (P00029) (Figure 2).	('overrepresented', 'PosReg', (88, 103))	('huntington disease', 'Disease', (328, 346))	('serine', 'Chemical', 'MESH:D012694', (170, 176))	('de novo purine biosynthesis', 'MPA', (286, 313))	('P02738', 'Var', (315, 321))	('pathways', 'Pathway', (79, 87))	('purine', 'Chemical', 'MESH:C030985', (294, 300))	('P02776', 'Var', (199, 205))	('pentose phosphate', 'Chemical', 'MESH:D010428', (208, 225))	('5-hydroxytryptamine', 'Chemical', 'MESH:D012701', (244, 263))	('huntington disease', 'Disease', 'MESH:D006816', (328, 346))	('P02762', 'Var', (235, 241))	('pentose phosphate pathway', 'Pathway', (208, 233))	('5-hydroxytryptamine', 'MPA', (244, 263))	('serine', 'MPA', (170, 176))	('P04372', 'Var', (277, 283))
63663	33374813	discusses the various gene mutations that were found to be present and possibly link various neurodegenerative diseases, such as Huntington's, with CNS tumors.	('neurodegenerative diseases', 'Disease', (93, 119))	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (93, 119))	('CNS tumors', 'Disease', (148, 158))	('Huntington', 'Disease', (129, 139))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (93, 119))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('CNS tumors', 'Disease', 'MESH:D016543', (148, 158))	('Huntington', 'Disease', 'MESH:D006816', (129, 139))
63665	33374813	It is moreover relevant to focus on the nine proteins exclusively identified in ND GBM CUSA CORE, namely, tubulin 2B chain (Q9BVA1), CD59 glycoprotein (P13987), Far upstream element-binding (Q92945), CD44 antigen (P16070), histone H1.4 (P10412), caldesmon (Q05682), osteopontin (P10451), tropomyosin chain (P07951), and metallothionein-2 (P02795), and on the eight elements common to ND CUSA CORE and ND CUSA A+, and to outline their main molecular functions.	('CD59 glycoprotein', 'Gene', (133, 150))	('P10412', 'Var', (237, 243))	('metallothionein-2', 'Gene', (320, 337))	('histone H1.4', 'Gene', (223, 235))	('P16070', 'Var', (214, 220))	('P02795', 'Var', (339, 345))	('Q05682', 'Var', (257, 263))	('caldesmon', 'Gene', (246, 255))	('osteopontin', 'Gene', '6696', (266, 277))	('CD59 glycoprotein', 'Gene', '966', (133, 150))	('P13987', 'Var', (152, 158))	('P07951', 'Var', (307, 313))	('caldesmon', 'Gene', '800', (246, 255))	('Q92945', 'Var', (191, 197))	('P10451', 'Var', (279, 285))	('osteopontin', 'Gene', (266, 277))	('metallothionein-2', 'Gene', '4502', (320, 337))	('histone H1.4', 'Gene', '3008', (223, 235))
63671	33374813	This role is also reported by Wei et al., discussing all the pathological roles of osteopontin upregulation in GBM, which includes promotion of angiogenesis through modulation of COX-2 expression, myeloid-derived suppressor cell expansion through the activation of STAT3 pathway and suppression of antitumor immunity by promoting extramedullary myelopoiesis.	('myeloid-derived suppressor cell expansion', 'CPA', (197, 238))	('modulation', 'Var', (165, 175))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('STAT3', 'Gene', (265, 270))	('osteopontin', 'Gene', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('promotion', 'PosReg', (131, 140))	('promoting', 'PosReg', (320, 329))	('tumor', 'Disease', (302, 307))	('extramedullary myelopoiesis', 'CPA', (330, 357))	('upregulation', 'PosReg', (95, 107))	('COX-2', 'Gene', '4513', (179, 184))	('angiogenesis', 'CPA', (144, 156))	('extramedullary myelopoiesis', 'Phenotype', 'HP:0001978', (330, 357))	('COX-2', 'Gene', (179, 184))	('osteopontin', 'Gene', '6696', (83, 94))	('STAT3', 'Gene', '6774', (265, 270))
63675	33374813	Selected missplicing of exons of the gene are exclusively found in glioma microvessels leading to the upregulation of the protein level with proportional downregulation of tight junction proteins and effects on the permeability of GBM microvasculature.	('tight junction proteins', 'MPA', (172, 195))	('permeability', 'MPA', (215, 227))	('missplicing of exons', 'Var', (9, 29))	('glioma', 'Disease', (67, 73))	('downregulation', 'NegReg', (154, 168))	('effects', 'Reg', (200, 207))	('upregulation', 'PosReg', (102, 114))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('protein level', 'MPA', (122, 135))
63682	33374813	Immunoglobulin lambda 2 constant (P0DOY2) protein, namely, is the much highly represented in both tumor zones compared to the other seven proteins.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('P0DOY2', 'Var', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
63683	33374813	Out of the eight proteins, four of them showed statistically significant (p-value <0.05) different levels in the two tumor zones, namely: leucine-rich alpha-2 glycoprotein (P02750), 60s acidic ribosomal protein P1 (P05386), immunoglobulin lambda constant 2 (P0DOY2), and ezrin (P15311), all exhibiting higher levels in CUSA A+ compared to CUSA CORE.	('P0DOY2', 'Var', (258, 264))	('60s acidic ribosomal protein P1', 'Gene', (182, 213))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('P02750', 'Var', (173, 179))	('leucine-rich alpha-2 glycoprotein', 'Gene', (138, 171))	('tumor', 'Disease', (117, 122))	('leucine-rich alpha-2 glycoprotein', 'Gene', '116844', (138, 171))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('P15311', 'Var', (278, 284))	('ezrin', 'Gene', '7430', (271, 276))	('P05386', 'Var', (215, 221))	('ezrin', 'Gene', (271, 276))	('60s acidic ribosomal protein P1', 'Gene', '6176', (182, 213))	('higher', 'PosReg', (302, 308))	('immunoglobulin lambda constant 2', 'Gene', '3538', (224, 256))	('immunoglobulin lambda constant 2', 'Gene', (224, 256))
63696	33374813	Heterogeneous nuclear ribonucleoprotein D-like (hnRNPDL) (O14979) is, on the other hand, statistically higher in CUSA CORE compared to CUSA A-, and it was identified as over-expressed in GBM as reported in the pathology section of The Human Protein Atlas.	('hnRNPDL', 'Gene', '9987', (48, 55))	('higher', 'PosReg', (103, 109))	('hnRNPDL', 'Gene', (48, 55))	('O14979', 'Var', (58, 64))	('Human', 'Species', '9606', (235, 240))	('Heterogeneous nuclear ribonucleoprotein D-like', 'Gene', '9987', (0, 46))	('Heterogeneous nuclear ribonucleoprotein D-like', 'Gene', (0, 46))
63697	33374813	Investigating on the non-statistically different proteins, apolipoprotein CIII (P02656) and stathmin (P16949) are classified as cancer-related genes, the latter additionally identified as a poor prognostic factor for liver cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('apolipoprotein CIII', 'Gene', '345', (59, 78))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('liver cancer', 'Phenotype', 'HP:0002896', (217, 229))	('liver cancer', 'Disease', 'MESH:D006528', (217, 229))	('apolipoprotein CIII', 'Gene', (59, 78))	('P16949', 'Var', (102, 108))	('stathmin', 'Gene', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('liver cancer', 'Disease', (217, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('stathmin', 'Gene', '3925', (92, 100))	('cancer', 'Disease', (223, 229))	('P02656', 'Var', (80, 86))	('cancer', 'Disease', (128, 134))
63703	33374813	It is furthermore noteworthy to underline that 5 out of the 40 exclusive proteins characterized in CUSA A- are enclosed in the Protein Atlas list of cancer related proteins, namely the macrophage migration inhibitory factor (P14174), protein S100-A8 (P05109), complement component C6 (P13671), calpastatin (P20810) and Tropomyosin alpha-1 chain (P09493).	('cancer', 'Disease', (149, 155))	('S100-A8', 'Gene', (242, 249))	('complement component C6', 'Gene', '729', (260, 283))	('P09493', 'Var', (346, 352))	('macrophage migration inhibitory factor', 'Gene', (185, 223))	('P14174', 'Var', (225, 231))	('P20810', 'Var', (307, 313))	('Tropomyosin alpha-1 chain', 'Gene', (319, 344))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('macrophage migration inhibitory factor', 'Gene', '4282', (185, 223))	('Tropomyosin alpha-1 chain', 'Gene', '7168', (319, 344))	('S100-A8', 'Gene', '6279', (242, 249))	('P13671', 'Var', (285, 291))	('P05109', 'Var', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('complement component C6', 'Gene', (260, 283))
63748	33374813	Dynamic methionine oxidation (+15.99 Da) and static carbamidomethylation of cysteine (+57.02 Da) were also set.	('methionine oxidation', 'MPA', (8, 28))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('+15.99', 'Var', (30, 36))	('methionine', 'Chemical', 'MESH:D008715', (8, 18))
63844	32280748	Also, T2 differences between intracellular and extracellular water could affect the estimated Vin values, which will be discussed further in the last paragraph.	('T2 differences', 'Var', (6, 20))	('Vin', 'Chemical', '-', (94, 97))	('affect', 'Reg', (73, 79))	('water', 'Chemical', 'MESH:D014867', (61, 66))	('estimated Vin values', 'MPA', (84, 104))
63870	32280748	A previous simulation work suggests that omitting water exchange at the boundary of the restriction space of water diffusion leads to an underestimation of Vin but has little influence on the estimation of the space size.	('omitting', 'Var', (41, 49))	('water', 'Chemical', 'MESH:D014867', (50, 55))	('water', 'Chemical', 'MESH:D014867', (109, 114))	('underestimation', 'NegReg', (137, 152))	('Vin', 'MPA', (156, 159))	('Vin', 'Chemical', '-', (156, 159))
63876	31639020	Different in vitro glioblastoma models are monitored to evaluate if the impaired DNA damage repair may chemo/radiosensitize the tumour cells.	('tumour', 'Disease', (128, 134))	('glioblastoma', 'Disease', (19, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (19, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (19, 31))	('chemo/radiosensitize', 'CPA', (103, 123))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('DNA damage', 'Gene', (81, 91))	('impaired', 'Var', (72, 80))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
63879	31639020	SAR showed radiosensitizing effects on the induction of apoptosis and on the reduction of long-term survival in p53-mut and p53-wt glioblastoma cell lines and primary cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('reduction', 'NegReg', (77, 86))	('p53-mut', 'Var', (112, 119))	('long-term survival', 'CPA', (90, 108))	('apoptosis', 'CPA', (56, 65))	('glioblastoma', 'Disease', (131, 143))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
63896	31639020	Inhibition of Chk1 in vitro and in vivo has been shown to have radio- and chemosensitizing effects on cell survival and several Chk1 inhibitors have already been applied in clinical trials (reviewed in).	('Chk1', 'Gene', (14, 18))	('Chk1', 'Gene', (128, 132))	('Inhibition', 'Var', (0, 10))	('Chk1', 'Gene', '1111', (14, 18))	('Chk1', 'Gene', '1111', (128, 132))	('cell survival', 'CPA', (102, 115))
63903	31639020	Decitabine is an epigenetic DNA-hypomethylating and cytotoxic drug leading to proliferation inhibition and induction of apoptosis by reactivating cancer-related hypermethylation-induced gene silencing of tumour suppressor genes or by induction of DNA damage.	('cancer', 'Disease', (146, 152))	('tumour', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('gene', 'MPA', (186, 190))	('hypermethylation-induced', 'Var', (161, 185))	('proliferation inhibition', 'CPA', (78, 102))	('reactivating', 'PosReg', (133, 145))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Decitabine', 'Chemical', 'MESH:C014347', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
63905	31639020	Although in glioblastoma, the CpG island methylation phenotype (G-CIMP; about 9% of all GBMs) showed a better prognosis, G-CIMP-negative tumours also harbor about 1000 hypermethylated genes involved mainly in regulation of cell development, migration, cell-cell adhesion and transcription factors.	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('harbor', 'Reg', (150, 156))	('hypermethylated', 'Var', (168, 183))	('tumours', 'Disease', (137, 144))	('glioblastoma', 'Disease', (12, 24))	('glioblastoma', 'Disease', 'MESH:D005909', (12, 24))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
63918	31639020	T98G, LN405, and A172 were maintained in DMEM with 4.5 g/l glucose (Biozym) supplemented with 10% FCS (fetal calf serum; Biochrom).	('LN405', 'Var', (6, 11))	('calf', 'Species', '9913', (109, 113))	('T98G', 'Var', (0, 4))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))	('A172', 'Var', (17, 21))
63964	31639020	Multimodal treatment mechanisms were analysed on two human glioblastoma cell lines (LN405 and T98G) to analyse effects of SAR specifically in p53-mut tumours (Figs.	('p53-mut', 'Var', (142, 149))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('glioblastoma', 'Disease', (59, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('human', 'Species', '9606', (53, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
63965	31639020	A172 and DBRTG cell lines were additionally implemented for comparative analysis of long-term survival in p53-wt glioblastomas (Fig.	('glioblastomas', 'Phenotype', 'HP:0012174', (113, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('glioblastomas', 'Disease', 'MESH:D005909', (113, 126))	('p53-wt', 'Var', (106, 112))	('glioblastomas', 'Disease', (113, 126))
63966	31639020	In addition, key experiments (DSB induction, proliferation effects, clonogenicity, stem cell ratio) were verified on primary glioblastoma cells obtained from one p53-mut and one p53-wt patient (Figs.	('p53-mut', 'Var', (162, 169))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('patient', 'Species', '9606', (185, 192))	('glioblastoma', 'Disease', (125, 137))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
63984	31639020	TMZ, 5-aza-dC, or SAR had significant radioadditive effects on OSF, at TMZ >= 50 muM, 5-aza-dC >= 0.5 muM, and SAR >= 0.25 muM (Fig.	('muM', 'Gene', (123, 126))	('TMZ', 'Chemical', 'MESH:C047246', (0, 3))	('OSF', 'Disease', (63, 66))	('muM', 'Gene', (102, 105))	('5-aza-dC >= 0.5', 'Var', (86, 101))	('5-aza-dC', 'Chemical', 'MESH:C047553', (86, 94))	('5-aza-dC', 'Var', (5, 13))	('muM', 'Gene', '56925', (81, 84))	('TMZ', 'Chemical', 'MESH:C047246', (71, 74))	('muM', 'Gene', '56925', (123, 126))	('muM', 'Gene', '56925', (102, 105))	('5-aza-dC', 'Chemical', 'MESH:C047553', (5, 13))	('muM', 'Gene', (81, 84))
63985	31639020	5a) Additionally, the anti-clonogenic effect of the orally bioavailable Chk1 inhibitor CCT244747, most closely related to SAR, was evaluated in T98G and LN405 cell lines.	('Chk1', 'Gene', '1111', (72, 76))	('CCT244747', 'Var', (87, 96))	('anti-clonogenic effect', 'CPA', (22, 44))	('Chk1', 'Gene', (72, 76))	('CCT244747', 'Chemical', 'MESH:C577959', (87, 96))
63986	31639020	Concentration-dependent reduction of OSF and radiosensitization by CCT244747 was found to be very similar to SAR, at >= 0.125 muM (Fig.	('muM', 'Gene', '56925', (126, 129))	('CCT244747', 'Chemical', 'MESH:C577959', (67, 76))	('muM', 'Gene', (126, 129))	('OSF', 'MPA', (37, 40))	('CCT244747', 'Var', (67, 76))	('reduction', 'NegReg', (24, 33))	('radiosensitization', 'MPA', (45, 63))
63991	31639020	5a) to use the following drug concentrations which induced significant but submaximal effects on OSF: 50 muM TMZ, 0.1 muM 5-aza-dC, 0.25 muM SAR.	('muM', 'Gene', '56925', (137, 140))	('5-aza-dC', 'Chemical', 'MESH:C047553', (122, 130))	('0.1', 'Var', (114, 117))	('muM', 'Gene', (137, 140))	('muM', 'Gene', '56925', (118, 121))	('muM', 'Gene', '56925', (105, 108))	('TMZ', 'Chemical', 'MESH:C047246', (109, 112))	('muM', 'Gene', (118, 121))	('muM', 'Gene', (105, 108))
63992	31639020	To examine, whether effects are p53-dependent, p53-mut (LN405, T98G) and p53-wt glioblastoma cell lines (A172, DBTRG) were employed.	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('LN405', 'Var', (56, 61))
63996	31639020	After treatment with SAR, a stronger decrease of clonogenicity was observed in p53-mut than in p53-wt cell lines, although SAR induced significant additive effects on irradiated cells and also on combined-treated cells receiving IR/TMZ or IR/5-aza-dC in both cells.	('decrease', 'NegReg', (37, 45))	('clonogenicity', 'CPA', (49, 62))	('TMZ', 'Chemical', 'MESH:C047246', (232, 235))	('5-aza-dC', 'Chemical', 'MESH:C047553', (242, 250))	('p53-mut', 'Var', (79, 86))
63998	31639020	The multimodal treatment composed of TMZ, 5-aza-dC, SAR, and IR was most effective, e. g. leading to OSFs between < 4E-11 (LN405, no colonies were grown) and 3.7E-10 +- 3.7E-10 (T98G) (Fig.	('leading to', 'Reg', (90, 100))	('TMZ', 'Var', (37, 40))	('5-aza-dC', 'Var', (42, 50))	('5-aza-dC', 'Chemical', 'MESH:C047553', (42, 50))	('OSFs', 'Disease', (101, 105))	('TMZ', 'Chemical', 'MESH:C047246', (37, 40))
64003	31639020	The DNA damage-induced G1/S arrest is accompanied by the non-homologous end joining (NHEJ) repair pathway which is inactive in about 50% of glioblastomas due to aberrant p53 signalling.	('S arrest', 'Disease', 'MESH:D018455', (26, 34))	('S arrest', 'Disease', (26, 34))	('p53', 'Protein', (170, 173))	('aberrant', 'Var', (161, 169))	('glioblastomas', 'Phenotype', 'HP:0012174', (140, 153))	('glioblastomas', 'Disease', 'MESH:D005909', (140, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('glioblastomas', 'Disease', (140, 153))
64011	31639020	suggested that the inhibition of Chk1 in S phase cells increased the binding of pRPA to single-stranded DNA leading to genomic instability and DSB.	('Chk1', 'Gene', (33, 37))	('inhibition', 'Var', (19, 29))	('Chk1', 'Gene', '1111', (33, 37))	('increased', 'PosReg', (55, 64))	('DSB', 'Disease', (143, 146))	('binding', 'Interaction', (69, 76))	('genomic instability', 'CPA', (119, 138))	('pRPA', 'Protein', (80, 84))
64016	31639020	Clonogenic survival experiments in the fractionated setting underlined the above findings, showing accelerated reproductive cell death by SAR in all four glioblastoma cell lines after IR, 5-aza-dC, or TMZ treatment with slightly less response in p53-wt cell lines.	('5-aza-dC', 'Chemical', 'MESH:C047553', (188, 196))	('accelerated', 'PosReg', (99, 110))	('glioblastoma', 'Disease', (154, 166))	('TMZ', 'Chemical', 'MESH:C047246', (201, 204))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('reproductive cell death', 'CPA', (111, 134))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('5-aza-dC', 'Var', (188, 196))
64025	31639020	The efficiency of such treatments also in p53-wt glioblastoma patients is of high clinical relevance as, although about 30% of patients with primary and about 60% of patients with secondary glioblastoma have mutant p53, intratumoural heterogeneity of p53 mutation status has been reported and is thought to trigger tumour recurrence after p53-dependent treatment.	('glioblastoma', 'Disease', 'MESH:D005909', (190, 202))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', 'MESH:D009369', (315, 321))	('tumour', 'Disease', (225, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (190, 202))	('glioblastoma', 'Disease', (49, 61))	('p53', 'Gene', (215, 218))	('tumour', 'Disease', (315, 321))	('mutant', 'Var', (208, 214))	('patients', 'Species', '9606', (127, 135))	('tumour', 'Phenotype', 'HP:0002664', (315, 321))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (166, 174))	('glioblastoma', 'Disease', (190, 202))	('trigger', 'Reg', (307, 314))
64046	31430337	A high cHsp70 expression was associated with a prolonged PFS (hazard ratio = 0.374, p = 0.001) and OS (hazard ratio = 0.416, p = 0.014) in GBM patients treated according to the standard Stupp protocol with surgery, radiotherapy and temozolomide.	('Hsp70', 'Gene', '3308', (8, 13))	('temozolomide', 'Chemical', 'MESH:D000077204', (232, 244))	('PFS', 'MPA', (57, 60))	('high', 'Var', (2, 6))	('Hsp70', 'Gene', (8, 13))	('patients', 'Species', '9606', (143, 151))	('expression', 'MPA', (14, 24))	('prolonged', 'PosReg', (47, 56))	('GBM', 'Phenotype', 'HP:0012174', (139, 142))
64054	31430337	Patients with a methylation of the MGMT promoter benefit significantly more from the therapy with TMZ and show a better survival; moreover, this predictive marker not only reflects the outcome after TMZ, but also RT and other treatments, even if the underlying mechanisms are not fully explicable to date.	('TMZ', 'Chemical', 'MESH:D000077204', (199, 202))	('benefit', 'PosReg', (49, 56))	('more', 'PosReg', (71, 75))	('MGMT', 'Gene', (35, 39))	('MGMT', 'Gene', '4255', (35, 39))	('Patients', 'Species', '9606', (0, 8))	('reflects', 'Reg', (172, 180))	('TMZ', 'Chemical', 'MESH:D000077204', (98, 101))	('methylation', 'Var', (16, 27))
64061	31430337	While in some tumor entities a high cHsp70 expression is associated with bad prognosis, in others, it is associated with a more favorable prognosis.	('Hsp70', 'Gene', '3308', (37, 42))	('tumor entities', 'Disease', 'MESH:D009369', (14, 28))	('Hsp70', 'Gene', (37, 42))	('high', 'Var', (31, 35))	('expression', 'MPA', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor entities', 'Disease', (14, 28))
64088	31430337	The PFS of patients with low cHsp70 expressing tumors (median = 9.7 months) was 0.374 times (p = 0.001) shorter than of patients with high expressing tumors (median = 15.6 months) (Fig 3a).	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('Hsp70', 'Gene', '3308', (30, 35))	('shorter', 'NegReg', (104, 111))	('PFS', 'MPA', (4, 7))	('low', 'Var', (25, 28))	('patients', 'Species', '9606', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('patients', 'Species', '9606', (11, 19))	('Hsp70', 'Gene', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
64089	31430337	These results are comparable to the OS of these patients; GBM patients with a high cHsp70 expressing tumor had a median OS of 18.4 months, whereas the median OS of patients with low cHsp70 expressing tumors was 15.5 months (Fig 3b).	('Hsp70', 'Gene', '3308', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('Hsp70', 'Gene', '3308', (84, 89))	('high', 'Var', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('GBM', 'Phenotype', 'HP:0012174', (58, 61))	('Hsp70', 'Gene', (183, 188))	('tumor', 'Disease', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (200, 205))	('Hsp70', 'Gene', (84, 89))	('patients', 'Species', '9606', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
64090	31430337	The adjusted Hazard-Ratio for mortality associated with a high cHsp70 expression was 0.416 (p = 0.014).	('expression', 'MPA', (70, 80))	('Hsp70', 'Gene', (64, 69))	('high', 'Var', (58, 62))	('Hsp70', 'Gene', '3308', (64, 69))
64091	31430337	The MGMT promoter methylation status is well known to impact OS.	('MGMT', 'Gene', '4255', (4, 8))	('impact', 'Reg', (54, 60))	('methylation status', 'Var', (18, 36))	('MGMT', 'Gene', (4, 8))
64094	31430337	In line with the literature, PFS was not significantly different between patients with methylated MGMT promoter and unmethylated MGMT promoter.	('MGMT', 'Gene', (129, 133))	('MGMT', 'Gene', '4255', (129, 133))	('MGMT', 'Gene', (98, 102))	('methylated', 'Var', (87, 97))	('MGMT', 'Gene', '4255', (98, 102))	('patients', 'Species', '9606', (73, 81))
64103	31430337	On the other hand, in hepatocellular carcinoma, intestinal cancer, or colon cancer, high cHsp70 expression in tumors is associated with a poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (22, 46))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancer', 'Disease', (70, 82))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('expression', 'MPA', (96, 106))	('tumors', 'Disease', (110, 116))	('hepatocellular carcinoma', 'Disease', (22, 46))	('intestinal cancer', 'Disease', (48, 65))	('high', 'Var', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('Hsp70', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (22, 46))	('intestinal cancer', 'Disease', 'MESH:D007414', (48, 65))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))	('Hsp70', 'Gene', '3308', (90, 95))
64105	31430337	As IDH1-wildtype (primary) and mutant (secondary) GBM have a different pathogenesis and a different outcome, in the present study only primary GBM were investigated as they reflect a homogeneous histological group of patients.	('mutant', 'Var', (31, 37))	('GBM', 'Phenotype', 'HP:0012174', (50, 53))	('GBM', 'Phenotype', 'HP:0012174', (143, 146))	('IDH1', 'Gene', (3, 7))	('patients', 'Species', '9606', (217, 225))	('IDH1', 'Gene', '3417', (3, 7))
64106	31430337	In line with the literature, the patient collective comprises 62% MGMT unmethylated GBM and 38% methylated GBM.	('GBM', 'Phenotype', 'HP:0012174', (84, 87))	('patient', 'Species', '9606', (33, 40))	('MGMT', 'Gene', (66, 70))	('MGMT', 'Gene', '4255', (66, 70))	('methylated', 'Var', (96, 106))	('GBM', 'Phenotype', 'HP:0012174', (107, 110))
64107	31430337	Our study demonstrated that PFS and OS was significantly better in GBM patients with high cHsp70 expression levels.	('Hsp70', 'Gene', '3308', (91, 96))	('patients', 'Species', '9606', (71, 79))	('GBM', 'Disease', (67, 70))	('high', 'Var', (85, 89))	('expression levels', 'MPA', (97, 114))	('Hsp70', 'Gene', (91, 96))	('better', 'PosReg', (57, 63))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))
64145	31193037	It has been shown that high peripheral blood NLR and PLR and low LMR were associated with a poor prognosis in solid tumors, such as esophageal, hepatic, thoracic, and colorectal tumors.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('PLR', 'MPA', (53, 56))	('low', 'Var', (61, 64))	('solid tumors', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('colorectal tumors', 'Disease', 'MESH:D015179', (167, 184))	('hepatic', 'Disease', (144, 151))	('esophageal', 'Disease', (132, 142))	('thoracic', 'Disease', (153, 161))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('LMR', 'MPA', (65, 68))	('colorectal tumors', 'Disease', (167, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
64218	30498094	Furthermore, we found increased levels of activation and exhaustion markers on PD-1+ TILs when compared to PD-1+ peripheral blood T cells, while we found increased markers of memory/antigen experience on the peripheral blood PD-1+ T cells.	('exhaustion markers', 'MPA', (57, 75))	('activation', 'MPA', (42, 52))	('PD-1+', 'Var', (79, 84))	('TIL', 'Gene', (85, 88))	('levels', 'MPA', (32, 38))	('increased', 'PosReg', (22, 31))	('TIL', 'Gene', '7096', (85, 88))
64226	30498094	MT35060CI) and 10% DMSO (Sigma Cat.	('DMSO', 'Chemical', 'MESH:D004121', (19, 23))	('MT35060CI', 'Chemical', '-', (0, 9))	('MT35060CI', 'Var', (0, 9))	('DMSO', 'Var', (19, 23))
64295	30498094	Meanwhile, among the antigen experience and T cell memory markers: CD45RA, CD27, and CD127, there was a significant decrease in the TIL population compared to the PBMC population (Fig.	('CD27', 'Var', (75, 79))	('decrease', 'NegReg', (116, 124))	('CD127', 'Var', (85, 90))	('TIL', 'Gene', '7096', (132, 135))	('CD45', 'Gene', (67, 71))	('TIL', 'Gene', (132, 135))	('CD45', 'Gene', '5788', (67, 71))
64302	30498094	When the normalized RNA counts of PD-1+ T cells and PD-1- T cells were divided to create a ratio, we found that the ratio of PD-1+/PD-1- gene expression in malignant glioma TILs had an elevated fold change for markers of exhaustion (TIM-3, CTLA-4, TIGIT) when compared to the peripheral blood T cells (Suppl.	('malignant glioma', 'Disease', (156, 172))	('malignant glioma', 'Disease', 'MESH:D005910', (156, 172))	('TIL', 'Gene', '7096', (173, 176))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('elevated', 'PosReg', (185, 193))	('TIL', 'Gene', (173, 176))	('fold', 'MPA', (194, 198))	('PD-1+/PD-1- gene expression', 'Var', (125, 152))
64328	30498094	PD-1+ TILs are enriched for markers of activation and exhaustion (CTLA-4, TIM-3, HLA-DR, and CD38) when compared to PD-1+ peripheral blood T cells.	('TIL', 'Gene', '7096', (6, 9))	('TIL', 'Gene', (6, 9))	('PD-1+', 'Var', (0, 5))
64329	30498094	In contrast, peripheral blood PD-1+ T cells express a complete array of central memory, effector memory, and even the CD45RA+ effector memory T cell subsets (CD45RO, CD45RA, CD27, and CD127), suggesting diverging functionality between PD-1+ T cells obtained from distinct anatomical locale.	('memory T', 'Disease', (135, 143))	('CD27', 'Var', (174, 178))	('CD45', 'Gene', '5788', (158, 162))	('CD45', 'Gene', (166, 170))	('memory T', 'Disease', 'MESH:D008569', (135, 143))	('CD45', 'Gene', (118, 122))	('CD45', 'Gene', '5788', (166, 170))	('CD45', 'Gene', '5788', (118, 122))	('CD127', 'Var', (184, 189))	('CD45', 'Gene', (158, 162))
64333	30498094	In contrast, previous reports have shown that in healthy controls, PD-1+ peripheral CD8+ T cells do not show exhausted characteristics, but instead exhibit hallmarks of effector memory T cells.	('PD-1+', 'Var', (67, 72))	('CD8', 'Gene', '925', (84, 87))	('hallmarks of effector memory T', 'Disease', 'MESH:D008569', (156, 186))	('exhibit', 'Reg', (148, 155))	('hallmarks of effector memory T', 'Disease', (156, 186))	('CD8', 'Gene', (84, 87))
64344	30498094	The increase of clonality and CD39 expression in the PD-1+ TILs further supports their dual function phenotype of anti-tumor specific activation and exhaustion.	('tumor', 'Disease', (119, 124))	('clonality', 'CPA', (16, 25))	('TIL', 'Gene', '7096', (59, 62))	('CD39', 'Gene', (30, 34))	('expression', 'MPA', (35, 45))	('CD39', 'Gene', '953', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TIL', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('PD-1+', 'Var', (53, 58))	('increase', 'PosReg', (4, 12))
64345	30498094	Increased TCR clonality has been correlated with better outcomes after anti-PD-1 therapy in melanoma and has been associated with higher PD-1 expression in soft tissue sarcomas.	('PD-1', 'Gene', (137, 141))	('sarcomas', 'Disease', 'MESH:D012509', (168, 176))	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('higher', 'PosReg', (130, 136))	('sarcomas', 'Disease', (168, 176))	('TCR', 'Gene', '6962', (10, 13))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (156, 176))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('better', 'PosReg', (49, 55))	('expression', 'MPA', (142, 152))	('anti-PD-1', 'Var', (71, 80))	('TCR', 'Gene', (10, 13))
64353	30498094	Inhibition of the PD-1/PD-L1 axis is currently being explored as one potential immunotherapy for patients with malignant gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (121, 128))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('malignant gliomas', 'Disease', (111, 128))	('malignant gliomas', 'Disease', 'MESH:D005910', (111, 128))	('Inhibition', 'Var', (0, 10))	('patients', 'Species', '9606', (97, 105))
64366	30584325	Among these, isocitrate dehydrogenase (IDH) mutant diffuse astrocytoma WHO grade II (low-grade astrocytoma, LGA) are well-differentiated tumors with a comparatively good prognosis.	('astrocytoma', 'Disease', 'MESH:D001254', (59, 70))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('astrocytoma', 'Disease', (59, 70))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('astrocytoma', 'Phenotype', 'HP:0009592', (95, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('isocitrate dehydrogenase', 'Gene', (13, 37))	('astrocytoma', 'Disease', 'MESH:D001254', (95, 106))	('isocitrate dehydrogenase', 'Gene', '3417', (13, 37))	('IDH', 'Gene', (39, 42))	('astrocytoma', 'Disease', (95, 106))	('mutant', 'Var', (44, 50))	('IDH', 'Gene', '3417', (39, 42))
64367	30584325	However, as the characteristic mutation of IDH1/IDH2 leads to genome-wide changes in DNA methylation, it might represent the initial event in the development of these tumors.	('IDH2', 'Gene', '3418', (48, 52))	('changes', 'Reg', (74, 81))	('DNA methylation', 'MPA', (85, 100))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('mutation', 'Var', (31, 39))	('IDH1', 'Gene', (43, 47))	('IDH2', 'Gene', (48, 52))	('IDH1', 'Gene', '3417', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
64396	30584325	IHC was performed to evaluate the IDH1 R132H mutation status, as well as the Ki67 and the ATF5 protein expression of tumor samples.	('IDH1', 'Gene', '3417', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('R132H', 'Var', (39, 44))	('R132H', 'Mutation', 'rs121913500', (39, 44))	('IDH1', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Ki67', 'Chemical', '-', (77, 81))
64401	30584325	The immunoreaction for IDH1 R132H was scored positive when tumor cells showed a strong cytoplasmic staining.	('R132H', 'Var', (28, 33))	('tumor', 'Disease', (59, 64))	('R132H', 'Mutation', 'rs121913500', (28, 33))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
64433	30584325	However, whereas the ECOG, extent of tumor resection, and treatment with TMZ chemotherapy were almost equally distributed between the high and low ATF5 expression groups, patients in the high expression group were significantly older (P=0.003) and showed a lower Ki67 proliferation index (P=0.014) (Table 2).	('ATF5', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('TMZ', 'Chemical', 'MESH:D000077204', (73, 76))	('Ki67', 'Chemical', '-', (263, 267))	('lower', 'NegReg', (257, 262))	('patients', 'Species', '9606', (171, 179))	('low', 'Var', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Ki67 proliferation index', 'CPA', (263, 287))	('high', 'Var', (187, 191))
64443	30584325	Some reports provide evidence that high ATF5 expression correlates with a poor prognosis in systemic cancer as well as in malignant glioma.	('systemic cancer', 'Disease', 'MESH:D009369', (92, 107))	('ATF5', 'Protein', (40, 44))	('systemic cancer', 'Disease', (92, 107))	('malignant glioma', 'Disease', (122, 138))	('expression', 'MPA', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('malignant glioma', 'Disease', 'MESH:D005910', (122, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('high', 'Var', (35, 39))
64444	30584325	In a retrospective analysis of 23 patients with GBM, those with high ATF5 levels in their tumors had a substantially shorter survival than those with low or undetectable ATF5.	('high', 'Var', (64, 68))	('survival', 'MPA', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('shorter', 'NegReg', (117, 124))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (34, 42))	('GBM', 'Phenotype', 'HP:0012174', (48, 51))
64452	30584325	As such expression is also found in neural progenitor cells, this may indicate that tumor cells with high ATF5 expression might support tumor growth by promoting cell survival and avoiding apoptosis rather than leading to a high proliferation.	('support', 'PosReg', (128, 135))	('expression', 'Var', (111, 121))	('avoiding', 'NegReg', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('promoting', 'PosReg', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cell survival', 'CPA', (162, 175))	('apoptosis', 'CPA', (189, 198))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('high', 'Var', (101, 105))	('tumor', 'Disease', (136, 141))	('ATF5', 'Gene', (106, 110))
64454	30584325	High ATF5 expression correlated with an unfavorable prognosis of GBM patients and a higher age.	('High', 'Var', (0, 4))	('GBM', 'Disease', (65, 68))	('expression', 'MPA', (10, 20))	('ATF5', 'Protein', (5, 9))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('patients', 'Species', '9606', (69, 77))
64468	30155931	In the course of the study, unexpectedly, we found that an AMF enhances the cytotoxicity of Compound C, an activated protein kinase (AMPK) inhibitor, although this compound is not magnetic.	('AMF', 'Var', (59, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (76, 88))	('AMF', 'Chemical', '-', (59, 62))	('AMPK', 'Gene', (133, 137))	('enhances', 'PosReg', (63, 71))	('cytotoxicity', 'Disease', (76, 88))	('AMPK', 'Gene', '5563', (133, 137))
64480	30155931	We have previously examined hyperthermia treatment for tumors using magnetic material and an AMF.14, 15, 16, 17 In the course of our study, we unexpectedly found that an AMF increased the cytotoxicity of an AMP-activated protein kinase (AMPK) inhibitor, that is, Compound C, which is not a magnetic material.	('hyperthermia', 'Disease', (28, 40))	('AMF', 'Chemical', '-', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cytotoxicity', 'Disease', (188, 200))	('AMP-activated protein kinase', 'Gene', '5563', (207, 235))	('AMPK', 'Gene', '5563', (237, 241))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('AMF', 'Var', (170, 173))	('AMP-activated protein kinase', 'Gene', (207, 235))	('tumors', 'Disease', (55, 61))	('cytotoxicity', 'Disease', 'MESH:D064420', (188, 200))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('hyperthermia', 'Disease', 'MESH:D005334', (28, 40))	('AMF', 'Chemical', '-', (93, 96))	('increased', 'PosReg', (174, 183))	('AMPK', 'Gene', (237, 241))	('hyperthermia', 'Phenotype', 'HP:0001945', (28, 40))
64510	30155931	We previously reported that hyperthermia generated with ferucarbotran (Risovist) in an AMF enhanced cisplatin-induced apoptosis of oral cancer cells in culture.16 Similarly, we demonstrated that the use of hyperthermia and chemotherapy with mu-oxo N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, greatly enhanced its cytotoxicity in oral cancer and glioblastoma because Fe(Salen) generates heat when exposed to an AMF and exhibited a hyperthermic effect.15, 17 In the course of our study, we hypothesized that an AMF enhanced the cytotoxicity of an anti-tumor agent that does not possess magnetism.	('AMF', 'Chemical', '-', (451, 454))	('oral cancer', 'Disease', 'MESH:D009062', (370, 381))	('oral cancer', 'Disease', (370, 381))	('glioblastoma', 'Disease', 'MESH:D005909', (386, 398))	('AMF', 'Var', (550, 553))	('cytotoxicity', 'Disease', 'MESH:D064420', (567, 579))	('tumor', 'Disease', (591, 596))	('iron', 'Chemical', 'MESH:D007501', (286, 290))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('hyperthermia', 'Disease', 'MESH:D005334', (206, 218))	('glioblastoma', 'Disease', (386, 398))	('tumor', 'Disease', 'MESH:D009369', (591, 596))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('hyperthermia', 'Disease', (28, 40))	('glioblastoma', 'Phenotype', 'HP:0012174', (386, 398))	('oral cancer', 'Disease', 'MESH:D009062', (131, 142))	('AMF', 'Chemical', '-', (550, 553))	('oral cancer', 'Disease', (131, 142))	('hyperthermia', 'Phenotype', 'HP:0001945', (206, 218))	('tumor', 'Phenotype', 'HP:0002664', (591, 596))	('cytotoxicity', 'Disease', (354, 366))	('enhanced', 'PosReg', (554, 562))	('hyperthermia', 'Disease', 'MESH:D005334', (28, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (354, 366))	('hyperthermia', 'Disease', (206, 218))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('AMF', 'Chemical', '-', (87, 90))	('cytotoxicity', 'Disease', (567, 579))	('hyperthermia', 'Phenotype', 'HP:0001945', (28, 40))
64514	30155931	Compound C exhibited cytotoxicity in gliomas.10 In the current study, Compound C suppressed the cell proliferation of GB cells (T98 and U251) and normal human astrocytes (NHA) in a dose-dependent manner (Figure 1E).	('suppressed', 'NegReg', (81, 91))	('cytotoxicity', 'Disease', (21, 33))	('cell proliferation', 'CPA', (96, 114))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('GB', 'Phenotype', 'HP:0012174', (118, 120))	('gliomas', 'Disease', (37, 44))	('human', 'Species', '9606', (153, 158))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('T98', 'CellLine', 'CVCL:B368', (128, 131))	('Compound', 'Var', (70, 78))
64530	30155931	AMPK is a key regulator of cellular energy metabolism and is activated under metabolic stress for survival.10 To examine the effect of an AMF, we next investigated a mechanism whereby an AMF enhanced the cytotoxicity of Compound C in GB cells.	('cytotoxicity', 'Disease', (204, 216))	('AMPK', 'Gene', '5563', (0, 4))	('GB', 'Phenotype', 'HP:0012174', (234, 236))	('AMF', 'Var', (187, 190))	('cytotoxicity', 'Disease', 'MESH:D064420', (204, 216))	('enhanced', 'PosReg', (191, 199))	('AMPK', 'Gene', (0, 4))	('AMF', 'Chemical', '-', (187, 190))	('AMF', 'Chemical', '-', (138, 141))
64532	30155931	These 2 pathways can exert complementary and redundant functions when only a single pathway is inhibited.32  Our results showed that Compound C or Compound C+ AMF, inhibited the phosphorylation of Akt in T98 and U251 cells (Figure S3).	('Akt', 'Gene', '207', (197, 200))	('T98', 'CellLine', 'CVCL:B368', (204, 207))	('phosphorylation', 'MPA', (178, 193))	('Compound C', 'Var', (133, 143))	('Akt', 'Gene', (197, 200))	('inhibited', 'NegReg', (164, 173))	('AMF', 'Chemical', '-', (159, 162))	('Compound C+ AMF', 'Var', (147, 162))
64536	30155931	To our knowledge, this is the first study to report that Compound C increased the phosphorylation of ERK (Figure 4A).	('Compound C', 'Var', (57, 67))	('ERK', 'Gene', '5594', (101, 104))	('phosphorylation', 'MPA', (82, 97))	('ERK', 'Gene', (101, 104))	('increased', 'PosReg', (68, 77))
64537	30155931	Interestingly, Compound C did not increase but rather decreased ERK signaling in NHA (Figure S2).	('Compound', 'Var', (15, 23))	('ERK', 'Gene', '5594', (64, 67))	('ERK', 'Gene', (64, 67))	('decreased', 'NegReg', (54, 63))	('decreased ERK', 'Phenotype', 'HP:0000654', (54, 67))
64541	30155931	Interestingly, the AMF negated the Compound C-induced phosphorylation of ERK.	('AMF', 'Chemical', '-', (19, 22))	('ERK', 'Gene', (73, 76))	('negated', 'NegReg', (23, 30))	('AMF', 'Var', (19, 22))	('Compound C-induced phosphorylation', 'MPA', (35, 69))	('ERK', 'Gene', '5594', (73, 76))
64543	30155931	U0126, MEK inhibitor, decreased phosphorylation of ERK, resulting in increasing ROS generation and cleaved caspase 3 in the presence of Compound C (Figure S4).	('ERK', 'Gene', (51, 54))	('MEK', 'Gene', (7, 10))	('MEK', 'Gene', '5609', (7, 10))	('U0126', 'Var', (0, 5))	('ERK', 'Gene', '5594', (51, 54))	('increasing', 'PosReg', (69, 79))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('phosphorylation', 'MPA', (32, 47))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('ROS generation', 'MPA', (80, 94))	('cleaved caspase', 'MPA', (99, 114))	('decreased', 'NegReg', (22, 31))
64545	30155931	To confirm this hypothesis, we examined whether U0126, an MEK1 and MEK2 inhibitor, also negated Compound C-induced ERK phosphorylation and suppressed cell proliferation.	('MEK2', 'Gene', '5605', (67, 71))	('U0126', 'Chemical', 'MESH:C113580', (48, 53))	('MEK2', 'Gene', (67, 71))	('cell proliferation', 'CPA', (150, 168))	('ERK', 'Gene', (115, 118))	('MEK1', 'Gene', '5604', (58, 62))	('negated', 'NegReg', (88, 95))	('U0126', 'Var', (48, 53))	('MEK1', 'Gene', (58, 62))	('suppressed', 'NegReg', (139, 149))	('ERK', 'Gene', '5594', (115, 118))
64546	30155931	In fact, U0126 decreased the phosphorylation of ERK in the presence of Compound C and increased the expression of cleaved caspase-3 (Figure 4D,E).	('caspase-3', 'Gene', '836', (122, 131))	('ERK', 'Gene', (48, 51))	('increased', 'PosReg', (86, 95))	('caspase-3', 'Gene', (122, 131))	('expression', 'MPA', (100, 110))	('U0126', 'Chemical', 'MESH:C113580', (9, 14))	('decreased', 'NegReg', (15, 24))	('ERK', 'Gene', '5594', (48, 51))	('U0126', 'Var', (9, 14))	('phosphorylation', 'MPA', (29, 44))
64551	30155931	Although Compound C increased autophagy, Compound C did not increase the expression of BAX and cleaved Caspase 3, and did not decrease the expression of BCL-2 in NHA (Figure S2).	('increased', 'PosReg', (20, 29))	('Compound', 'Var', (9, 17))	('BAX', 'Gene', (87, 90))	('BCL-2', 'Gene', '596', (153, 158))	('BAX', 'Gene', '581', (87, 90))	('BCL-2', 'Gene', (153, 158))	('autophagy', 'CPA', (30, 39))
64553	30155931	U0126 also decreased Compound C-induced autophagy in T98 cells (Figure S4).	('T98', 'CellLine', 'CVCL:B368', (53, 56))	('decreased', 'NegReg', (11, 20))	('U0126', 'Var', (0, 5))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('Compound', 'CPA', (21, 29))
64555	30155931	In contrast, the AMF decreased the number of autophagosomes.	('decreased', 'NegReg', (21, 30))	('number of autophagosomes', 'CPA', (35, 59))	('AMF', 'Chemical', '-', (17, 20))	('AMF', 'Var', (17, 20))
64557	30155931	To investigate the effect of an AMF, we evaluated the effect of chloroquine in the presence of Compound C. Chloroquine increased the cytotoxicity of Compound C in T98 and U251 cells (Figure S5).	('cytotoxicity', 'Disease', (133, 145))	('Chloroquine', 'Chemical', 'MESH:D002738', (107, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (133, 145))	('Chloroquine', 'Var', (107, 118))	('chloroquine', 'Chemical', 'MESH:D002738', (64, 75))	('T98', 'CellLine', 'CVCL:B368', (163, 166))	('AMF', 'Chemical', '-', (32, 35))	('increased', 'PosReg', (119, 128))
64564	30155931	Interestingly, the AMF also increased the cytotoxicity of TMZ and BCNU induced-cytotoxicity in U251 glioma cells (Figure S6).	('increased', 'PosReg', (28, 37))	('glioma', 'Disease', (100, 106))	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('AMF', 'Chemical', '-', (19, 22))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('cytotoxicity', 'Disease', (79, 91))	('BCNU', 'Chemical', 'MESH:D002330', (66, 70))	('cytotoxicity', 'Disease', (42, 54))	('AMF', 'Var', (19, 22))	('TMZ', 'Chemical', 'MESH:D000077204', (58, 61))
64567	30155931	The AMF also enhanced the cytotoxicity of various anti-cancer drugs (TMZ and BCNU), which are used clinically in GB cells.	('AMF', 'Var', (4, 7))	('TMZ', 'Chemical', 'MESH:D000077204', (69, 72))	('enhanced', 'PosReg', (13, 21))	('BCNU', 'Chemical', 'MESH:D002330', (77, 81))	('cytotoxicity', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('AMF', 'Chemical', '-', (4, 7))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('GB', 'Phenotype', 'HP:0012174', (113, 115))
64575	30155931	Therefore, the AMF may affect the metal in the mitochondria and induce instability of the mitochondrial electron transport system.	('induce', 'Reg', (64, 70))	('metal', 'Chemical', 'MESH:D008670', (34, 39))	('mitochondrial electron transport system', 'MPA', (90, 129))	('instability', 'MPA', (71, 82))	('AMF', 'Var', (15, 18))	('affect', 'Reg', (23, 29))	('metal in the mitochondria', 'MPA', (34, 59))	('AMF', 'Chemical', '-', (15, 18))
64590	30167084	Silencing FGFR1 or FOXM1 downregulated genes involved in mesenchymal transition such as GLI2, TWIST1, and ZEB1 in glioblastoma stem-like cells.	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('FOXM1', 'Gene', (19, 24))	('FGFR1', 'Gene', (10, 15))	('TWIST1', 'Gene', (94, 100))	('downregulated', 'NegReg', (25, 38))	('TWIST1', 'Gene', '7291', (94, 100))	('glioblastoma', 'Disease', (114, 126))	('genes', 'MPA', (39, 44))	('mesenchymal transition', 'CPA', (57, 79))	('Silencing', 'Var', (0, 9))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
64600	30167084	We recently showed that silencing FGFR1 induces an in vitro and in vivo radiosensitization of GBM cell lines via PLCgamma and HIF1alpha.	('HIF1alpha', 'Gene', (126, 135))	('FGFR1', 'Gene', (34, 39))	('HIF1alpha', 'Gene', '3091', (126, 135))	('silencing', 'Var', (24, 33))	('radiosensitization', 'CPA', (72, 90))
64610	30167084	To investigate whether the specific inhibition of FGFR1 may modify the cellular radiosensitivity, we performed 3D clonogenic assay in the FGFR1 silenced GSLC cell lines.	('silenced', 'Var', (144, 152))	('inhibition', 'NegReg', (36, 46))	('cellular radiosensitivity', 'Phenotype', 'HP:0010997', (71, 96))	('modify', 'Reg', (60, 66))	('FGFR1', 'Gene', (138, 143))	('GSLC', 'Chemical', '-', (153, 157))	('cellular radiosensitivity', 'CPA', (71, 96))
64612	30167084	SubG1 level was increased in GC1FGFR1(-) and GC2FGFR1(-) compared to control cells by 61% and 75%, respectively (Figure 2C and Figure 2D) strongly suggesting that FGFR1 silencing increased glioblastoma stem-like cell death induced by radiation.	('silencing', 'Var', (169, 178))	('glioblastoma', 'Disease', (189, 201))	('SubG1', 'MPA', (0, 5))	('increased', 'PosReg', (16, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('increased', 'PosReg', (179, 188))	('FGFR1', 'Gene', (163, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))
64616	30167084	A family of proteins involved in many cancers, known to regulate cell cycle, associated with stem cells and drug resistance (for review) and whose expressions have been variously affected by FGFR1 silencing, has particularly attracted our attention, the Forkhead box (FOX) family.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('FGFR1', 'Gene', (191, 196))	('expressions', 'MPA', (147, 158))	('affected', 'Reg', (179, 187))	('cell cycle', 'CPA', (65, 75))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('drug resistance', 'Phenotype', 'HP:0020174', (108, 123))	('silencing', 'Var', (197, 206))	('regulate', 'Reg', (56, 64))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
64619	30167084	We first checked by RT-PCR that silencing FGFR1 in GSLCs induced an overexpression of FOXN3 and a downregulation of FOXM1.	('GSLC', 'Chemical', '-', (51, 55))	('downregulation', 'NegReg', (98, 112))	('FGFR1', 'Gene', (42, 47))	('silencing', 'Var', (32, 41))	('overexpression', 'PosReg', (68, 82))	('FOXM1', 'Gene', (116, 121))	('FOXN3', 'Gene', (86, 91))
64620	30167084	As shown in Figure 3A (left panel), FOXN3 expression is significantly increased in GC1FGFR1(-) and GC2FGFR1(-) compared to control cells by 2.1 fold (p < 0.05) and 2.4 fold (p < 0.01), respectively, while FOXM1 is significantly decreased (2 fold in GSLC FGFR1(-) compared to GSLC control cells).	('FOXN3', 'Gene', (36, 41))	('increased', 'PosReg', (70, 79))	('expression', 'MPA', (42, 52))	('GSLC', 'Chemical', '-', (249, 253))	('GC2FGFR1', 'Var', (99, 107))	('GC1FGFR1', 'Var', (83, 91))	('GSLC', 'Chemical', '-', (275, 279))
64621	30167084	We then performed clonogenic assay in FOXN3 or FOXM1 silenced GSLC to evaluate their respective roles in the control of intrinsic cellular radiosensitivity.	('GSLC', 'Chemical', '-', (62, 66))	('FOXM1', 'Gene', (47, 52))	('FOXN3', 'Gene', (38, 43))	('cellular radiosensitivity', 'Phenotype', 'HP:0010997', (130, 155))	('silenced', 'Var', (53, 61))
64622	30167084	The survival after irradiation of GSLC (GC1 and GC2) was significantly increased after FOXN3 silencing (Figure 3B) while FOXM1 inhibition significantly radiosensitizes GC1 and GC2 cells (Figure 3C).	('FOXM1', 'Gene', (121, 126))	('GC1', 'Gene', '10562', (168, 171))	('silencing', 'Var', (93, 102))	('GSLC', 'Chemical', '-', (34, 38))	('radiosensitizes', 'NegReg', (152, 167))	('GC2', 'Gene', (176, 179))	('GC2', 'Gene', (48, 51))	('survival', 'CPA', (4, 12))	('GC1', 'Gene', (40, 43))	('GC2', 'Gene', '83733', (176, 179))	('GC2', 'Gene', '83733', (48, 51))	('GC1', 'Gene', '10562', (40, 43))	('GC1', 'Gene', (168, 171))	('FOXN3', 'Gene', (87, 92))	('inhibition', 'NegReg', (127, 137))	('increased', 'PosReg', (71, 80))
64625	30167084	MELK-regulated phosphorylation of FOXM1 transcriptional activity and induces the expression of various mitotic regulators such as survivin, Aurora B and CDC25B.	('survivin', 'Protein', (130, 138))	('FOXM1', 'Gene', (34, 39))	('Aurora B', 'Gene', '9212', (140, 148))	('phosphorylation', 'Var', (15, 30))	('Aurora B', 'Gene', (140, 148))	('induces', 'PosReg', (69, 76))	('CDC25B', 'Gene', '994', (153, 159))	('transcriptional activity', 'MPA', (40, 64))	('CDC25B', 'Gene', (153, 159))	('expression', 'MPA', (81, 91))
64633	30167084	Furthermore, the analysis of GSLC migration in Boyden chambers revealed that GC1FGFR1(-) and GC1FOXM1(-) migrations were inhibited by 54% (29% for GC2) and 56% (68% for GSC2) respectively compared to control cells (Figure 4B) demonstrating that silencing FGFR1 or FOXM1 dramatically reduced GSC migration.	('GC2', 'Gene', (147, 150))	('migrations', 'CPA', (105, 115))	('GC2', 'Gene', '83733', (147, 150))	('silencing', 'Var', (245, 254))	('GSC migration', 'CPA', (291, 304))	('GSLC', 'Chemical', '-', (29, 33))	('GC1FOXM1', 'Gene', (93, 101))	('reduced', 'NegReg', (283, 290))	('GC1FGFR1', 'Gene', (77, 85))	('FGFR1', 'Gene', (255, 260))	('FOXM1', 'Gene', (264, 269))	('inhibited', 'NegReg', (121, 130))	('GSC2', 'Gene', (169, 173))	('GSC2', 'Gene', '2928', (169, 173))
64639	30167084	Our previous works have demonstrated that FGFR1 tumor expression was an independent prognostic factor of time to progression and overall survival in patients treated with radiotherapy for glioblastoma and that inhibiting FGFR, and more specifically FGFR1, increased the radiosensitivity of glioblastoma differentiated cells.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('patients', 'Species', '9606', (149, 157))	('tumor', 'Disease', (48, 53))	('glioblastoma', 'Disease', (188, 200))	('glioblastoma', 'Disease', 'MESH:D005909', (290, 302))	('inhibiting', 'Var', (210, 220))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('glioblastoma', 'Phenotype', 'HP:0012174', (290, 302))	('FGFR1', 'Gene', (42, 47))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('FGFR', 'Gene', (221, 225))	('increased', 'PosReg', (256, 265))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('FGFR1', 'Gene', (249, 254))	('glioblastoma', 'Disease', (290, 302))
64643	30167084	Our present results clearly establish that silencing FGFR1 significantly increases GSLC sensitivity to ionizing radiation by increasing radiation-induced cell death.	('FGFR1', 'Gene', (53, 58))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (88, 121))	('increases', 'PosReg', (73, 82))	('GSLC', 'Chemical', '-', (83, 87))	('radiation-induced cell death', 'CPA', (136, 164))	('silencing', 'Var', (43, 52))	('increasing', 'PosReg', (125, 135))	('GSLC sensitivity to ionizing radiation', 'MPA', (83, 121))
64647	30167084	A recent meta-analysis of several published studies revealed that elevated FOXM1 expression is associated with poor survival in most solid tumors.	('elevated', 'Var', (66, 74))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('solid tumors', 'Disease', (133, 145))	('FOXM1', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (81, 91))	('poor', 'NegReg', (111, 115))
64650	30167084	Our present data clearly showed that FOXN3 inhibition significantly decreased GSLC sensitivity to radiation in vitro.	('decreased', 'NegReg', (68, 77))	('FOXN3', 'Gene', (37, 42))	('inhibition', 'Var', (43, 53))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (83, 107))	('GSLC', 'Chemical', '-', (78, 82))	('GSLC sensitivity to radiation', 'MPA', (78, 107))
64653	30167084	We then demonstrated that silencing FGFR1/FOXM1 pathway reduced the expression of EMT-associated genes as GLI2, ZEB1 and TWIST1 in GSLC.	('expression', 'MPA', (68, 78))	('TWIST1', 'Gene', (121, 127))	('reduced', 'NegReg', (56, 63))	('TWIST1', 'Gene', '7291', (121, 127))	('GSLC', 'Chemical', '-', (131, 135))	('ZEB1', 'Gene', (112, 116))	('GLI2', 'Gene', (106, 110))	('silencing', 'Var', (26, 35))	('FGFR1/FOXM1', 'Gene', (36, 47))	('EMT', 'Gene', (82, 85))	('EMT', 'Gene', '3702', (82, 85))
64662	30167084	It could reasonably be hypothesized, even if complementally analyses should be performed, that this genes set might be useful to discriminate GBM patients whose tumor will respond to an association of a specific FGFR1 inhibitor with radiotherapy.	('tumor', 'Disease', (161, 166))	('FGFR1', 'Gene', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('association', 'Interaction', (186, 197))	('patients', 'Species', '9606', (146, 154))	('inhibitor', 'Var', (218, 227))
64664	30167084	In particular, FGFR-TACC fusions which is clonal tumor-initiating events appear in 3% of glioblastoma for FGFR3- TACC3 fusion, confer strong sensitivity to FGFR tyrosine kinase in preclinical and preliminary clinical data.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TACC3', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('glioblastoma', 'Disease', (89, 101))	('fusion', 'Var', (119, 125))	('sensitivity', 'MPA', (141, 152))	('FGFR3', 'Gene', (106, 111))	('tumor', 'Disease', (49, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('FGFR3', 'Gene', '2261', (106, 111))	('TACC3', 'Gene', '10460', (113, 118))
64699	29896287	IDH (isocitrate dehydrogenase) mutations and ATRX (alpha thalassemia/mental retardation syndrome X-linked) loss were detected with IHC (Immunohistochemistry).	('mental retardation', 'Phenotype', 'HP:0001249', (69, 87))	('mutations', 'Var', (31, 40))	('IDH', 'Gene', (0, 3))	('ATRX', 'Gene', (45, 49))	('isocitrate dehydrogenase', 'Gene', (5, 29))	('IDH', 'Gene', '3417', (0, 3))	('isocitrate dehydrogenase', 'Gene', '3417', (5, 29))	('ATRX', 'Gene', '546', (45, 49))	('thalassemia/mental retardation syndrome X-linked) loss', 'Disease', 'MESH:C538258', (57, 111))
64704	29896287	Univariate analysis found that younger age, higher KPS (Karnofsky Performance Score), gross total resection, complete chemoradiotherapy, IDH-1R132H mutations and lower levels of fibrinogen were associated with favorable outcomes.	('mutations', 'Var', (148, 157))	('IDH', 'Gene', '3417', (137, 140))	('higher', 'PosReg', (44, 50))	('lower', 'NegReg', (162, 167))	('fibrinogen', 'Gene', '2244', (178, 188))	('KPS', 'MPA', (51, 54))	('lower levels of fibrinogen', 'Phenotype', 'HP:0011900', (162, 188))	('fibrinogen', 'Gene', (178, 188))	('IDH', 'Gene', (137, 140))
64715	29896287	The association between plasma fibrinogen and tumor prognosis, IDH (isocitrate dehydrogenase) mutations and ATRX (alpha thalassemia/mental retardation syndrome X-linked) loss were also investigated here.	('thalassemia/mental retardation syndrome X-linked) loss', 'Disease', 'MESH:C538258', (120, 174))	('fibrinogen', 'Gene', '2244', (31, 41))	('fibrinogen', 'Gene', (31, 41))	('mental retardation', 'Phenotype', 'HP:0001249', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('IDH', 'Gene', (63, 66))	('mutations', 'Var', (94, 103))	('isocitrate dehydrogenase', 'Gene', (68, 92))	('tumor', 'Disease', (46, 51))	('IDH', 'Gene', '3417', (63, 66))	('ATRX', 'Gene', (108, 112))	('isocitrate dehydrogenase', 'Gene', '3417', (68, 92))	('ATRX', 'Gene', '546', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
64721	29896287	The Immunohistochemistry (IHC) was performed to evaluate the IDH-1R132H mutations and ATRX loss in GBMs, according to our previous report.	('ATRX', 'Gene', '546', (86, 90))	('mutations', 'Var', (72, 81))	('IDH', 'Gene', '3417', (61, 64))	('GBMs', 'Phenotype', 'HP:0012174', (99, 103))	('ATRX', 'Gene', (86, 90))	('loss', 'NegReg', (91, 95))	('IDH', 'Gene', (61, 64))
64739	29896287	It was well acknowledged that IDH mutation and ATRX loss were the most important genetic alternations in GBMs.	('ATRX', 'Gene', (47, 51))	('loss', 'NegReg', (52, 56))	('GBMs', 'Phenotype', 'HP:0012174', (105, 109))	('mutation', 'Var', (34, 42))	('ATRX', 'Gene', '546', (47, 51))	('IDH', 'Gene', (30, 33))	('IDH', 'Gene', '3417', (30, 33))
64744	29896287	IDH mutations significantly distinguished gliomas in genetics changes and survival, and served as a biomarker for GBM classification.	('IDH', 'Gene', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
64747	29896287	The univariate analysis suggested that younger age, higher preoperative KPS, GTR, complete chemoradiotherapy, IDH-1R132H mutations and lower levels of fibrinogen were associated with improved OS.	('GTR', 'Disease', (77, 80))	('KPS', 'MPA', (72, 75))	('lower levels of fibrinogen', 'Phenotype', 'HP:0011900', (135, 161))	('mutations', 'Var', (121, 130))	('IDH', 'Gene', (110, 113))	('improved', 'PosReg', (183, 191))	('IDH', 'Gene', '3417', (110, 113))	('lower', 'NegReg', (135, 140))	('OS', 'Gene', '17451', (192, 194))	('fibrinogen', 'Gene', '2244', (151, 161))	('fibrinogen', 'Gene', (151, 161))
64749	29896287	In the present study, we first observed that preoperative plasma fibrinogen was significantly decreased in younger patients, IDH-1R132H mutations and ATRX loss from 315 GBM patients' data.	('loss', 'NegReg', (155, 159))	('patients', 'Species', '9606', (115, 123))	('fibrinogen', 'Gene', (65, 75))	('ATRX', 'Gene', (150, 154))	('patients', 'Species', '9606', (173, 181))	('IDH', 'Gene', (125, 128))	('decreased', 'NegReg', (94, 103))	('ATRX', 'Gene', '546', (150, 154))	('mutations', 'Var', (136, 145))	('IDH', 'Gene', '3417', (125, 128))	('fibrinogen', 'Gene', '2244', (65, 75))
64755	29896287	Reynes G and colleges observed that plasma fibrinogen were significantly increased in patients with GBMs compared with heathy controls.	('increased', 'PosReg', (73, 82))	('fibrinogen', 'Gene', '2244', (43, 53))	('fibrinogen', 'Gene', (43, 53))	('GBMs', 'Var', (100, 104))	('GBMs', 'Phenotype', 'HP:0012174', (100, 104))	('patients', 'Species', '9606', (86, 94))
64758	29896287	A significant increase of plasma fibrinogen was observed in the subtype of IDH wildtype and ATRX expression, which also indicated a negative role of fibrinogen in GBMs.	('ATRX', 'Gene', (92, 96))	('fibrinogen', 'Gene', '2244', (149, 159))	('GBMs', 'Phenotype', 'HP:0012174', (163, 167))	('fibrinogen', 'Gene', (149, 159))	('expression', 'Var', (97, 107))	('fibrinogen', 'Gene', (33, 43))	('fibrinogen', 'Gene', '2244', (33, 43))	('ATRX', 'Gene', '546', (92, 96))	('increase of plasma fibrinogen', 'Phenotype', 'HP:0011899', (14, 43))	('IDH', 'Gene', (75, 78))	('IDH', 'Gene', '3417', (75, 78))	('increase', 'PosReg', (14, 22))
64767	29896287	IDH mutations were rarely detected in mesenchymal subtype, and most likely to positively correlate with coagulation-related gene expression.	('IDH', 'Gene', (0, 3))	('correlate', 'Reg', (89, 98))	('coagulation-related', 'MPA', (104, 123))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (4, 13))
64795	28860959	The high mitotic activity was highlighted by Ki67 positivity demonstrating a mean labeling index of 15% (Figure 3 (Fig.	('Ki67', 'Chemical', '-', (45, 49))	('Ki67', 'Var', (45, 49))	('labeling', 'MPA', (82, 90))	('positivity', 'Var', (50, 60))	('mitotic activity', 'CPA', (9, 25))
64799	28860959	GFAP negativity excluded the possibility of glioma.	('negativity', 'Var', (5, 15))	('GFAP', 'Gene', (0, 4))	('glioma', 'Disease', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (44, 50))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('GFAP', 'Gene', '2670', (0, 4))
64824	27698479	Multiphoton imaging reveals that nanosecond pulsed electric fields collapse tumor and normal vascular perfusion in human glioblastoma xenografts Despite the biomedical advances of the last century, many cancers including glioblastoma are still resistant to existing therapies leaving patients with poor prognoses.	('glioblastoma', 'Disease', 'MESH:D005909', (221, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (221, 233))	('patients', 'Species', '9606', (284, 292))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('human', 'Species', '9606', (115, 120))	('collapse tumor', 'Disease', 'MESH:D001261', (67, 81))	('nanosecond', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('glioblastoma', 'Disease', (221, 233))	('glioblastoma', 'Disease', (121, 133))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('collapse tumor', 'Disease', (67, 81))	('cancers', 'Disease', (203, 210))
64852	27698479	Approximately 75% (129/172) of U87-MG grafts implanted into quail CAM developed into vascularized tumor organoids by embryonic day 10.	('CAM', 'Gene', '71817', (66, 69))	('U87-MG', 'CellLine', 'CVCL:0022', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('U87-MG', 'Var', (31, 37))	('quail', 'Species', '9091', (60, 65))	('vascularized tumor', 'Phenotype', 'HP:0100742', (85, 103))	('CAM', 'Gene', (66, 69))	('tumor', 'Disease', (98, 103))
64891	27698479	It is important to also note that irreversible electroporation is typically associated with necrosis, whilst nsPEFs lead to apoptosis.	('associated', 'Reg', (76, 86))	('necrosis', 'Disease', (92, 100))	('irreversible electroporation', 'Var', (34, 62))	('necrosis', 'Disease', 'MESH:D009336', (92, 100))
64896	27698479	Indeed, in the CAM model MT depolymerization collapses capillary structures.	('depolymerization', 'Var', (28, 44))	('CAM', 'Gene', (15, 18))	('collapses capillary', 'Phenotype', 'HP:0030005', (45, 64))	('collapses', 'NegReg', (45, 54))	('CAM', 'Gene', '71817', (15, 18))	('capillary structures', 'MPA', (55, 75))	('MT depolymerization', 'Var', (25, 44))
64910	27698479	Human U87-MG glioblastoma cells (ATCC HTB-14) were modified by lentiviral infection to stably express fLuc2 and eGFP (U87-fLuc2/eGFP, maximum excitation lambda = 488 nm, maximum emission lambda = 509 nm) under the control of the CMV promoter (kindly provided by Dr. S.A. Collins from Department of Medicine-Digestive Diseases, UCLA, USA).	('Human', 'Species', '9606', (0, 5))	('Digestive Diseases', 'Phenotype', 'HP:0011024', (307, 325))	('U87-MG glioblastoma', 'Disease', (6, 25))	('U87-MG glioblastoma', 'Disease', 'MESH:D005909', (6, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('U87-fLuc2/eGFP', 'Var', (118, 132))	('fLuc2', 'Gene', (102, 107))
64926	27698479	The different components of the light emitted from the sample were separated using a further dichroic mirror (570 nm) distributing the green and red fluorescence to two photomultiplier tubes (PMT voltage 350 V and PMT voltage 444 V) with fluorophore specific emission filters (BA 575-630 for Rhodamine B, GFP 495-540 for GFP).	('BA 575-630', 'Var', (277, 287))	('BA', 'Chemical', 'MESH:D001464', (277, 279))	('Rhodamine B', 'Chemical', 'MESH:C029773', (292, 303))	('GFP', 'Var', (305, 308))
64928	27698479	Multiphoton imaging reveals that nanosecond pulsed electric fields collapse tumor and normal vascular perfusion in human glioblastoma xenografts.	('glioblastoma', 'Phenotype', 'HP:0012174', (121, 133))	('nanosecond pulsed electric fields', 'Var', (33, 66))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('human', 'Species', '9606', (115, 120))	('collapse tumor', 'Disease', 'MESH:D001261', (67, 81))	('glioblastoma', 'Disease', (121, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (121, 133))	('collapse tumor', 'Disease', (67, 81))
64932	27462980	Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control.	('mice', 'Species', '10090', (68, 72))	('breast carcinoma', 'Phenotype', 'HP:0003002', (142, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('MT1-MMP', 'Var', (115, 122))	('MCF-7', 'CellLine', 'CVCL:0031', (166, 171))	('breast carcinoma', 'Disease', 'MESH:D001943', (142, 158))	('breast carcinoma', 'Disease', (142, 158))	('human', 'Species', '9606', (81, 86))
64935	27462980	Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('GBM tumors', 'Disease', (138, 148))	('GBM tumors', 'Disease', 'MESH:D005910', (138, 148))	('DFO', 'Chemical', 'MESH:D003676', (48, 51))	('89Zr-DFO-LEM2/15', 'Var', (43, 59))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('89Zr', 'Chemical', 'MESH:C000615502', (43, 47))
64936	27462980	PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors.	('breast tumors', 'Disease', 'MESH:D001943', (131, 144))	('89Zr', 'Chemical', 'MESH:C000615502', (52, 56))	('breast tumors', 'Disease', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GBM tumors', 'Disease', (93, 103))	('GBM tumors', 'Disease', 'MESH:D005910', (93, 103))	('MT1-MMP+ U251', 'Var', (79, 92))	('MCF-7', 'CellLine', 'CVCL:0031', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('breast tumors', 'Phenotype', 'HP:0100013', (131, 144))	('89Zr-DFO-LEM2/15', 'MPA', (52, 68))	('uptake', 'MPA', (69, 75))	('DFO', 'Chemical', 'MESH:D003676', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
64937	27462980	Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors.	('disrupted', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('BBB', 'Gene', (90, 93))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
64959	27462980	In addition, a growing body of evidence reveals that overexpression of MT1-MMP plays also a significant role in promoting gliomagenesis.	('overexpression', 'PosReg', (53, 67))	('glioma', 'Disease', (122, 128))	('MT1-MMP', 'Var', (71, 78))	('promoting', 'PosReg', (112, 121))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
64970	27462980	U251, T98G, U87-MG, SF-268, SF-295, MCF-7 and SK-mel103 cell lines were grown at 37 C in Dulbecco's Modified Eagle's Medium (Sigma) containing 10% FBS (Sigma).	('U87-MG', 'Var', (12, 18))	('SF-295', 'CellLine', 'CVCL:1690', (28, 34))	('SF-268', 'CellLine', 'CVCL:1689', (20, 26))	('T98G', 'Var', (6, 10))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (89, 123))	('MCF-7', 'CellLine', 'CVCL:0031', (36, 41))
65037	27462980	A higher level of expression of MT1-MMP in GBM (HGG) was found as compared to low-grade gliomas (LGG) (Fig 1A) and it could be detected mainly in tumors but also in some endothelial cells.	('higher', 'PosReg', (2, 8))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('gliomas', 'Disease', (88, 95))	('MT1-MMP', 'Var', (32, 39))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('expression', 'MPA', (18, 28))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('tumors', 'Disease', (146, 152))
65047	27462980	89Zr-DFO-LEM 2/15 small-animal PET was conducted on mice harboring xenograft tumors at opposite flanks with MT1-MMP+ GBM U251 cells and MT1-MMP- breast MCF7 cells.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('89Zr', 'Chemical', 'MESH:C000615502', (0, 4))	('MCF7', 'CellLine', 'CVCL:0031', (152, 156))	('xenograft tumors', 'Disease', 'MESH:D009369', (67, 83))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('DFO', 'Chemical', 'MESH:D003676', (5, 8))	('MT1-MMP+ GBM', 'Var', (108, 120))	('xenograft tumors', 'Disease', (67, 83))
65051	27462980	The uptake in MT1-MMP+ tumors was significantly higher than in MT1-MMP- tumors at all times.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('higher', 'PosReg', (48, 54))	('uptake', 'MPA', (4, 10))	('MT1-MMP+', 'Var', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
65057	27462980	We determined that tumor cells (Ki67+) immunostained strongly positive for MT1-MMP while most endothelial cells (CD31+) did not stain at all.	('Ki67', 'Gene', (32, 36))	('CD31', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('positive', 'Reg', (62, 70))	('CD31', 'Gene', '5175', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MT1-MMP', 'Var', (75, 82))	('Ki67', 'Gene', '17345', (32, 36))	('tumor', 'Disease', (19, 24))
65062	27462980	The brain PET image (Fig 4A and S2 Video) shows that 89Zr-DFO-LEM2/15 was specifically accumulated in tumor, enabling its accurate localization and delineation.	('DFO', 'Chemical', 'MESH:D003676', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('enabling', 'PosReg', (109, 117))	('89Zr', 'Chemical', 'MESH:C000615502', (53, 57))	('89Zr-DFO-LEM2/15', 'Var', (53, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
65065	27462980	Interestingly, the 89Zr-DFO-LEM2/15 antibody only caused a very weak signal in an orthotopic U251 tumor model and did not show a significant difference between tumor/blood ratios of the specific labeled antibody and control 89Zr-DFO-IgG1 (0.23+-0.04 and 0.30+-0.03 versus 0.17+- 0.05 and 0.21+- 0.10, at 2 and 4 days p.i., respectively) (S3A Fig), despite the considerably higher expression of MT1-MMP on U251 cells as compared with TS543 neurospheres (Fig 1C).	('expression', 'MPA', (380, 390))	('IgG1', 'Gene', (233, 237))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('89Zr', 'Chemical', 'MESH:C000615502', (19, 23))	('DFO', 'Chemical', 'MESH:D003676', (24, 27))	('higher', 'PosReg', (373, 379))	('IgG1', 'Gene', '105243590', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DFO', 'Chemical', 'MESH:D003676', (229, 232))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (160, 165))	('MT1-MMP', 'Var', (394, 401))	('89Zr', 'Chemical', 'MESH:C000615502', (224, 228))
65076	27462980	Furthermore, we evaluated the in vitro and in vivo properties of this labeled antibody to develop a new PET probe for glioma detection, showing that 89Zr-DFO-LEM2/15-mediated PET yields high resolution detailed images with high tumor-to-background contrast in flank and orthotopic xenograft models of GBM.	('glioma', 'Disease', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('89Zr', 'Chemical', 'MESH:C000615502', (149, 153))	('89Zr-DFO-LEM2/15-mediated', 'Var', (149, 174))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('tumor', 'Disease', (228, 233))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('DFO', 'Chemical', 'MESH:D003676', (154, 157))
65079	27462980	Further validation was carried out at protein level, detecting MT1-MMP in a panel of glioma cells by immunoblotting and FACS; and in a TMA immunohistochemistry staining with glioma samples of various grades, in which we documented a marked increase in expression of MT1-MMP in GBM compared to low-grade gliomas.	('gliomas', 'Disease', 'MESH:D005910', (303, 310))	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('gliomas', 'Disease', (303, 310))	('gliomas', 'Phenotype', 'HP:0009733', (303, 310))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('glioma', 'Disease', (303, 309))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('MT1-MMP', 'Var', (266, 273))	('glioma', 'Disease', (174, 180))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (303, 309))	('glioma', 'Disease', 'MESH:D005910', (303, 309))	('expression', 'MPA', (252, 262))	('GBM', 'Disease', (277, 280))	('increase', 'PosReg', (240, 248))
65090	27462980	Tumor/blood ratios of 89Zr-DFO LEM2/15 in GBM MT1-MMP+ tumors were significantly higher than those in breast MT1-MMP- tumors, indicating the specificity of 89Zr-DFO-LEM2/15 toward MT1-MMP.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DFO', 'Chemical', 'MESH:D003676', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('89Zr-DFO LEM2/15', 'Var', (22, 38))	('DFO', 'Chemical', 'MESH:D003676', (161, 164))	('breast MT1-MMP- tumors', 'Disease', (102, 124))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('89Zr', 'Chemical', 'MESH:C000615502', (156, 160))	('tumors', 'Disease', (55, 61))	('89Zr', 'Chemical', 'MESH:C000615502', (22, 26))	('tumors', 'Disease', (118, 124))	('MT1-MMP+', 'Var', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('Tumor/blood ratios', 'MPA', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('breast MT1-MMP- tumors', 'Disease', 'MESH:D001943', (102, 124))	('higher', 'PosReg', (81, 87))
65096	27462980	Accordingly, 89Zr-DFO LEM2/15 was able to detect orthotopically growing GBM implants from TS543 but not from U251, which correlates with the integrity of the BBB, as analyzed by Evans blue staining.	('TS543', 'Var', (90, 95))	('orthotopically growing GBM implants', 'CPA', (49, 84))	('DFO', 'Chemical', 'MESH:D003676', (18, 21))	('Evans blue', 'Chemical', 'MESH:D005070', (178, 188))	('89Zr', 'Chemical', 'MESH:C000615502', (13, 17))
65098	27462980	The minituarized antibodies can enhance BBB penetration and therefore result in an improved tumor-targeted imaging.	('improved', 'PosReg', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('minituarized', 'Var', (4, 16))	('tumor', 'Disease', (92, 97))	('enhance', 'PosReg', (32, 39))	('BBB penetration', 'CPA', (40, 55))
65101	32532965	Regulating tumor suppressor genes: post-translational modifications Tumor suppressor genes cooperate with each other in tumors.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('Tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor suppressor', 'Gene', '7248', (11, 27))	('Tumor suppressor', 'Gene', '7248', (68, 84))	('post-translational modifications', 'Var', (35, 67))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Tumor suppressor', 'Gene', (68, 84))	('tumor suppressor', 'Gene', (11, 27))
65105	32532965	Although a lot of studies focus on the importance of each kind of PTM, further discoveries shows that tumor suppressor genes (TSGs) form a complex "network" by the interaction of modification.	('interaction', 'Interaction', (164, 175))	('modification', 'Var', (179, 191))	('tumor suppressor', 'Gene', (102, 118))	('tumor suppressor', 'Gene', '7248', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
65109	32532965	It has generally acknowledged that cancer is caused by somatic mutations, which is a concept significantly confirmed by demonstrating that cellular proto-oncogenes contribute to carcinogenesis when mutations deregulated or abnormally overexpressed.	('mutations deregulated', 'Var', (198, 219))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('contribute', 'Reg', (164, 174))	('carcinogenesis', 'Disease', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('overexpressed', 'PosReg', (234, 247))
65110	32532965	Our understanding is that many of these genes encode proteins that control cell proliferation, differentiation, and development, while mutations that affect their function constitutively deregulate specific signal pathways, providing some of the clearest insights into how and why abnormal behave of cancer cells happen.	('specific signal pathways', 'Pathway', (198, 222))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('mutations', 'Var', (135, 144))	('development', 'CPA', (116, 127))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('deregulate', 'Reg', (187, 197))	('cancer', 'Disease', (300, 306))	('cell proliferation', 'CPA', (75, 93))
65113	32532965	Carcinogenesis is a very complicated process, which can be attributed to either mutation of oncogene function or tumor suppressor gene (TSGs).	('Carcinogenesis', 'Disease', (0, 14))	('oncogene function', 'Gene', (92, 109))	('tumor suppressor', 'Gene', (113, 129))	('tumor suppressor', 'Gene', '7248', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutation', 'Var', (80, 88))
65114	32532965	Our understanding of TSGs mostly comes from the preliminary study of retinoblastoma genes, the first discovery of a TSG, and mutation causes retinoblastoma in children.	('children', 'Species', '9606', (159, 167))	('retinoblastoma', 'Disease', 'MESH:D012175', (141, 155))	('retinoblastoma', 'Disease', (141, 155))	('retinoblastoma', 'Disease', (69, 83))	('causes', 'Reg', (134, 140))	('retinoblastoma', 'Disease', 'MESH:D012175', (69, 83))	('retinoblastoma', 'Phenotype', 'HP:0009919', (141, 155))	('retinoblastoma', 'Phenotype', 'HP:0009919', (69, 83))	('mutation', 'Var', (125, 133))
65115	32532965	This is a genetic disease caused by the retinoblastoma susceptibility gene (Rb1) gene inactivation mutation.	('retinoblastoma', 'Phenotype', 'HP:0009919', (40, 54))	('Rb1', 'Gene', (76, 79))	('genetic disease', 'Disease', (10, 25))	('caused by', 'Reg', (26, 35))	('retinoblastoma', 'Disease', 'MESH:D012175', (40, 54))	('retinoblastoma', 'Disease', (40, 54))	('genetic disease', 'Disease', 'MESH:D030342', (10, 25))	('Rb1', 'Gene', '5925', (76, 79))	('Rb', 'Phenotype', 'HP:0009919', (76, 78))	('gene inactivation mutation', 'Var', (81, 107))
65121	32532965	It is now supported that for many TSGs, loss of heterozygote function is associated with tumorigenesis by reduced gene dosage and haploinsufficiency.	('TSGs', 'Disease', (34, 38))	('haploinsufficiency', 'Disease', 'MESH:D058495', (130, 148))	('gene', 'MPA', (114, 118))	('tumor', 'Disease', (89, 94))	('haploinsufficiency', 'Disease', (130, 148))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('reduced', 'NegReg', (106, 113))	('loss of heterozygote', 'Var', (40, 60))
65126	32532965	Previous studies indicate that only a copy of a TSG is enough to manipulate cell proliferation; in this way, two alleles of a TSG must be consistently inactivated or deleted to bring about tumorigenesis.	('tumor', 'Disease', (189, 194))	('bring about', 'Reg', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('deleted', 'Var', (166, 173))	('TSG', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
65128	32532965	Second, the pass on of a single mutated allele benefits the susceptibility of the tumor, since only the other additional mutation is needed for gene function completely lost.	('pass', 'Var', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('benefits', 'PosReg', (47, 55))	('susceptibility', 'MPA', (60, 74))	('tumor', 'Disease', (82, 87))	('S', 'Chemical', 'MESH:D012694', (0, 1))
65129	32532965	Thus, germline mutations may be the root cause of familial cancer syndromes that will inherit.	('familial cancer', 'Disease', 'MESH:D009369', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('germline mutations', 'Var', (6, 24))	('cause', 'Reg', (41, 46))	('familial cancer', 'Disease', (50, 65))
65133	32532965	Hypermethylation of CpG islands which are in TSG promoters, such as Braca1, Rb, or p53 promoters, leads to inactivation of each protein, causing cancer.	('cancer', 'Disease', (145, 151))	('inactivation', 'MPA', (107, 119))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('protein', 'Protein', (128, 135))	('Rb', 'Phenotype', 'HP:0009919', (76, 78))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Rb', 'Gene', '5925', (76, 78))	('causing', 'Reg', (137, 144))
65137	32532965	TSGs are often affected by mutation or epigenetic disorder in cancer, therefore occurrence and development of all types of cancer along with an important signal molecule in cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('affected', 'Reg', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('epigenetic disorder', 'Disease', (39, 58))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('epigenetic disorder', 'Disease', 'MESH:D030342', (39, 58))	('TSGs', 'Disease', (0, 4))
65141	32532965	Improper cell loss can result in degenerative and autoimmune diseases, and the mutant cells were not eliminated from the constraints of normal cell growth control causes cancer.	('autoimmune diseases', 'Disease', (50, 69))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (50, 69))	('cancer', 'Disease', (170, 176))	('degenerative', 'CPA', (33, 45))	('loss', 'NegReg', (14, 18))	('result in', 'Reg', (23, 32))	('mutant', 'Var', (79, 85))	('autoimmune disease', 'Phenotype', 'HP:0002960', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('autoimmune diseases', 'Disease', 'MESH:D001327', (50, 69))	('Improper', 'Var', (0, 8))
65144	32532965	In cancer cells, the oncogene activation and/or inactivation of TSGs supply with ongoing proliferation signals by regulating the diversity of PTMs states of effector proteins involved in cell survival, cell cycle, and proliferation regulation, resulting in abnormal proliferation of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('abnormal proliferation of cancer cells', 'Phenotype', 'HP:0031377', (257, 295))	('cancer', 'Disease', (283, 289))	('resulting in', 'Reg', (244, 256))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('inactivation', 'Var', (48, 60))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('TSGs', 'Gene', (64, 68))	('diversity', 'MPA', (129, 138))
65145	32532965	Specific protein modification manages almost all cellular physiological processes, such as immune function, as well as the precise location, duration, and intensity of physiological processes to ensure rapid and dynamic cellular responses to extracellular and intracellular stimuli.	('modification', 'Var', (17, 29))	('manages', 'Reg', (30, 37))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('protein', 'Protein', (9, 16))
65166	32532965	Mutations in BRCA1 bring about not only familial breast and ovarian cancers but are also the promoters of different kinds of sporadic cancers.	('sporadic cancers', 'Disease', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('ovarian cancers', 'Phenotype', 'HP:0100615', (60, 75))	('BRCA1', 'Gene', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('Mutations', 'Var', (0, 9))	('bring about', 'Reg', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('sporadic cancers', 'Disease', 'MESH:D009369', (125, 141))	('familial breast and ovarian cancers', 'Disease', 'MESH:D000071298', (40, 75))	('BRCA1', 'Gene', '672', (13, 18))
65169	32532965	The double allele mutation in PALB2 results in Fanconi anemia (FA) subtype FA-N, while monoallelic mutation is prone to breast and pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (47, 61))	('breast and pancreatic cancer', 'Disease', 'MESH:D001943', (120, 148))	('anemia', 'Phenotype', 'HP:0001903', (55, 61))	('FA', 'Phenotype', 'HP:0001994', (63, 65))	('Fanconi anemia', 'Disease', (47, 61))	('PALB2', 'Gene', '79728', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('results in', 'Reg', (36, 46))	('PALB2', 'Gene', (30, 35))	('Fanconi anemia', 'Disease', 'MESH:D005199', (47, 61))	('FA', 'Phenotype', 'HP:0001994', (75, 77))	('double allele mutation', 'Var', (4, 26))
65171	32532965	Tuberous sclerosis complex (TSC) is an autosomal dominant disease, which is caused by the loss of function mutation of TSC1 or TSC2.	('TSC2', 'Gene', (127, 131))	('TSC', 'Gene', '7248;7249', (127, 130))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('Tuberous sclerosis', 'Disease', (0, 18))	('TSC1', 'Gene', '7248', (119, 123))	('TSC', 'Gene', (127, 130))	('TSC', 'Gene', (119, 122))	('TSC', 'Gene', '7248;7249', (28, 31))	('autosomal dominant disease', 'Disease', (39, 65))	('TSC1', 'Gene', (119, 123))	('TSC', 'Gene', (28, 31))	('TSC2', 'Gene', '7249', (127, 131))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (39, 65))	('mutation', 'Var', (107, 115))	('TSC', 'Gene', '7248;7249', (119, 122))
65173	32532965	Mutations in both genes can lead to multiple benign tumors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('benign tumors', 'Disease', (45, 58))	('Mutations', 'Var', (0, 9))	('lead to', 'Reg', (28, 35))	('benign tumors', 'Disease', 'MESH:D009369', (45, 58))
65174	32532965	The products of TSC1 and TSC2 gene form a functional complex with GTP enzyme activating protein (GAP) activity, which has the effect of inhibiting the target of mammalian rapamycin complex 1 (mTORC1), while mTORC1 is constitutively activated in TSC mutant tumor.	('TSC1', 'Gene', '7248', (16, 20))	('TSC', 'Gene', '7248;7249', (245, 248))	('mutant', 'Var', (249, 255))	('mTORC1', 'Gene', (192, 198))	('tumor', 'Disease', (256, 261))	('TSC2', 'Gene', '7249', (25, 29))	('inhibiting', 'NegReg', (136, 146))	('mTORC1', 'Gene', '382056', (192, 198))	('mTORC1', 'Gene', (207, 213))	('TSC', 'Gene', (25, 28))	('target', 'MPA', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('mammalian', 'Species', '9606', (161, 170))	('mTORC1', 'Gene', '382056', (207, 213))	('TSC', 'Gene', (16, 19))	('TSC2', 'Gene', (25, 29))	('TSC', 'Gene', '7248;7249', (25, 28))	('TSC1', 'Gene', (16, 20))	('rapamycin', 'Chemical', 'MESH:D020123', (171, 180))	('TSC', 'Gene', '7248;7249', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('TSC', 'Gene', (245, 248))
65190	32532965	The genomic changes of p53, PTEN, and Rb in early and late prostate cancer (as well as the combined loss of these genes) indicate a poor prognosis.	('PTEN', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('genomic changes', 'Var', (4, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('late prostate cancer', 'Disease', (54, 74))	('Rb', 'Phenotype', 'HP:0009919', (38, 40))	('Rb', 'Gene', '5925', (38, 40))	('p53', 'Gene', (23, 26))	('late prostate cancer', 'Disease', 'MESH:D011471', (54, 74))
65194	32532965	Genetic aberrations influencing the intermediates of these three pathways have been found in almost all glioblastomas.	('found', 'Reg', (84, 89))	('Genetic aberrations', 'Var', (0, 19))	('glioblastomas', 'Phenotype', 'HP:0012174', (104, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('glioblastomas', 'Disease', 'MESH:D005909', (104, 117))	('glioblastomas', 'Disease', (104, 117))
65196	32532965	The mouse model verified the tumor promoting effect of Rb, p53, and PTEN deletion on fibroblasts, which can transform normal fibroblasts into cancer-related fibroblasts (CAFs).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('p53', 'Gene', (59, 62))	('mouse', 'Species', '10090', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('PTEN', 'Gene', (68, 72))	('tumor', 'Disease', (29, 34))	('transform', 'Reg', (108, 117))	('deletion', 'Var', (73, 81))	('Rb', 'Phenotype', 'HP:0009919', (55, 57))	('Rb', 'Gene', '5925', (55, 57))	('cancer', 'Disease', (142, 148))
65204	32532965	Except a few cases, phosphorylation of Rb brings about inactivation, transcriptional inhibition, and cell cycle progression.	('Rb', 'Gene', '5925', (39, 41))	('inactivation', 'MPA', (55, 67))	('cell cycle progression', 'CPA', (101, 123))	('transcriptional', 'CPA', (69, 84))	('phosphorylation', 'Var', (20, 35))	('Rb', 'Phenotype', 'HP:0009919', (39, 41))
65205	32532965	Phosphorylation of Rb regulates the interaction between Rb and other proteins, and this modification usually promotes conformational transition from disordered structure to ordered structure, thus concealing the protein binding surface.	('conformational transition', 'MPA', (118, 143))	('protein', 'Protein', (212, 219))	('Rb', 'Phenotype', 'HP:0009919', (19, 21))	('regulates', 'Reg', (22, 31))	('promotes', 'Reg', (109, 117))	('Phosphorylation', 'Var', (0, 15))	('Rb', 'Gene', '5925', (19, 21))	('binding', 'Interaction', (220, 227))	('Rb', 'Phenotype', 'HP:0009919', (56, 58))	('disordered structure', 'MPA', (149, 169))	('interaction', 'Interaction', (36, 47))	('Rb', 'Gene', '5925', (56, 58))
65209	32532965	Rb deletion allows cancer cells to bypass two different barriers in the progression of tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('Rb', 'Phenotype', 'HP:0009919', (0, 2))	('tumors', 'Disease', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Rb', 'Gene', '5925', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('deletion', 'Var', (3, 11))
65212	32532965	Secondly, Rb inactivation relieves the expression of cell state determinants, promotes lineage infidelity, and increases the acquisition of metastasis ability.	('promotes', 'PosReg', (78, 86))	('inactivation', 'Var', (13, 25))	('lineage infidelity', 'CPA', (87, 105))	('increases', 'PosReg', (111, 120))	('acquisition', 'CPA', (125, 136))	('Rb', 'Phenotype', 'HP:0009919', (10, 12))	('Rb', 'Gene', '5925', (10, 12))	('expression', 'MPA', (39, 49))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('relieves', 'NegReg', (26, 34))
65215	32532965	The mono-phosphorylation of Rb at serine 811 (S811) alters the transcriptional activity of Rb by promoting its binding with nucleosome remodeling and histone deacetylation (NuRD) complex.	('serine', 'Chemical', 'MESH:D012694', (34, 40))	('Rb', 'Phenotype', 'HP:0009919', (91, 93))	('Rb', 'Gene', '5925', (91, 93))	('transcriptional activity', 'MPA', (63, 87))	('promoting', 'PosReg', (97, 106))	('R', 'Chemical', 'MESH:D001120', (91, 92))	('R', 'Chemical', 'MESH:D001120', (175, 176))	('binding', 'Interaction', (111, 118))	('alters', 'Reg', (52, 58))	('R', 'Chemical', 'MESH:D001120', (28, 29))	('S', 'Chemical', 'MESH:D012694', (46, 47))	('Rb', 'Phenotype', 'HP:0009919', (28, 30))	('Rb', 'Gene', '5925', (28, 30))	('mono-phosphorylation', 'Var', (4, 24))
65216	32532965	Mono-phosphorylation of Rb at S811 or threonine (T826) activates the expression of oxidative phosphorylation genes, which increases cell oxygen consumption.	('oxidative phosphorylation genes', 'Gene', (83, 114))	('threonine', 'Chemical', 'MESH:D013912', (38, 47))	('activates', 'PosReg', (55, 64))	('oxygen', 'Chemical', 'MESH:D010100', (137, 143))	('cell oxygen', 'CPA', (132, 143))	('at S811', 'Var', (27, 34))	('expression', 'MPA', (69, 79))	('Rb', 'Phenotype', 'HP:0009919', (24, 26))	('Rb', 'Gene', '5925', (24, 26))	('S', 'Chemical', 'MESH:D012694', (30, 31))	('increases', 'PosReg', (122, 131))	('Mono-phosphorylation', 'Var', (0, 20))
65218	32532965	The interaction between Rb and nuclear factor-kappa B (NF-kappa B) protein p65 is mainly dependent on the phosphorylation of S249/T252 mediated by CDK4/6 of Rb, and S249/T252 phosphorylated Rb was negatively correlated with programmed death ligand-1 (PD-L1) expression in patient samples, which indicates that hyperphosphorylated Rb-NF-kappa B axis can be used to overcome cancer immune evasion induced by traditional or targeted therapies.	('p65', 'Gene', (75, 78))	('S249/T252', 'Mutation', 'p.S249,252T', (125, 134))	('dependent', 'Reg', (89, 98))	('NF-kappa B', 'Gene', (55, 65))	('Rb', 'Phenotype', 'HP:0009919', (157, 159))	('Rb', 'Phenotype', 'HP:0009919', (330, 332))	('CDK4', 'Gene', (147, 151))	('programmed death ligand-1', 'Gene', (224, 249))	('patient', 'Species', '9606', (272, 279))	('nuclear factor-kappa B', 'Gene', '4790', (31, 53))	('correlated', 'Reg', (208, 218))	('p65', 'Gene', '5970', (75, 78))	('programmed death ligand-1', 'Gene', '29126', (224, 249))	('cancer', 'Disease', (373, 379))	('CDK4', 'Gene', '1019', (147, 151))	('Rb', 'Gene', '5925', (190, 192))	('interaction', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('S249/T252', 'Var', (165, 174))	('NF-kappa B', 'Gene', '4790', (333, 343))	('PD-L1', 'Gene', (251, 256))	('Rb', 'Gene', '5925', (24, 26))	('Rb', 'Phenotype', 'HP:0009919', (190, 192))	('NF-kappa B', 'Gene', '4790', (55, 65))	('S249/T252', 'Var', (125, 134))	('PD-L1', 'Gene', '29126', (251, 256))	('nuclear factor-kappa B', 'Gene', (31, 53))	('Rb', 'Gene', '5925', (157, 159))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('Rb', 'Phenotype', 'HP:0009919', (24, 26))	('negatively', 'NegReg', (197, 207))	('Rb', 'Gene', '5925', (330, 332))	('S249/T252', 'Mutation', 'p.S249,252T', (165, 174))	('NF-kappa B', 'Gene', (333, 343))
65219	32532965	Phosphorylated proteomics data suggest that Rb phosphorylation is associated with reduced proliferation and inhibited apoptosis in colon cancer cells, explaining why this classical tumor suppressor is enrichment in colon cancer and provides a theoretical basis for the application of targeted Rb phosphorylation.	('Rb', 'Gene', '5925', (44, 46))	('reduced', 'NegReg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('inhibited', 'NegReg', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colon cancer', 'Disease', 'MESH:D015179', (131, 143))	('colon cancer', 'Phenotype', 'HP:0003003', (215, 227))	('Rb', 'Phenotype', 'HP:0009919', (44, 46))	('tumor suppressor', 'Gene', (181, 197))	('colon cancer', 'Disease', 'MESH:D015179', (215, 227))	('colon cancer', 'Disease', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Rb', 'Gene', '5925', (293, 295))	('tumor suppressor', 'Gene', '7248', (181, 197))	('proliferation', 'CPA', (90, 103))	('colon cancer', 'Disease', (215, 227))	('phosphorylation', 'Var', (47, 62))	('Rb', 'Phenotype', 'HP:0009919', (293, 295))	('colon cancer', 'Phenotype', 'HP:0003003', (131, 143))
65220	32532965	Those results reveal that Rb activation signals can be integrated in a phosphorylation code that will control the diversity of Rb activity, indicating that phosphorylation of Rb manages interaction with different proteome, chooses different targets, and controls different aspects of Rb function.	('Rb', 'Phenotype', 'HP:0009919', (284, 286))	('phosphorylation', 'Var', (156, 171))	('Rb', 'Gene', '5925', (284, 286))	('Rb', 'Phenotype', 'HP:0009919', (26, 28))	('Rb', 'Gene', '5925', (26, 28))	('controls', 'Reg', (254, 262))	('Rb', 'Phenotype', 'HP:0009919', (127, 129))	('Rb', 'Phenotype', 'HP:0009919', (175, 177))	('Rb', 'Gene', '5925', (127, 129))	('Rb', 'Gene', '5925', (175, 177))	('interaction', 'Interaction', (186, 197))	('proteome', 'Protein', (213, 221))
65227	32532965	However, CMV PP71 promotes Rb degradation through non-ubiquitin dependent pathway.	('ubiquitin', 'Gene', (54, 63))	('promotes', 'PosReg', (18, 26))	('CMV PP71', 'Var', (9, 17))	('Rb', 'Phenotype', 'HP:0009919', (27, 29))	('Rb', 'Gene', '5925', (27, 29))	('ubiquitin', 'Gene', '850620', (54, 63))
65231	32532965	On the contrary, the lack of SUMO in Rb led to the decrease of Rb phosphorylation, the CDK2 binding, and E2F-1 isolation.	('binding', 'Interaction', (92, 99))	('E2F-1', 'Gene', (105, 110))	('Rb', 'Gene', '5925', (37, 39))	('CDK2', 'Gene', (87, 91))	('S', 'Chemical', 'MESH:D012694', (29, 30))	('phosphorylation', 'MPA', (66, 81))	('lack', 'Var', (21, 25))	('E2F-1', 'Gene', '1869', (105, 110))	('Rb', 'Phenotype', 'HP:0009919', (63, 65))	('decrease', 'NegReg', (51, 59))	('CDK2', 'Gene', '1017', (87, 91))	('Rb', 'Gene', '5925', (63, 65))	('Rb', 'Phenotype', 'HP:0009919', (37, 39))
65239	32532965	Rb at Lys873 and Lys874 can be acetylated, resulting in increased their affinity for MDM2, and then reduced phosphorylation of Rb.	('affinity', 'Interaction', (72, 80))	('Lys873', 'Var', (6, 12))	('MDM2', 'Protein', (85, 89))	('Lys873', 'Chemical', '-', (6, 12))	('increased', 'PosReg', (56, 65))	('reduced', 'NegReg', (100, 107))	('Lys874', 'Var', (17, 23))	('Rb', 'Phenotype', 'HP:0009919', (127, 129))	('Rb', 'Phenotype', 'HP:0009919', (0, 2))	('Rb', 'Gene', '5925', (127, 129))	('Rb', 'Gene', '5925', (0, 2))	('phosphorylation', 'MPA', (108, 123))	('Lys874', 'Chemical', '-', (17, 23))
65242	32532965	Given the loss or inactivation of Rb function in most human malignancies, further research is necessary to explore whether PTMs affect the molecular interactions of Rb and mediate Rb's cell cycle function, as well as the immune function that mediates Rb overlap, or whether it is possible to target various aspects of Rb.	('cell cycle', 'CPA', (185, 195))	('malignancies', 'Disease', (60, 72))	('Rb', 'Phenotype', 'HP:0009919', (318, 320))	('affect', 'Reg', (128, 134))	('inactivation', 'Var', (18, 30))	('Rb', 'Phenotype', 'HP:0009919', (34, 36))	('Rb', 'Gene', '5925', (318, 320))	('Rb', 'Gene', '5925', (34, 36))	('interactions', 'Interaction', (149, 161))	('Rb', 'Phenotype', 'HP:0009919', (251, 253))	('Rb', 'Phenotype', 'HP:0009919', (165, 167))	('Rb', 'Gene', '5925', (251, 253))	('Rb', 'Gene', '5925', (165, 167))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('Rb', 'Phenotype', 'HP:0009919', (180, 182))	('loss', 'NegReg', (10, 14))	('human', 'Species', '9606', (54, 59))	('Rb', 'Gene', '5925', (180, 182))
65254	32532965	The canonical model of Rb as a TSG developed in the past 30 years is based on the modulation of E2F transcription factors to limit cell cycle progression.	('modulation', 'Var', (82, 92))	('cell cycle progression', 'CPA', (131, 153))	('Rb', 'Phenotype', 'HP:0009919', (23, 25))	('Rb', 'Gene', '5925', (23, 25))	('E2F', 'Protein', (96, 99))	('limit', 'NegReg', (125, 130))
65261	32532965	In summary, Rb can be protected by high levels of CDK activity (thus maintaining low phosphorylation levels of Rb), high phosphorylation of Rb preserves function, and Rb relies on histone modification characteristics through the cell cycle.	('Rb', 'Phenotype', 'HP:0009919', (12, 14))	('Rb', 'Gene', '5925', (12, 14))	('Rb', 'Phenotype', 'HP:0009919', (167, 169))	('Rb', 'Gene', '5925', (167, 169))	('high', 'Var', (116, 120))	('phosphorylation levels', 'MPA', (85, 107))	('Rb', 'Phenotype', 'HP:0009919', (140, 142))	('Rb', 'Gene', '5925', (140, 142))	('Rb', 'Phenotype', 'HP:0009919', (111, 113))	('function', 'MPA', (153, 161))	('Rb', 'Gene', '5925', (111, 113))
65264	32532965	A mutation in Rb invalidates the interaction between its labeled box domain and E2F1, which has been shown to break the binding of Rb and E2F1 with different types of repetitive sequences.	('Rb', 'Gene', '5925', (14, 16))	('mutation', 'Var', (2, 10))	('binding', 'Interaction', (120, 127))	('interaction', 'Interaction', (33, 44))	('Rb', 'Phenotype', 'HP:0009919', (131, 133))	('Rb', 'Phenotype', 'HP:0009919', (14, 16))	('Rb', 'Gene', '5925', (131, 133))	('invalidates', 'NegReg', (17, 28))
65266	32532965	These modifications decrease phosphorylation of Rb by CDK, which further implies that Rb-E2F1 complexes may have a protective effect on CDK activity when it participates in the function of non-homologous end joining (NHEJ) and homologous recombination (HR), for E2F1 is recruited to the sites of DNA double strand break, which is very important for NHEJ, HR (Fig.	('modifications', 'Var', (6, 19))	('R', 'Chemical', 'MESH:D001120', (356, 357))	('decrease', 'NegReg', (20, 28))	('R', 'Chemical', 'MESH:D001120', (86, 87))	('Rb', 'Phenotype', 'HP:0009919', (48, 50))	('Rb', 'Gene', '5925', (48, 50))	('R', 'Chemical', 'MESH:D001120', (254, 255))	('R', 'Chemical', 'MESH:D001120', (48, 49))	('Rb', 'Phenotype', 'HP:0009919', (86, 88))	('Rb', 'Gene', '5925', (86, 88))	('activity', 'MPA', (140, 148))	('phosphorylation', 'MPA', (29, 44))
65272	32532965	The loss of Rb in both regulatory pathways in cancer may produce a powerful synergistic cancer promotion combination.	('Rb', 'Phenotype', 'HP:0009919', (12, 14))	('Rb', 'Gene', '5925', (12, 14))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('promotion', 'PosReg', (95, 104))	('loss', 'Var', (4, 8))
65282	32532965	In addition, ATM depleted and p53 mutation are usually mutually exclusive, which shows that these proteins are the same in promoting the survival of cancer cells.	('promoting', 'PosReg', (123, 132))	('cancer', 'Disease', (149, 155))	('survival', 'CPA', (137, 145))	('mutation', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('p53', 'Gene', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
65283	32532965	The phosphorylation of Ser15 also triggers a series of other p53 phosphorylation events that contribute to p53 induction and activation, suggesting that Ser15 phosphorylation is a key point in p53 activation.	('Ser15', 'Chemical', '-', (153, 158))	('Ser15', 'Chemical', '-', (23, 28))	('phosphorylation', 'Var', (4, 19))	('triggers', 'Reg', (34, 42))
65284	32532965	It was reported that phosphorylation of Ser15 led to the dissociation of MDM2 from p53, which increases the stability of p53.	('Ser15', 'Chemical', '-', (40, 45))	('led to', 'Reg', (46, 52))	('stability', 'MPA', (108, 117))	('dissociation', 'MPA', (57, 69))	('increases', 'PosReg', (94, 103))	('MDM2', 'Gene', (73, 77))	('phosphorylation', 'Var', (21, 36))	('Ser15', 'Var', (40, 45))
65285	32532965	Ser15 can also be phosphorylated via the AMP-activated protein kinase (AMPK) pathway, which is mediated by glucose-dependent cell cycle arrest at G1/S.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (125, 142))	('Ser15', 'Var', (0, 5))	('Ser15', 'Chemical', '-', (0, 5))	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('AMPK', 'Gene', '5564', (71, 75))	('AMP-activated protein kinase', 'Gene', (41, 69))	('AMPK', 'Gene', (71, 75))	('S', 'Chemical', 'MESH:D012694', (149, 150))	('AMP-activated protein kinase', 'Gene', '5564', (41, 69))	('arrest', 'Disease', 'MESH:D006323', (136, 142))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('arrest', 'Disease', (136, 142))
65288	32532965	The function of Ser46 phosphorylation in p53 is closely related to the killer function of p53 bringing about apoptosis and can be phosphorylated by a number of candidate kinases, such as homeodomain-interacting protein kinase 2 (HIPK2), p38 and dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2).	('DYRK2', 'Gene', '8445', (307, 312))	('homeodomain-interacting protein kinase 2', 'Gene', (187, 227))	('Ser46', 'Chemical', '-', (16, 21))	('Ser46', 'Var', (16, 21))	('HIPK2', 'Gene', (229, 234))	('apoptosis', 'CPA', (109, 118))	('p38', 'Gene', '1432', (237, 240))	('dual specificity tyrosine-phosphorylation-regulated kinase 2', 'Gene', '8445', (245, 305))	('homeodomain-interacting protein kinase 2', 'Gene', '28996', (187, 227))	('HIPK2', 'Gene', '28996', (229, 234))	('DYRK2', 'Gene', (307, 312))	('p38', 'Gene', (237, 240))
65293	32532965	Smad plays as crucial platforms in mutant-p53/p63 protein complex, and when Ras signaling accelerates mutant-p53 phosphorylation, mutant p53 and Smad interrupt p63 to form a ternary complex, in doing so, the p63 transcriptional functions are antagonized.	('p63', 'Gene', '8626', (208, 211))	('R', 'Chemical', 'MESH:D001120', (76, 77))	('p63', 'Gene', '8626', (160, 163))	('phosphorylation', 'MPA', (113, 128))	('S', 'Chemical', 'MESH:D012694', (145, 146))	('accelerates', 'PosReg', (90, 101))	('p63', 'Gene', (46, 49))	('p63', 'Gene', (208, 211))	('mutant', 'Var', (130, 136))	('p53', 'Gene', (137, 140))	('p63', 'Gene', (160, 163))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('mutant-p53', 'Var', (102, 112))	('p63', 'Gene', '8626', (46, 49))
65297	32532965	Six p53 lysine (K) residues within the C-terminal regulatory domain (K370, K372, K373, K381, K382, and K386) can be targeted by MDM2.	('K382', 'Var', (93, 97))	('K373', 'Var', (81, 85))	('lysine', 'Chemical', 'MESH:D008239', (8, 14))	('K372', 'Var', (75, 79))	('K381', 'Var', (87, 91))	('K386', 'Var', (103, 107))	('K382', 'Chemical', '-', (93, 97))	('K370', 'Var', (69, 73))	('S', 'Chemical', 'MESH:D012694', (0, 1))
65298	32532965	For one thing, an interaction between p300 and either p53 or E2F1 has a significant impact on early cell cycle progression, suggesting that a critical role for p300 in cooperation with the pathways of growth arrest regulated by E2F and p53.	('impact', 'Reg', (84, 90))	('growth arrest', 'Phenotype', 'HP:0001510', (201, 214))	('growth arrest', 'Disease', 'MESH:D006323', (201, 214))	('interaction', 'Interaction', (18, 29))	('p300', 'Var', (38, 42))	('p53', 'Gene', (54, 57))	('early cell cycle progression', 'CPA', (94, 122))	('p300', 'Var', (160, 164))	('E2F1', 'Gene', (61, 65))	('growth arrest', 'Disease', (201, 214))
65299	32532965	For another, they facilitate the ubiquitination of p53 by MDM2, which decreases p53 levels in the presence of genotoxic stress.	('ubiquitin', 'Gene', '850620', (33, 42))	('decreases', 'NegReg', (70, 79))	('genotoxic stress', 'Disease', 'MESH:D000079225', (110, 126))	('ubiquitin', 'Gene', (33, 42))	('MDM2', 'Var', (58, 62))	('genotoxic stress', 'Disease', (110, 126))	('facilitate', 'PosReg', (18, 28))	('p53', 'Protein', (51, 54))	('p53 levels', 'MPA', (80, 90))
65301	32532965	K320, present in the tetramerization domain, can be acetylated by PCAF after DNA damage, and this acetylation is beneficial for cell survival as it boosts the expression of p53-controlled cell cycle arrest target genes, such as cyclin-dependent kinase inhibitor 1A (CDKN1A, commonly known as p21).	('p21', 'Gene', '1026', (292, 295))	('CDKN1A', 'Gene', (266, 272))	('arrest', 'Disease', (199, 205))	('p21', 'Gene', (292, 295))	('cyclin-dependent kinase inhibitor 1A', 'Gene', (228, 264))	('K320', 'Chemical', '-', (0, 4))	('CDKN1A', 'Gene', '1026', (266, 272))	('PCAF', 'Gene', '8850', (66, 70))	('expression', 'MPA', (159, 169))	('cyclin-dependent kinase inhibitor 1A', 'Gene', '1026', (228, 264))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (188, 205))	('PCAF', 'Gene', (66, 70))	('boosts', 'PosReg', (148, 154))	('K320', 'Var', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (199, 205))
65302	32532965	Unique to these residues, K120-acetylated p53 accumulates at mitochondria, which is thought to negatively regulate apoptosis by affecting the Bak/Mcl-1 interaction.	('p53', 'Gene', (42, 45))	('Bak', 'Gene', (142, 145))	('Bak', 'Gene', '578', (142, 145))	('accumulates', 'PosReg', (46, 57))	('Mcl-1', 'Gene', '4170', (146, 151))	('K120', 'Chemical', '-', (26, 30))	('Mcl-1', 'Gene', (146, 151))	('K120-acetylated', 'Var', (26, 41))	('affecting', 'Reg', (128, 137))
65303	32532965	In the p53 DNA-binding domain, K120 also can be acetylated by human males absent on the first (hMOF) and Tip60, which is quite essential for the activation of target genes connected to apoptosis but not to those involved in cell cycle arrest.	('K120', 'Var', (31, 35))	('K120', 'Chemical', '-', (31, 35))	('human', 'Species', '9606', (62, 67))	('Tip60', 'Gene', (105, 110))	('hMOF', 'Gene', '84148', (95, 99))	('Tip60', 'Gene', '10524', (105, 110))	('arrest', 'Disease', 'MESH:D006323', (235, 241))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (224, 241))	('hMOF', 'Gene', (95, 99))	('arrest', 'Disease', (235, 241))
65304	32532965	In addition, K120 and K164 are present in the p53 DNA-binding domain, which is the most common region for p53 mutations in malignant solid tumors, indicating that they might be connected with p53 function in cancer.	('connected', 'Reg', (177, 186))	('cancer', 'Disease', (208, 214))	('malignant solid tumors', 'Disease', (123, 145))	('mutations', 'Var', (110, 119))	('malignant solid tumors', 'Disease', 'MESH:D009369', (123, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('K120', 'Var', (13, 17))	('K120', 'Chemical', '-', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('p53', 'Gene', (106, 109))	('K164', 'Var', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
65305	32532965	A K120 mutation was found in Ewing's Sarcoma and esophageal SCC cells, while a mutation in K164 was discovered in glioblastoma and bladder carcinoma.	('esophageal SCC', 'Disease', (49, 63))	('glioblastoma and bladder carcinoma', 'Disease', 'MESH:D001749', (114, 148))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (131, 148))	('K120', 'Var', (2, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	("Ewing's Sarcoma", 'Disease', (29, 44))	("Ewing's Sarcoma", 'Phenotype', 'HP:0012254', (29, 44))	('K120', 'Chemical', '-', (2, 6))	('S', 'Chemical', 'MESH:D012694', (37, 38))	("Ewing's Sarcoma", 'Disease', 'MESH:C563168', (29, 44))	('S', 'Chemical', 'MESH:D012694', (60, 61))	('Sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
65308	32532965	Methylation of lysine and arginine residues in histones has long been known to impact chromatin structure and gene expression.	('arginine', 'Protein', (26, 34))	('arginine', 'Chemical', 'MESH:D001120', (26, 34))	('Methylation', 'Var', (0, 11))	('chromatin structure', 'MPA', (86, 105))	('lysine', 'Protein', (15, 21))	('lysine', 'Chemical', 'MESH:D008239', (15, 21))	('gene expression', 'MPA', (110, 125))	('impact', 'Reg', (79, 85))
65309	32532965	In recent years, the methylation of p53 has emerged as an important modification that affects its function in various processes, such as cell cycle arrest, DNA repair, senescence, apoptosis, and tumourigenesis.	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('p53', 'Gene', (36, 39))	('methylation', 'Var', (21, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (137, 154))	('arrest', 'Disease', (148, 154))	('senescence', 'CPA', (168, 178))	('affects', 'Reg', (86, 93))	('tumourigenesis', 'CPA', (195, 209))	('apoptosis', 'CPA', (180, 189))	('DNA repair', 'CPA', (156, 166))	('function', 'MPA', (98, 106))
65311	32532965	Protein arginine N-methyl transferase 5 (PRMT5) was first shown to methylate p53 at several arginine residues (R333, R335, and R337) in the tetramerization domain, which specifically controls the functions of p53 in cell cycle arrest and is suggested to inactivate p53 during lymphomagenesis.	('arginine', 'Chemical', 'MESH:D001120', (92, 100))	('R', 'Chemical', 'MESH:D001120', (127, 128))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (216, 233))	('R337', 'Var', (127, 131))	('R', 'Chemical', 'MESH:D001120', (117, 118))	('Protein arginine N-methyl transferase 5', 'Gene', '10419', (0, 39))	('lymphomagenesis', 'Disease', (276, 291))	('PRMT5', 'Gene', '10419', (41, 46))	('arrest', 'Disease', (227, 233))	('arginine', 'Chemical', 'MESH:D001120', (8, 16))	('lymphomagenesis', 'Disease', 'None', (276, 291))	('lymphoma', 'Phenotype', 'HP:0002665', (276, 284))	('Protein arginine N-methyl transferase 5', 'Gene', (0, 39))	('p53', 'Gene', (77, 80))	('controls', 'Reg', (183, 191))	('R', 'Chemical', 'MESH:D001120', (42, 43))	('PRMT5', 'Gene', (41, 46))	('arrest', 'Disease', 'MESH:D006323', (227, 233))	('R335', 'Var', (117, 121))	('R333', 'Var', (111, 115))	('R', 'Chemical', 'MESH:D001120', (111, 112))
65313	32532965	Monomethylation of p53 by SET and MYND domain-containing protein 2 (SMYD2) at K370, which was shown to repress p53-mediated transactivation, decreases the binding of p53 to the promoters of its target genes, such as p21.	('promoters', 'MPA', (177, 186))	('p21', 'Gene', (216, 219))	('SMYD2', 'Gene', '56950', (68, 73))	('K370', 'Var', (78, 82))	('p53', 'Gene', (166, 169))	('binding', 'Interaction', (155, 162))	('decreases', 'NegReg', (141, 150))	('SMYD2', 'Gene', (68, 73))	('Monomethylation', 'Var', (0, 15))	('SET and MYND domain-containing protein 2', 'Gene', '56950', (26, 66))	('p21', 'Gene', '1026', (216, 219))
65314	32532965	Monomethylation at K372 by SET7/9 boosts the activation of p53 downstream target genes, but monomethylation of K370 by SET8 inhibits p53 transcriptional activity.	('boosts', 'PosReg', (34, 40))	('inhibits', 'NegReg', (124, 132))	('p53 transcriptional activity', 'MPA', (133, 161))	('activation', 'MPA', (45, 55))	('p53 downstream target genes', 'Gene', (59, 86))	('SET7/9', 'Gene', '80854', (27, 33))	('Monomethylation', 'Var', (0, 15))	('SET8', 'Gene', (119, 123))	('SET8', 'Gene', '387893', (119, 123))	('SET7/9', 'Gene', (27, 33))
65315	32532965	In addition, a second methyl group can be conjugated to p53 to form K370me2, which then promotes p53 function via stimulating its binding to the Tudor-domain-containing reader, p53 binding protein 1(p53BP1).	('promotes', 'PosReg', (88, 96))	('p53', 'Gene', (97, 100))	('p53 binding protein 1', 'Gene', '7158', (177, 198))	('p53BP1', 'Gene', (199, 205))	('p53BP1', 'Gene', '7158', (199, 205))	('K370me2', 'Var', (68, 75))	('p53 binding protein 1', 'Gene', (177, 198))	('stimulating', 'PosReg', (114, 125))	('function', 'MPA', (101, 109))	('binding', 'Interaction', (130, 137))
65316	32532965	Like K370Me2, K382Me2 has also been shown to be related to the stabilization and activation of p53.	('K370Me2', 'Var', (5, 12))	('K382Me2', 'Var', (14, 21))	('K382', 'Chemical', '-', (14, 18))	('activation', 'PosReg', (81, 91))	('p53', 'Protein', (95, 98))	('stabilization', 'MPA', (63, 76))
65320	32532965	The N-terminal transactivation domain of p53 seems containing another NES, in which phosphorylation blocks the nuclear output of p53, bring about its nuclear accumulation.	('nuclear output', 'MPA', (111, 125))	('S', 'Chemical', 'MESH:D012694', (72, 73))	('phosphorylation', 'Var', (84, 99))	('nuclear accumulation', 'MPA', (150, 170))	('blocks', 'NegReg', (100, 106))	('p53', 'Gene', (129, 132))	('p53', 'Gene', (41, 44))
65321	32532965	SUMOylation occurs at K386 of p53 and SUMO-1, SUMO-2, or SUMO-3 that accelerates the output of the p53 from nucleus.	('S', 'Chemical', 'MESH:D012694', (38, 39))	('SUMO-1', 'Gene', (38, 44))	('K386', 'Var', (22, 26))	('SUMO-1', 'Gene', '7341', (38, 44))	('SUMO-2', 'Gene', '6613', (46, 52))	('p53', 'Gene', (30, 33))	('S', 'Chemical', 'MESH:D012694', (46, 47))	('SUMO-2', 'Gene', (46, 52))	('output of the p53 from nucleus', 'MPA', (85, 115))	('SUMO-3', 'Gene', '6612', (57, 63))	('S', 'Chemical', 'MESH:D012694', (57, 58))	('accelerates', 'PosReg', (69, 80))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('SUMO-3', 'Gene', (57, 63))
65322	32532965	p53 in the nucleus not only promotes the expression of pro-apoptotic genes but also prevents cell death by increasing p21 expression.	('death', 'Disease', 'MESH:D003643', (98, 103))	('expression', 'MPA', (122, 132))	('death', 'Disease', (98, 103))	('prevents', 'NegReg', (84, 92))	('expression', 'MPA', (41, 51))	('p21', 'Gene', '1026', (118, 121))	('p21', 'Gene', (118, 121))	('promotes', 'PosReg', (28, 36))	('p53', 'Var', (0, 3))	('increasing', 'PosReg', (107, 117))
65323	32532965	p53 is normally SUMOylated at a single site, K386, by the protein inhibitor of activated stat (PIAS) family members and Topors.	('Topors', 'Gene', (120, 126))	('Topors', 'Gene', '10210', (120, 126))	('K386', 'Var', (45, 49))	('S', 'Chemical', 'MESH:D012694', (16, 17))	('S', 'Chemical', 'MESH:D012694', (98, 99))
65325	32532965	The combination of PAISy to p53 and then PAISy activated Tip60 resulted K386 sumoylation and K120 acetylation of p53, respectively.	('K120', 'Var', (93, 97))	('K120', 'Chemical', '-', (93, 97))	('Tip60', 'Gene', (57, 62))	('S', 'Chemical', 'MESH:D012694', (22, 23))	('p53', 'Gene', (113, 116))	('Tip60', 'Gene', '10524', (57, 62))	('K386', 'Var', (72, 76))	('S', 'Chemical', 'MESH:D012694', (44, 45))
65327	32532965	Moreover, the SUMOylation of p53 releases it from the chromosomal region maintenance 1 (CRM1) Huntington-EF3-PP2A subunit-HEAT9 loop to disassemble the transporting complex and promote the translocation of p53 to the cytoplasm.	('Huntington', 'Disease', (94, 104))	('SUMOylation', 'Var', (14, 25))	('promote', 'PosReg', (177, 184))	('S', 'Chemical', 'MESH:D012694', (14, 15))	('chromosomal region maintenance 1', 'Gene', (54, 86))	('PP2A', 'Gene', (109, 113))	('CRM1', 'Gene', '7514', (88, 92))	('CRM1', 'Gene', (88, 92))	('translocation', 'MPA', (189, 202))	('p53', 'Gene', (29, 32))	('Huntington', 'Disease', 'MESH:D006816', (94, 104))	('PP2A', 'Gene', '5524', (109, 113))	('chromosomal region maintenance 1', 'Gene', '7514', (54, 86))	('p53', 'Protein', (206, 209))
65329	32532965	In addition, p53-Bcl-2 binding depends on p53 SUMOylation, and a lot of cytoplasmic p53 localization is clinically associated with poor prognosis and disease progression to hormone-resistance status.	('Bcl-2', 'Gene', (17, 22))	('Bcl-2', 'Gene', '596', (17, 22))	('associated', 'Reg', (115, 125))	('S', 'Chemical', 'MESH:D012694', (46, 47))	('p53', 'Var', (42, 45))	('binding', 'Interaction', (23, 30))
65332	32532965	Consequently, ubiquitination includes three main steps: activation, conjugation, and ligation by E1s, E2s, and E3s, respectively.	('ubiquitin', 'Gene', (14, 23))	('E1s', 'Var', (97, 100))	('E3s', 'Var', (111, 114))	('conjugation', 'MPA', (68, 79))	('activation', 'MPA', (56, 66))	('ubiquitin', 'Gene', '850620', (14, 23))	('E2s', 'Var', (102, 105))	('ligation', 'MPA', (85, 93))
65341	32532965	Polyubiquitination, in which four or more ubiquitin monomers are bound to a substrate, occurs mostly on K48 and K29 and is regarded as a "molecular kiss of death" as it is associated with proteasome-dependent degradation.	('death', 'Disease', 'MESH:D003643', (156, 161))	('ubiquitin', 'Gene', (42, 51))	('death', 'Disease', (156, 161))	('K29', 'Var', (112, 115))	('bound', 'Interaction', (65, 70))	('ubiquitin', 'Gene', '850620', (4, 13))	('K48', 'Var', (104, 107))	('ubiquitin', 'Gene', '850620', (42, 51))	('ubiquitin', 'Gene', (4, 13))
65342	32532965	K63-linked ubiquitination is associated with aggregate formation, lysosomal degradation, and protein interactions.	('ubiquitin', 'Gene', (11, 20))	('K63-linked', 'Var', (0, 10))	('protein', 'Protein', (93, 100))	('lysosomal degradation', 'MPA', (66, 87))	('interactions', 'Interaction', (101, 113))	('ubiquitin', 'Gene', '850620', (11, 20))	('associated', 'Reg', (29, 39))	('aggregate formation', 'MPA', (45, 64))
65348	32532965	Physiologically, MDM2 antagonizes tumor suppressor p53.	('MDM2', 'Var', (17, 21))	('tumor suppressor', 'Gene', '7248', (34, 50))	('antagonizes', 'NegReg', (22, 33))	('tumor suppressor', 'Gene', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
65353	32532965	CBP/p300 and MDM2 target six lysine residues (K370, K372, K373, K381, K382, and K386) in the C-terminal regulatory domain respectively for acetylation and ubiquitination, which are essential for the nuclear export of p53.	('K370', 'Var', (46, 50))	('ubiquitin', 'Gene', (155, 164))	('K381', 'Var', (64, 68))	('acetylation', 'MPA', (139, 150))	('lysine', 'Chemical', 'MESH:D008239', (29, 35))	('K373', 'Var', (58, 62))	('ubiquitin', 'Gene', '850620', (155, 164))	('K386', 'Var', (80, 84))	('K382', 'Chemical', '-', (70, 74))	('K372', 'Var', (52, 56))	('K382', 'Var', (70, 74))
65358	32532965	Moreover, when p53 is ubiquitinated by MDM2, it cannot be acetylated by p300/CBP, and, therefore, rapid proteasome-mediated degradation takes place.	('ubiquitin', 'Gene', '850620', (22, 31))	('proteasome-mediated degradation', 'MPA', (104, 135))	('ubiquitin', 'Gene', (22, 31))	('CBP', 'Gene', (77, 80))	('CBP', 'Gene', '1387', (77, 80))	('MDM2', 'Var', (39, 43))
65359	32532965	When modifications occur on MDM2, the direct interaction between p53 and MDM2 is broken, such as during a DNA damage event in which MDM2 is phosphorylated at serine 395.	('interaction', 'Interaction', (45, 56))	('modifications', 'Var', (5, 18))	('serine', 'Chemical', 'MESH:D012694', (158, 164))
65361	32532965	In summary, MDM2 suppresses p53 in two ways: (i) MDM2 works as an E3 ligase to ubiquitinate p53, thus stimulating its degradation by the proteasomal pathway, and (ii) MDM2 inhibits p53 transcriptional activation by binding to it (Fig.	('p53', 'Gene', (28, 31))	('MDM2', 'Var', (167, 171))	('p53', 'Gene', (181, 184))	('ubiquitin', 'Gene', (79, 88))	('degradation', 'MPA', (118, 129))	('stimulating', 'PosReg', (102, 113))	('inhibits', 'NegReg', (172, 180))	('MDM2', 'Var', (49, 53))	('suppresses', 'NegReg', (17, 27))	('ubiquitin', 'Gene', '850620', (79, 88))	('binding', 'Interaction', (215, 222))	('transcriptional activation', 'MPA', (185, 211))	('MDM2', 'Var', (12, 16))
65369	32532965	For example, phosphorylation of Pirh2 can bring about its own inactivation.	('inactivation', 'MPA', (62, 74))	('bring about', 'Reg', (42, 53))	('phosphorylation', 'Var', (13, 28))	('Pirh2', 'Gene', (32, 37))	('Pirh2', 'Gene', '25898', (32, 37))
65372	32532965	Thus, it is possible that MDM2 specifically polyubiquitinates and degrades p53, whereas Pirh2 can control the protein stability of other p53 family members.	('ubiquitin', 'Gene', (48, 57))	('Pirh2', 'Gene', '25898', (88, 93))	('p53', 'Protein', (75, 78))	('protein stability', 'MPA', (110, 127))	('ubiquitin', 'Gene', '850620', (48, 57))	('Pirh2', 'Gene', (88, 93))	('p53 family', 'Gene', '7158;7157;8626;7161', (137, 147))	('degrades', 'NegReg', (66, 74))	('MDM2', 'Var', (26, 30))	('p53 family', 'Gene', (137, 147))
65382	32532965	ARF-BP1 contains a ubiquitin-associated domain (UBA, 1318-54), a WWE domain (1612-92), and a HECT domain in the C-terminal sequences (4036-4734).	('ubiquitin', 'Gene', '850620', (19, 28))	('ARF-BP1', 'Gene', '10075', (0, 7))	('UBA', 'Chemical', '-', (48, 51))	('ubiquitin', 'Gene', (19, 28))	('ARF-BP1', 'Gene', (0, 7))	('4036-4734', 'Var', (134, 143))
65391	32532965	Furthermore, Trim24 is phosphorylated at S768 in response to DNA damage by ATM, which destabilizes Trim24 and interrupts the Trim24-p53 interaction.	('Trim24', 'Gene', (99, 105))	('S', 'Chemical', 'MESH:D012694', (41, 42))	('Trim24', 'Gene', '8805', (125, 131))	('S768', 'Var', (41, 45))	('destabilizes', 'NegReg', (86, 98))	('Trim24', 'Gene', (13, 19))	('Trim24', 'Gene', (125, 131))	('Trim24', 'Gene', '8805', (99, 105))	('Trim24', 'Gene', '8805', (13, 19))	('interrupts', 'NegReg', (110, 120))	('interaction', 'Interaction', (136, 147))
65392	32532965	However, DNA-damage-activated p53 induces Trim24 transcription via an interaction with p53 response elements.	('induces', 'PosReg', (34, 41))	('interaction', 'Interaction', (70, 81))	('Trim24', 'Gene', (42, 48))	('p53', 'Gene', (30, 33))	('Trim24', 'Gene', '8805', (42, 48))	('DNA-damage-activated', 'Var', (9, 29))
65402	32532965	In addition to apical caspases, CARPs, which are overexpressed in cancer, physically interact with and target p53 or phospho-p53 for ubiquitination and degradation with or without MDM2.	('p53', 'Gene', (110, 113))	('ubiquitin', 'Gene', '850620', (133, 142))	('degradation', 'MPA', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ubiquitin', 'Gene', (133, 142))	('target', 'Reg', (103, 109))	('CARPs', 'Species', '7962', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('phospho-p53', 'Var', (117, 128))
65409	32532965	p300 and CREB-binding (CBP) were regarded as multifunctional modulators of p53 through their acetylase and poly-ubiquitin ligase (E4) activities.	('CREB', 'Gene', '1385', (9, 13))	('CBP', 'Gene', '1387', (23, 26))	('ubiquitin', 'Gene', '850620', (112, 121))	('p300', 'Var', (0, 4))	('acetylase', 'MPA', (93, 102))	('ubiquitin', 'Gene', (112, 121))	('CREB', 'Gene', (9, 13))	('CBP', 'Gene', (23, 26))	('activities', 'MPA', (134, 144))
65413	32532965	In addition, p53 turnover is observed in p300-deficient or CBP-deficient cells via polyubiquitination of mono-p53.	('ubiquitin', 'Gene', (87, 96))	('CBP', 'Gene', (59, 62))	('CBP', 'Gene', '1387', (59, 62))	('ubiquitin', 'Gene', '850620', (87, 96))	('p53', 'Gene', (13, 16))	('p300-deficient', 'Var', (41, 55))
65418	32532965	E4F1-mediated modification p53 plays a crucial role in the cellular life-or-death decision.	('E4F1', 'Gene', (0, 4))	('E4F1', 'Gene', '1877', (0, 4))	('p53', 'Gene', (27, 30))	('death', 'Disease', 'MESH:D003643', (76, 81))	('modification', 'Var', (14, 26))	('death', 'Disease', (76, 81))
65431	32532965	The major function of DUBs is to process and recycle ubiquitin; therefore, DUBs reverse ubiquitination of specific substrate proteins, similar to the reversal of protein phosphorylation by phosphatases.	('ubiquitin', 'Gene', '850620', (88, 97))	('ubiquitin', 'Gene', '850620', (53, 62))	('DUBs', 'Var', (75, 79))	('ubiquitin', 'Gene', (88, 97))	('reverse', 'NegReg', (80, 87))	('ubiquitin', 'Gene', (53, 62))
65445	32532965	Unlike HAUSP, USP10 can interact only with p53, and not with MDM2.	('HAUSP', 'Gene', (7, 12))	('HAUSP', 'Gene', '7874', (7, 12))	('USP10', 'Gene', '9100', (14, 19))	('interact', 'Interaction', (24, 32))	('p53', 'Var', (43, 46))	('USP10', 'Gene', (14, 19))
65458	32532965	Knock down of USP2a results in increased p53 protein accumulation and activation of its target genes.	('increased', 'PosReg', (31, 40))	('USP2', 'Gene', '9099', (14, 18))	('p53 protein', 'Protein', (41, 52))	('USP2', 'Gene', (14, 18))	('Knock down', 'Var', (0, 10))	('activation', 'PosReg', (70, 80))
65468	32532965	As a pro-apoptotic stabilizer of p53, USP29 expression is restricted in most tissues and cells through DNA methylation or repressive chromatin compaction.	('USP29', 'Gene', (38, 43))	('DNA methylation', 'Var', (103, 118))	('USP29', 'Gene', '57663', (38, 43))
65478	32532965	Thus, it is not surprising that inappropriate activity of DUBs directly or indirectly causes many diseases, including cancer, and affects many signaling pathways.	('cancer', 'Disease', (118, 124))	('affects', 'Reg', (130, 137))	('signaling pathways', 'Pathway', (143, 161))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('activity', 'MPA', (46, 54))	('diseases', 'Disease', (98, 106))	('causes', 'Reg', (86, 92))	('inappropriate', 'Var', (32, 45))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
65481	32532965	The C terminus of p53 (positions K370, K372, K373, K381, K382, and K386) can be modified by both acetylation and ubiquitination (Fig.	('K373', 'Var', (45, 49))	('K386', 'Var', (67, 71))	('p53', 'Gene', (18, 21))	('K382', 'Chemical', '-', (57, 61))	('ubiquitin', 'Gene', '850620', (113, 122))	('K382', 'Var', (57, 61))	('K372', 'Var', (39, 43))	('K381', 'Var', (51, 55))	('ubiquitin', 'Gene', (113, 122))
65482	32532965	After DNA damage, N-terminal phosphorylation of p53 promotes the interaction of p53 with p300/CBP or PCAF and, subsequently, leads to the acetylation of the C-terminal K382 or K320 residues to active the DNA-binding activity of p53.	('p53', 'Gene', (48, 51))	('DNA-binding', 'Interaction', (204, 215))	('K320 residues', 'Var', (176, 189))	('CBP', 'Gene', (94, 97))	('interaction', 'Interaction', (65, 76))	('p53', 'Gene', (80, 83))	('C-terminal K382', 'MPA', (157, 172))	('PCAF', 'Gene', '8850', (101, 105))	('CBP', 'Gene', '1387', (94, 97))	('K320', 'Chemical', '-', (176, 180))	('active', 'PosReg', (193, 199))	('K382', 'Chemical', '-', (168, 172))	('leads to', 'Reg', (125, 133))	('promotes', 'PosReg', (52, 60))	('PCAF', 'Gene', (101, 105))	('acetylation', 'MPA', (138, 149))
65483	32532965	However, repressive K382 methylation prevents acetylation by CBP/p300 at this same site, and the level of methylation at K382 decreased upon DNA damage, counteracting its inhibitory effect and promoting CBP/p300-dependent acetylation of K382.	('K382', 'Var', (121, 125))	('decreased', 'NegReg', (126, 135))	('acetylation', 'MPA', (46, 57))	('K382', 'Gene', (20, 24))	('prevents', 'NegReg', (37, 45))	('K382', 'Chemical', '-', (20, 24))	('methylation', 'Var', (25, 36))	('K382', 'Chemical', '-', (237, 241))	('K382', 'Chemical', '-', (121, 125))
65484	32532965	Notably, phosphorylation at S46 and acetylation at K120 are crucial modifications for switching on p53's pro-apoptotic function, which enables tumor cells to be removed.	('S', 'Chemical', 'MESH:D012694', (28, 29))	('tumor', 'Disease', (143, 148))	('acetylation', 'MPA', (36, 47))	('pro-apoptotic', 'MPA', (105, 118))	('phosphorylation at S46', 'Var', (9, 31))	('p53', 'Gene', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('K120', 'Chemical', '-', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
65485	32532965	K372 and K382 residues can also be ubiquitinated and acetylated, and p53 activity can be increased or inhibited depending on the modification site and modification mode.	('ubiquitin', 'Gene', (35, 44))	('acetylated', 'MPA', (53, 63))	('p53', 'Gene', (69, 72))	('activity', 'MPA', (73, 81))	('inhibited', 'NegReg', (102, 111))	('ubiquitin', 'Gene', '850620', (35, 44))	('K372', 'Var', (0, 4))	('increased', 'PosReg', (89, 98))	('K382', 'Chemical', '-', (9, 13))	('K382 residues', 'Var', (9, 22))
65490	32532965	Methylation of lysine and arginine were normally regarded as a reversible mechanism that modulate p53 function.	('function', 'MPA', (102, 110))	('arginine', 'Chemical', 'MESH:D001120', (26, 34))	('Methylation', 'Var', (0, 11))	('lysine', 'Chemical', 'MESH:D008239', (15, 21))	('p53', 'Protein', (98, 101))	('modulate', 'Reg', (89, 97))
65493	32532965	Moreover, it is unclear how the modification of p53 influences cells and tissue in a tumor-specific manner.	('tumor', 'Disease', (85, 90))	('p53', 'Gene', (48, 51))	('influences', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('modification', 'Var', (32, 44))
65495	32532965	p53S18A knock-in mice, in which serine 18 was mutated to a non-phosphorylatable alanine.	('mice', 'Species', '10090', (17, 21))	('p53S18A', 'Var', (0, 7))	('alanine', 'Chemical', 'MESH:D000409', (80, 87))	('serine 18', 'MPA', (32, 41))	('S', 'Chemical', 'MESH:D012694', (3, 4))	('serine', 'Chemical', 'MESH:D012694', (32, 38))
65496	32532965	Phosphorylation of p53 serine 18 does not affect the stability of p53 protein, but contributes to the activation of p53 target genes, thus participating in p53-dependent apoptosis and delayed tumor suppression.	('serine', 'Chemical', 'MESH:D012694', (23, 29))	('Phosphorylation', 'Var', (0, 15))	('participating in', 'Reg', (139, 155))	('tumor suppression', 'Disease', 'MESH:D009369', (192, 209))	('activation', 'PosReg', (102, 112))	('tumor suppression', 'Disease', (192, 209))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('apoptosis', 'CPA', (170, 179))
65497	32532965	p53S23A knock-in mice, in which serine 23 was mutated to a non-phosphorylatable alanine.	('p53S23A', 'Var', (0, 7))	('mice', 'Species', '10090', (17, 21))	('serine', 'Chemical', 'MESH:D012694', (32, 38))	('serine 23', 'MPA', (32, 41))	('alanine', 'Chemical', 'MESH:D000409', (80, 87))	('S', 'Chemical', 'MESH:D012694', (3, 4))
65500	32532965	p53S389A knock-in mice was produced and studies have shown that serine 389 phosphorylation selectively promotes apoptosis and tumor suppression under ultraviolet irradiation.	('serine', 'Chemical', 'MESH:D012694', (64, 70))	('serine 389 phosphorylation', 'MPA', (64, 90))	('apoptosis', 'CPA', (112, 121))	('mice', 'Species', '10090', (18, 22))	('tumor suppression', 'Disease', 'MESH:D009369', (126, 143))	('p53S389A', 'Var', (0, 8))	('promotes', 'PosReg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('S', 'Chemical', 'MESH:D012694', (3, 4))	('tumor suppression', 'Disease', (126, 143))
65501	32532965	p53S312A knock-in mice was generated and at this site, ES cells play a key role in the Nanog inhibition and ES cell differentiation, suggesting that serine 315 phosphorylation also plays a role in stem cells.	('Nanog', 'Gene', (87, 92))	('S', 'Chemical', 'MESH:D012694', (56, 57))	('S', 'Chemical', 'MESH:D012694', (109, 110))	('p53S312A', 'Var', (0, 8))	('mice', 'Species', '10090', (18, 22))	('serine', 'Chemical', 'MESH:D012694', (149, 155))	('Nanog', 'Gene', '71950', (87, 92))	('S', 'Chemical', 'MESH:D012694', (3, 4))	('ES cell differentiation', 'CPA', (108, 131))
65502	32532965	Mouse p53 C-terminal contains many lysine residues (K367, K369, K370, K378, K379, K383, and K384), which can be modified by ubiquitination, acetylation, diacylation, sumoyation, or methylation.	('K369', 'Var', (58, 62))	('lysine', 'Chemical', 'MESH:D008239', (35, 41))	('K384', 'Var', (92, 96))	('K370', 'Var', (64, 68))	('diacylation', 'Protein', (153, 164))	('acetylation', 'MPA', (140, 151))	('ubiquitin', 'Gene', (124, 133))	('K379', 'Var', (76, 80))	('K383', 'Var', (82, 86))	('K367', 'Chemical', '-', (52, 56))	('methylation', 'Var', (181, 192))	('K367', 'Var', (52, 56))	('Mouse', 'Species', '10090', (0, 5))	('ubiquitin', 'Gene', '850620', (124, 133))	('K378', 'Var', (70, 74))
65503	32532965	Two knock-in mouse strains address the importance of these residues by mutating all C-terminal lysine into arginine to block any modification of these residues.	('block', 'NegReg', (119, 124))	('mouse', 'Species', '10090', (13, 18))	('lysine', 'Chemical', 'MESH:D008239', (95, 101))	('arginine', 'Chemical', 'MESH:D001120', (107, 115))	('mutating', 'Var', (71, 79))	('modification', 'MPA', (129, 141))
65504	32532965	The "p536KR" knock-in mouse strain carries six C-terminal lysine mutations (K367R, K369R, K370R, K378R, K379R, and K383R), while the second "p537KR" mouse strain has seven mutations, including the above mutation and one mutation at lysine 384 (K384R), which is a non-conservative sequence in human genes.	('R', 'Chemical', 'MESH:D001120', (119, 120))	('K378R', 'Var', (97, 102))	('R', 'Chemical', 'MESH:D001120', (101, 102))	('R', 'Chemical', 'MESH:D001120', (94, 95))	('K370R', 'Mutation', 'p.K370R', (90, 95))	('mouse', 'Species', '10090', (149, 154))	('mouse', 'Species', '10090', (22, 27))	('lysine', 'Chemical', 'MESH:D008239', (58, 64))	('K379R', 'Mutation', 'rs772640272', (104, 109))	('K369R', 'Mutation', 'rs772847941', (83, 88))	('R', 'Chemical', 'MESH:D001120', (146, 147))	('R', 'Chemical', 'MESH:D001120', (108, 109))	('human', 'Species', '9606', (292, 297))	('lysine', 'Chemical', 'MESH:D008239', (232, 238))	('K369R', 'Var', (83, 88))	('R', 'Chemical', 'MESH:D001120', (10, 11))	('K378R', 'Mutation', 'p.K378R', (97, 102))	('R', 'Chemical', 'MESH:D001120', (248, 249))	('K367R', 'Var', (76, 81))	('K383R', 'Mutation', 'rs905769605', (115, 120))	('K370R', 'Var', (90, 95))	('K383R', 'Var', (115, 120))	('K367R', 'Mutation', 'rs772847941', (76, 81))	('R', 'Chemical', 'MESH:D001120', (87, 88))	('K384R', 'Mutation', 'p.K384R', (244, 249))	('K379R', 'Var', (104, 109))	('R', 'Chemical', 'MESH:D001120', (80, 81))
65505	32532965	To clarify the role of a single lysine, some studies have examined the effects of altering a single lysine, such as a murine strain, p53K317R in lysine knock-in mice, causing acetylation loss on the residue, and acetylation at lysine 317 negatively regulates p53 transcriptional activity.	('lysine', 'Chemical', 'MESH:D008239', (227, 233))	('mice', 'Species', '10090', (161, 165))	('murine', 'Species', '10090', (118, 124))	('lysine', 'Chemical', 'MESH:D008239', (100, 106))	('lysine', 'Chemical', 'MESH:D008239', (145, 151))	('loss', 'NegReg', (187, 191))	('acetylation', 'Var', (212, 223))	('negatively', 'NegReg', (238, 248))	('R', 'Chemical', 'MESH:D001120', (140, 141))	('lysine', 'Chemical', 'MESH:D008239', (32, 38))	('acetylation', 'MPA', (175, 186))	('p53', 'Gene', (259, 262))	('transcriptional activity', 'MPA', (263, 287))	('p53K317R', 'Var', (133, 141))	('regulates', 'Reg', (249, 258))
65506	32532965	The Asn-to-Ser substitution p53 (p53N236S) knock in mice model promotes female embryos neural tube defects.	('p53 (p53N236S', 'Var', (28, 41))	('promotes', 'PosReg', (63, 71))	('mice', 'Species', '10090', (52, 56))	('female embryos neural tube defects', 'CPA', (72, 106))	('Asn-to-Ser substitution p53 (p53N236S)', 'Mutation', 'p.N53,236S,N,S', (4, 42))	('neural tube defects', 'Phenotype', 'HP:0045005', (87, 106))
65510	32532965	Thus, PTM site mutant mice may exhibit positive or negative regulation of p53 activity.	('positive', 'PosReg', (39, 47))	('p53', 'Protein', (74, 77))	('negative', 'NegReg', (51, 59))	('mutant', 'Var', (15, 21))	('activity', 'MPA', (78, 86))	('mice', 'Species', '10090', (22, 26))
65512	32532965	A variety of strategies for tumor expressing p53 mutant, for p53 having many different mutations.	('p53', 'Gene', (45, 48))	('tumor', 'Disease', (28, 33))	('mutant', 'Var', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
65513	32532965	Wild-type p53 in tumor cell is an effective activator of apoptosis and senescence, making the reactivation of certain wild-type functions of mutant p53 (usually overexpressed in cancer) a promising therapeutic pathway.	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mutant', 'Var', (141, 147))	('p53', 'Gene', (148, 151))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
65514	32532965	Interestingly, the wild-type loss of function caused by some unstable tumor-derived mutations can be remedied by another point mutations that help stabilize the integration of the p53 protein, suggesting that the change of structure is reversible.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('p53', 'Gene', (180, 183))	('tumor', 'Disease', (70, 75))	('mutations', 'Var', (84, 93))	('protein', 'Protein', (184, 191))	('mutations', 'Var', (127, 136))	('integration', 'MPA', (161, 172))
65515	32532965	Small molecules such as PhiKan083 and PK7088 bind to a site of p53 and form the Y220C mutant, which will stabilize this mutant and increase the level of wild-type p53.	('Y220C', 'Var', (80, 85))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('level', 'MPA', (144, 149))	('increase', 'PosReg', (131, 139))	('PK7088', 'Var', (38, 44))	('Y220C', 'Mutation', 'rs121912666', (80, 85))
65516	32532965	Further, other molecules bind to a variety of mutant p53 proteins and interact with DNA binding domains to promote the correct folding of the mutant protein and the recovery of p53 function, PRIMA-1, PRIMA-met/APR-246, CP-31398, and SCH29074 for example.	('R', 'Chemical', 'MESH:D001120', (201, 202))	('S', 'Chemical', 'MESH:D012694', (233, 234))	('PRIMA-1', 'Gene', (191, 198))	('p53', 'Gene', (177, 180))	('protein', 'Protein', (149, 156))	('function', 'MPA', (181, 189))	('mutant', 'Var', (142, 148))	('PRIMA-1', 'Gene', '145270', (191, 198))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('proteins', 'Protein', (57, 65))	('R', 'Chemical', 'MESH:D001120', (192, 193))	('R', 'Chemical', 'MESH:D001120', (212, 213))	('promote', 'PosReg', (107, 114))	('correct folding', 'MPA', (119, 134))
65517	32532965	Wild-type p53 needs to bind to Zn (2+) to fold correctly, while R175H p53 mutant is damaged in zinc binding.	('Zn', 'Chemical', 'MESH:D015032', (31, 33))	('p53', 'Gene', (70, 73))	('fold', 'MPA', (42, 46))	('R175H', 'Mutation', 'rs28934578', (64, 69))	('R175H', 'Var', (64, 69))
65518	32532965	While the addition of zinc to the conformational mutants G245C and G245D p53 partially recover the wild-type constellation.	('G245D', 'Mutation', 'rs121912656', (67, 72))	('G245D', 'Var', (67, 72))	('p53', 'Gene', (73, 76))	('wild-type', 'MPA', (99, 108))	('G245C', 'Mutation', 'rs28934573', (57, 62))	('G245C', 'Var', (57, 62))	('recover', 'PosReg', (87, 94))
65519	32532965	Therefore, the potential of zinc to restore wild-type folding has been discovered, and this method has been proved to recover chemosensitivity to anticancer drugs in cells which express mutant p53 protein.	('p53', 'Gene', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutant', 'Var', (186, 192))	('folding', 'MPA', (54, 61))	('cancer', 'Disease', (150, 156))	('wild-type', 'MPA', (44, 53))	('protein', 'Protein', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
65520	32532965	In addition, it was found that NSC31926, a thiourea metal chelator, can restore p53 wild-type function in many different cell lines expressing p53 mutants, possibly by enhancing the bioavailability of zinc to p53 mutants.	('thiourea', 'Chemical', 'MESH:D013890', (43, 51))	('wild-type', 'MPA', (84, 93))	('NSC31926', 'Chemical', '-', (31, 39))	('metal', 'Chemical', 'MESH:D008670', (52, 57))	('p53', 'Gene', (80, 83))	('restore', 'PosReg', (72, 79))	('bioavailability', 'MPA', (182, 197))	('enhancing', 'PosReg', (168, 177))	('mutants', 'Var', (147, 154))	('p53', 'Gene', (143, 146))
65521	32532965	Although there are components targeted to mutant p53, many of them also interact and inhibit p53 family proteins, p63 and p73.	('p73', 'Gene', (122, 125))	('mutant', 'Var', (42, 48))	('p53', 'Gene', (49, 52))	('interact', 'Interaction', (72, 80))	('p53 family', 'Gene', '7158;7157;8626;7161', (93, 103))	('p53 family', 'Gene', (93, 103))	('inhibit', 'NegReg', (85, 92))	('p63', 'Gene', (114, 117))	('p63', 'Gene', '8626', (114, 117))	('p73', 'Gene', '7161', (122, 125))
65524	32532965	Tumor suppressor, PTEN, a phosphatidylinositol 3,4,5-triphosphate (PIP3) lipid phosphatase, is frequently inactivated in cancer by mutation, epigenetic silencing, or PTMs.	('inactivated', 'NegReg', (106, 117))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PTEN', 'Gene', (18, 22))	('PIP3', 'Chemical', '-', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('phosphatidylinositol 3,4,5-triphosphate', 'Chemical', 'MESH:C060974', (26, 65))	('epigenetic silencing', 'Var', (141, 161))	('cancer', 'Disease', (121, 127))	('Tumor suppressor', 'Gene', '7248', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('Tumor suppressor', 'Gene', (0, 16))	('mutation', 'Var', (131, 139))
65526	32532965	Some post-translational modifications can lead to the deactivation of PTEN function rather than the goal of PTEN gene integrity.	('PTEN', 'Protein', (70, 74))	('deactivation', 'NegReg', (54, 66))	('modifications', 'Var', (24, 37))	('S', 'Chemical', 'MESH:D012694', (0, 1))
65527	32532965	Post-translational modification can dynamically change activity and function of PTEN and abnormal in the post-translational modulation of PTEN brings about cell proliferation, migration, and adhesion, which are related to the occurrence, development and metastasis of cancer.	('function', 'MPA', (68, 76))	('abnormal', 'Var', (89, 97))	('PTEN', 'Gene', (138, 142))	('activity', 'MPA', (55, 63))	('migration', 'CPA', (176, 185))	('change', 'Reg', (48, 54))	('Post-translational modification', 'Var', (0, 31))	('adhesion', 'CPA', (191, 199))	('cell proliferation', 'CPA', (156, 174))	('brings about', 'Reg', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('metastasis of cancer', 'Disease', 'MESH:D009362', (254, 274))	('post-translational modulation', 'MPA', (105, 134))	('metastasis of cancer', 'Disease', (254, 274))	('PTEN', 'Protein', (80, 84))
65531	32532965	Phosphorylation of Ser380, Thr382, Thr383, and Ser385 which are sites of PTEN in its C-tail region results in the intramolecular binding of C-terminal tail of PTEN with the rest of the PTEN body, which leads to the blocking/inactive conformation of PTEN, thus reducing the catalytic activity and membrane binding.	('Ser380', 'Chemical', '-', (19, 25))	('reducing', 'NegReg', (260, 268))	('membrane binding', 'MPA', (296, 312))	('PTEN', 'Gene', (159, 163))	('catalytic activity', 'MPA', (273, 291))	('PTEN', 'Protein', (249, 253))	('Ser385', 'Chemical', '-', (47, 53))	('results in', 'Reg', (99, 109))	('Ser385', 'Var', (47, 53))	('Thr382', 'Chemical', '-', (27, 33))	('blocking/inactive conformation', 'MPA', (215, 245))	('Thr383', 'Chemical', '-', (35, 41))	('binding', 'Interaction', (129, 136))	('Ser380', 'Var', (19, 25))
65533	32532965	Under the treatment of ionizing radiation (IR), the phosphorylation of PTEN at 240 sites facilitates the interaction between pY240-PTEN and Ki-67, which promotes the recruitment of RAD51 to accelerate DNA repair.	('RAD51', 'Gene', '5888', (181, 186))	('facilitates', 'PosReg', (89, 100))	('Ki', 'Chemical', 'MESH:C066186', (140, 142))	('recruitment', 'MPA', (166, 177))	('R', 'Chemical', 'MESH:D001120', (44, 45))	('R', 'Chemical', 'MESH:D001120', (181, 182))	('PTEN', 'Gene', (71, 75))	('pY240', 'Chemical', '-', (125, 130))	('accelerate', 'PosReg', (190, 200))	('interaction', 'Interaction', (105, 116))	('DNA repair', 'MPA', (201, 211))	('RAD51', 'Gene', (181, 186))	('pY240-PTEN', 'Var', (125, 135))
65534	32532965	In glioblastoma (GBM) preclinical model, blocking Y240 phosphorylation can enhance radio sensitivity and prolong survival and Y240F-PTEN knock in mice showed radio sensitivity.	('survival', 'CPA', (113, 121))	('Y240', 'Var', (50, 54))	('blocking Y240', 'Var', (41, 54))	('GBM', 'Phenotype', 'HP:0012174', (17, 20))	('Y240', 'Chemical', '-', (126, 130))	('radio sensitivity', 'CPA', (83, 100))	('glioblastoma', 'Disease', (3, 15))	('Y240F', 'Mutation', 'p.Y240F', (126, 131))	('prolong', 'PosReg', (105, 112))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('mice', 'Species', '10090', (146, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('Y240', 'Chemical', '-', (50, 54))	('enhance', 'PosReg', (75, 82))	('Y240F-PTEN', 'Var', (126, 136))
65535	32532965	FGFR-regulated pY240-PTEN is the key mechanism of anti-radiation therapy and an effective target to improve the efficacy of radiotherapy.	('FGFR', 'Gene', (0, 4))	('pY240-PTEN', 'Var', (15, 25))	('pY240', 'Chemical', '-', (15, 20))	('FGFR', 'Gene', '2263', (0, 4))
65538	32532965	Casein kinase 2 (CK2) interacts with PTEN physically, can phosphorylate PTEN on Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385 (Fig.	('Ser385', 'Chemical', '-', (124, 130))	('Thr383', 'Var', (112, 118))	('Thr366', 'Chemical', '-', (80, 86))	('Thr366', 'Var', (80, 86))	('Ser385', 'Var', (124, 130))	('PTEN', 'Gene', (72, 76))	('Ser380', 'Var', (96, 102))	('Ser370', 'Chemical', '-', (88, 94))	('Ser380', 'Chemical', '-', (96, 102))	('Thr382', 'Chemical', '-', (104, 110))	('phosphorylate', 'MPA', (58, 71))	('Ser370', 'Var', (88, 94))	('Thr382', 'Var', (104, 110))	('Thr383', 'Chemical', '-', (112, 118))
65539	32532965	Post-translational inactivation of PTEN mediated by CK2 is related to the over-activation of PI3K/AKT pathway, which is a common event in adult B-cell acute lymphoblastic leukemia, suggesting that inhibition of CK2-regulated PTEN may be an effective and novel therapeutic tool for this malignant tumor.	('lymphoblastic leukemia', 'Disease', (157, 179))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (151, 179))	('PTEN', 'Gene', (35, 39))	('malignant tumor', 'Disease', (286, 301))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (157, 179))	('AKT', 'Gene', '207', (98, 101))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (157, 179))	('malignant tumor', 'Disease', 'MESH:D009369', (286, 301))	('inactivation', 'NegReg', (19, 31))	('AKT', 'Gene', (98, 101))	('CK2', 'Var', (52, 55))	('over-activation', 'PosReg', (74, 89))
65540	32532965	Ser370, Ser380, Thr382, Thr383, and Ser385 of PTEN can be phosphorylated by liver kinase (LKB1), resulting in its inactivation.	('Thr382', 'Chemical', '-', (16, 22))	('Ser370', 'Var', (0, 6))	('Thr382', 'Var', (16, 22))	('inactivation', 'MPA', (114, 126))	('Ser370', 'Chemical', '-', (0, 6))	('Thr383', 'Chemical', '-', (24, 30))	('Ser385', 'Chemical', '-', (36, 42))	('PTEN', 'Gene', (46, 50))	('Thr383', 'Var', (24, 30))	('Ser385', 'Var', (36, 42))	('LKB1', 'Gene', (90, 94))	('LKB1', 'Gene', '6794', (90, 94))	('Ser380', 'Var', (8, 14))	('Ser380', 'Chemical', '-', (8, 14))
65541	32532965	Using the conditional gene knockout alleles of LKB1 and PTEN, the inactivation of the dual alleles of the two tumor suppressor factors in the lung resulted in the pure squamous cell phenotype of lung tumors.	('LKB1', 'Gene', '6794', (47, 51))	('lung tumors', 'Disease', 'MESH:D008175', (195, 206))	('tumor suppressor', 'Gene', '7248', (110, 126))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('PTEN', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('inactivation', 'Var', (66, 78))	('resulted in', 'Reg', (147, 158))	('lung tumors', 'Phenotype', 'HP:0100526', (195, 206))	('lung tumors', 'Disease', (195, 206))	('tumor suppressor', 'Gene', (110, 126))	('LKB1', 'Gene', (47, 51))
65543	32532965	R280T mutation of p53 mediates the proliferation of human glioma cells associated with GSK-3beta/PTEN pathway.	('GSK-3beta', 'Gene', (87, 96))	('p53', 'Gene', (18, 21))	('R280T', 'Var', (0, 5))	('proliferation', 'CPA', (35, 48))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('R280T', 'Mutation', 'rs121912660', (0, 5))	('human', 'Species', '9606', (52, 57))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('mediates', 'Reg', (22, 30))	('glioma', 'Disease', (58, 64))	('GSK-3beta', 'Gene', '2931', (87, 96))
65544	32532965	Moreover, rhoA-associated protein kinase (ROCK) can inhibit PTEN after phosphorylation of Ser229, Thr232, Thr319, and Thr321, and then transfer it to the membrane.	('phosphorylation', 'MPA', (71, 86))	('Thr232', 'Var', (98, 104))	('inhibit', 'NegReg', (52, 59))	('Ser229', 'Chemical', '-', (90, 96))	('Ser229', 'Var', (90, 96))	('transfer', 'Reg', (135, 143))	('PTEN', 'Protein', (60, 64))	('Thr321', 'Chemical', '-', (118, 124))	('Thr319', 'Chemical', '-', (106, 112))	('R', 'Chemical', 'MESH:D001120', (42, 43))	('Thr321', 'Var', (118, 124))	('Thr319', 'Var', (106, 112))	('Thr232', 'Chemical', '-', (98, 104))
65550	32532965	In conclusion, phosphorylation of PTEN have potential to restore or enhance PTEN activity, thereby inhibiting cancer cell proliferation and resistance to chemotherapy drugs.	('PTEN', 'Protein', (76, 80))	('cancer', 'Disease', (110, 116))	('restore', 'PosReg', (57, 64))	('inhibiting', 'NegReg', (99, 109))	('phosphorylation', 'Var', (15, 30))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('resistance to chemotherapy drugs', 'CPA', (140, 172))	('activity', 'MPA', (81, 89))	('PTEN', 'Gene', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('enhance', 'PosReg', (68, 75))
65557	32532965	Both gene ablation and drug inhibition of WWP1 can activate PTEN and release tumor suppressive activity.	('release', 'PosReg', (69, 76))	('PTEN', 'Protein', (60, 64))	('activate', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('WWP1', 'Gene', '11059', (42, 46))	('WWP1', 'Gene', (42, 46))	('gene ablation', 'Var', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
65560	32532965	Further, linc02023 specifically interacts PTEN, and inhibits its interaction and ubiquitination with PTEN through WWP2, making it stable and inhibiting its downstream expression, suggests that linc02023 may be a new therapeutic target by restoring the antitumor activity of PTEN.	('interacts', 'Interaction', (32, 41))	('interaction', 'Interaction', (65, 76))	('restoring', 'PosReg', (238, 247))	('linc02023', 'Var', (9, 18))	('WWP2', 'Gene', (114, 118))	('ubiquitin', 'Gene', '850620', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('WWP2', 'Gene', '11060', (114, 118))	('inhibits', 'NegReg', (52, 60))	('linc02023', 'Var', (193, 202))	('ubiquitin', 'Gene', (81, 90))	('inhibiting', 'NegReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('downstream expression', 'MPA', (156, 177))	('PTEN', 'Protein', (42, 46))	('tumor', 'Disease', (256, 261))
65562	32532965	The changes of PI3K/AKT/mTOR signaling pathway in PTEN mutant cancer patiens indicated that PI3K, AKT or mTOR are target for molecular therapy.	('AKT', 'Gene', (20, 23))	('mTOR', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('PTEN', 'Gene', (50, 54))	('mutant', 'Var', (55, 61))	('mTOR', 'Gene', (105, 109))	('AKT', 'Gene', '207', (98, 101))	('mTOR', 'Gene', '2475', (105, 109))	('changes', 'Reg', (4, 11))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('AKT', 'Gene', '207', (20, 23))	('AKT', 'Gene', (98, 101))	('mTOR', 'Gene', '2475', (24, 28))
65563	32532965	PTEN hamartoma tumor syndrome (PHTS) is caused by pathogenic PTEN mutation in germline.	('PTEN hamartoma tumor syndrome', 'Disease', (0, 29))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('hamartoma', 'Phenotype', 'HP:0010566', (5, 14))	('PTEN', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('PTEN hamartoma tumor syndrome', 'Disease', 'MESH:D006223', (0, 29))	('S', 'Chemical', 'MESH:D012694', (34, 35))
65566	32532965	In addition, the upstream proteins of PTEN signaling pathway, PI3K and AKT for example, can also be used as drug inhibition candidates for PTEN mutant patients.	('AKT', 'Gene', '207', (71, 74))	('PTEN signaling pathway', 'Pathway', (38, 60))	('PTEN', 'Gene', (139, 143))	('patients', 'Species', '9606', (151, 159))	('AKT', 'Gene', (71, 74))	('mutant', 'Var', (144, 150))
65571	32532965	In fact, mTORC1 inhibition has been demonstrated effectively bring about feedback activation of upstream signaling components.	('feedback', 'MPA', (73, 81))	('mTORC1', 'Gene', (9, 15))	('mTORC1', 'Gene', '382056', (9, 15))	('upstream signaling components', 'MPA', (96, 125))	('inhibition', 'Var', (16, 26))
65574	32532965	Since PTEN is the main controller of this pathway, it is not surprising that the destruction of PTEN leads to immune disorders.	('immune disorders', 'Disease', (110, 126))	('leads to', 'Reg', (101, 109))	('PTEN', 'Gene', (96, 100))	('destruction', 'Var', (81, 92))	('S', 'Chemical', 'MESH:D012694', (0, 1))
65581	32532965	Rb is the most common mutation gene in childhood cancer retinoblastoma, and its deletion leads to E2F transcription factor induced proliferation related genes.	('leads', 'Reg', (89, 94))	('deletion', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Rb', 'Phenotype', 'HP:0009919', (0, 2))	('retinoblastoma', 'Phenotype', 'HP:0009919', (56, 70))	('Rb', 'Gene', '5925', (0, 2))	('cancer retinoblastoma', 'Disease', 'MESH:D012175', (49, 70))	('cancer retinoblastoma', 'Disease', (49, 70))
65585	32532965	Further, mutated PTEN are discovered in rare autosomal dominant cancer susceptibility syndromes, such as Cowden's disease.	("Cowden's disease", 'Disease', 'MESH:D006223', (105, 121))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (45, 70))	('autosomal dominant cancer', 'Disease', (45, 70))	("Cowden's disease", 'Disease', (105, 121))	('mutated', 'Var', (9, 16))	('discovered', 'Reg', (26, 36))	('PTEN', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
65586	32532965	The gene p53 deleted, point mutated and allele lost are common in most human cancers.	('deleted', 'Var', (13, 20))	('human', 'Species', '9606', (71, 76))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('p53', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('point mutated', 'Var', (22, 35))
65587	32532965	p53 mutation is also related to Li Fraumeni syndrome which is susceptible to hereditary cancer.	('p53', 'Gene', (0, 3))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (32, 52))	('Li Fraumeni syndrome', 'Disease', (32, 52))	('mutation', 'Var', (4, 12))	('related', 'Reg', (21, 28))	('hereditary cancer', 'Disease', 'MESH:D009369', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hereditary cancer', 'Disease', (77, 94))
65588	32532965	Therefore, Rb, E2F, PTEN, PI3K, AKT, and p53 are all involved in the function of cell growth, and gain or loss function of TSGs and oncogene.	('involved', 'Reg', (53, 61))	('loss function', 'NegReg', (106, 119))	('AKT', 'Gene', '207', (32, 35))	('AKT', 'Gene', (32, 35))	('Rb', 'Phenotype', 'HP:0009919', (11, 13))	('E2F', 'Var', (15, 18))	('gain', 'PosReg', (98, 102))	('Rb', 'Gene', '5925', (11, 13))	('PTEN', 'Gene', (20, 24))	('p53', 'Gene', (41, 44))	('PI3K', 'Var', (26, 30))
65589	32532965	PTEN can inhibit PI3K-AKT pathway that can promote the nuclear localization of MDM2 and the downregulation of p53, which may reveal the mechanism of cancer chemotherapy resistance to a certain extent.	('nuclear localization', 'MPA', (55, 75))	('cancer', 'Disease', (149, 155))	('downregulation', 'NegReg', (92, 106))	('inhibit', 'NegReg', (9, 16))	('AKT', 'Gene', '207', (22, 25))	('promote', 'PosReg', (43, 50))	('p53', 'MPA', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('MDM2', 'Protein', (79, 83))	('AKT', 'Gene', (22, 25))	('PTEN', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
65590	32532965	Cancer produces growth and survival factors that activate PI3K through autocrine or paracrine mechanisms.	('PI3K', 'Var', (58, 62))	('activate', 'PosReg', (49, 57))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
65591	32532965	PI3K-kinase is a component that can be detected in many human cancers and it is associated with cell cycle arrest, inhibited apoptosis, increased tumor cells resistance to chemotherapy.	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('arrest', 'Disease', (107, 113))	('tumor', 'Disease', (146, 151))	('human', 'Species', '9606', (56, 61))	('PI3K-kinase', 'Var', (0, 11))	('associated', 'Reg', (80, 90))	('apoptosis', 'CPA', (125, 134))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('increased', 'PosReg', (136, 145))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('inhibited', 'NegReg', (115, 124))	('cancers', 'Disease', (62, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
65596	32532965	These genes act as a role in the normal survival of cells by modulating the cell cycle and activating other genes engaged in the cell's response to DNA damage, as well as inhibiting carcinogenesis, and mutation or deletion of these tumor suppressor genes may result in the deactivation of tumor suppressor, and then lead to the occurrence of malignant tumors.	('inhibiting', 'NegReg', (171, 181))	('tumor suppressor', 'Gene', '7248', (289, 305))	('tumor suppressor', 'Gene', (232, 248))	('mutation', 'Var', (202, 210))	('carcinogenesis', 'Disease', 'MESH:D063646', (182, 196))	('deletion', 'Var', (214, 222))	('deactivation', 'NegReg', (273, 285))	('tumor suppressor', 'Gene', '7248', (232, 248))	('response to DNA damage', 'MPA', (136, 158))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('tumor suppressor', 'Gene', (289, 305))	('activating', 'PosReg', (91, 101))	('modulating', 'Reg', (61, 71))	('malignant tumors', 'Disease', (342, 358))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('cell cycle', 'CPA', (76, 86))	('malignant tumors', 'Disease', 'MESH:D009369', (342, 358))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('lead to', 'Reg', (316, 323))	('carcinogenesis', 'Disease', (182, 196))
65597	32532965	However, Rb deletions are almost universal in neuroendocrine prostate cancer, characterized by frequent concurrent changes in PTEN and p53.	('deletions', 'Var', (12, 21))	('Rb', 'Phenotype', 'HP:0009919', (9, 11))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Rb', 'Gene', '5925', (9, 11))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (46, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('neuroendocrine prostate cancer', 'Disease', (46, 76))
65598	32532965	p53 mutation may also lead to poor response to androgen receptor targeted therapy of castration-resistant prostate cancer.	('p53', 'Gene', (0, 3))	('androgen receptor', 'Gene', '367', (47, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('mutation', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('androgen receptor', 'Gene', (47, 64))	('prostate cancer', 'Disease', (106, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
65600	32532965	The loss of PTEN accelerated the medullary thyroid carcinoma induced by the loss of p53 and Rb.	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (33, 60))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (43, 60))	('loss', 'Var', (76, 80))	('Rb', 'Phenotype', 'HP:0009919', (92, 94))	('Rb', 'Gene', '5925', (92, 94))	('p53', 'Protein', (84, 87))	('PTEN', 'Gene', (12, 16))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (43, 60))	('accelerated', 'PosReg', (17, 28))	('thyroid carcinoma', 'Disease', (43, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('loss', 'Var', (4, 8))
65602	32532965	In adult brain, the synergistic effect of PTEN, p53, and Rb pathway can produce high-grade astrocytoma.	('Rb', 'Phenotype', 'HP:0009919', (57, 59))	('p53', 'Gene', (48, 51))	('PTEN', 'Gene', (42, 46))	('Rb', 'Gene', '5925', (57, 59))	('astrocytoma', 'Disease', 'MESH:D001254', (91, 102))	('synergistic', 'Var', (20, 31))	('astrocytoma', 'Disease', (91, 102))	('produce', 'Reg', (72, 79))	('astrocytoma', 'Phenotype', 'HP:0009592', (91, 102))
65603	32532965	Inactivation of these three tumor suppressor genes was also detected in the stroma of oropharyngeal, breast, and other tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor suppressor', 'Gene', '7248', (28, 44))	('oropharyngeal', 'Disease', (86, 99))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('detected', 'Reg', (60, 68))	('tumor suppressor', 'Gene', (28, 44))	('breast', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Inactivation', 'Var', (0, 12))
65604	32532965	The mouse model demonstrated the tumor promoting effect of deletion of Rb, Pten, or p53 in fibroblasts, which transformed normal fibroblasts into cancer-related fibroblasts.	('Rb', 'Phenotype', 'HP:0009919', (71, 73))	('mouse', 'Species', '10090', (4, 9))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Rb', 'Gene', '5925', (71, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Pten', 'Gene', (75, 79))	('Pten', 'Gene', '19211', (75, 79))	('p53', 'Gene', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (33, 38))	('deletion', 'Var', (59, 67))
65609	32532965	Dysfunctional of TSG is part of signal pathway, and the carcinogenesis is regulated by over activation of the pathway.	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('TSG', 'Gene', (17, 20))	('carcinogenesis', 'Disease', (56, 70))	('Dysfunctional', 'Var', (0, 13))
65611	32532965	PTEN is inactivated with a significant proportion of mutations or deletions in a variety of cancer types, such as glioblastoma, endometrial, prostate, uterine and breast cancers, and melanoma.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancers', 'Disease', 'MESH:D001943', (163, 177))	('breast cancers', 'Disease', (163, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('endometrial', 'Disease', (128, 139))	('breast cancers', 'Phenotype', 'HP:0003002', (163, 177))	('deletions', 'Var', (66, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('glioblastoma', 'Disease', (114, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('prostate', 'Disease', (141, 149))	('cancer', 'Disease', (92, 98))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('mutations', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PTEN', 'Gene', (0, 4))	('uterine', 'Disease', (151, 158))
65612	32532965	Post-translational modifications of TSG impact downstream targets of TSG, and can influence their functions involving in cancer, ageing, heart failure, autoimmune disease and so on (Fig.	('autoimmune disease', 'Disease', (152, 170))	('heart failure', 'Disease', (137, 150))	('influence', 'Reg', (82, 91))	('Post-translational modifications', 'Var', (0, 32))	('impact', 'Reg', (40, 46))	('autoimmune disease', 'Phenotype', 'HP:0002960', (152, 170))	('ageing', 'Disease', (129, 135))	('TSG', 'Gene', (36, 39))	('autoimmune disease', 'Disease', 'MESH:D001327', (152, 170))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('heart failure', 'Phenotype', 'HP:0001635', (137, 150))	('functions', 'MPA', (98, 107))	('heart failure', 'Disease', 'MESH:D006333', (137, 150))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
65636	32457755	Microglia and peripheral macrophages, which extensively infiltrate GBMs, are collectively termed GAMs; tumor-infiltrating lymphocytes mostly comprise CD4+ T cells, CD8+ T cells, and regulatory T cells (Tregs).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CD4+ T', 'Var', (150, 156))	('CD8', 'Gene', (164, 167))	('tumor', 'Disease', (103, 108))	('CD8', 'Gene', '925', (164, 167))	('Tregs', 'Chemical', '-', (202, 207))	('GAM', 'Chemical', '-', (97, 100))	('GBM', 'Phenotype', 'HP:0012174', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
65678	32457755	The results showed a diminished T cell fraction in GBM patient peripheral blood compared to that in healthy donors (p < 0.01), while the proportions of NK cells and B cells were similar across all samples (Figures 2A,B).	('diminished T cell', 'Phenotype', 'HP:0005403', (21, 38))	('T cell fraction', 'CPA', (32, 47))	('GBM', 'Var', (51, 54))	('diminished', 'NegReg', (21, 31))	('GBM', 'Phenotype', 'HP:0012174', (51, 54))	('patient', 'Species', '9606', (55, 62))
65697	32457755	PD-1+, TIM-3+ or LAG-3+ T cells are recognized as exhausted subsets.	('TIM-3', 'Gene', (7, 12))	('LAG-3+ T cells', 'CPA', (17, 31))	('PD-1+', 'Var', (0, 5))	('TIM-3', 'Gene', '84868', (7, 12))
65727	32457755	Although the GBM microenvironment was infiltrated with CD4+ T cells, CD8+ T cells, and NK cells, the proportions of nonfunctional immune cell subpopulations and Tregs increased, while whole T cell numbers were reduced at the tumor site.	('Tregs', 'CPA', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Tregs', 'Chemical', '-', (161, 166))	('GBM', 'Phenotype', 'HP:0012174', (13, 16))	('tumor', 'Disease', (225, 230))	('increased', 'PosReg', (167, 176))	('CD8', 'Gene', (69, 72))	('CD8', 'Gene', '925', (69, 72))	('CD4+ T', 'Var', (55, 61))
65881	29721096	The pathologic molecular profiling associated with patients' survival, including MGMT methylation status, TERT mutational status, IDH mutational status and 1p19q codeletion status, and postoperative therapy were also shown.	('IDH', 'Gene', '3417', (130, 133))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('patients', 'Species', '9606', (51, 59))	('MGMT', 'Gene', '4255', (81, 85))	('MGMT', 'Gene', (81, 85))	('IDH', 'Gene', (130, 133))	('1p19q codeletion status', 'Var', (156, 179))	('mutational status', 'Var', (134, 151))
65917	28481871	We further observe that restoration of Nrdp1, a RING finger type E3 ubiquitin ligase whose suppression in GBM also correlates with poor prognosis, reduces GBM cell migration and invasiveness by suppressing PCP signaling.	('suppressing', 'NegReg', (194, 205))	('reduces', 'NegReg', (147, 154))	('restoration', 'Var', (24, 35))	('PCP', 'Chemical', '-', (206, 209))	('PCP signaling', 'MPA', (206, 219))	('invasiveness', 'CPA', (178, 190))	('Nrdp1', 'Gene', (39, 44))	('GBM cell migration', 'CPA', (155, 173))	('suppression', 'MPA', (91, 102))
65926	28481871	While GBM is a heterogeneous disease, common molecular drivers include overexpression or mutation of EGFR, elevation of PDGF ligands and receptors, and loss of the tumor suppressor PTEN.	('GBM', 'Disease', (6, 9))	('overexpression', 'PosReg', (71, 85))	('PTEN', 'Gene', (181, 185))	('loss of the tumor', 'Disease', 'MESH:D009369', (152, 169))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', (101, 105))	('loss of the tumor', 'Disease', (152, 169))	('PDGF', 'Protein', (120, 124))	('elevation', 'PosReg', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PTEN', 'Gene', '5728', (181, 185))
65927	28481871	Downstream signaling through the phosphatidylinostitol 3-kinase (PI3K)/Akt pathway promotes migration, and disruption of PI3K/Akt signaling in GBM cells can partially suppress cellular invasion.	('Akt', 'Gene', '207', (71, 74))	('Akt', 'Gene', (71, 74))	('Akt', 'Gene', '207', (126, 129))	('promotes', 'PosReg', (83, 91))	('phosphatidylinostitol 3-kinase', 'Gene', (33, 63))	('migration', 'CPA', (92, 101))	('phosphatidylinostitol 3-kinase', 'Gene', '5293', (33, 63))	('cellular invasion', 'CPA', (176, 193))	('disruption', 'Var', (107, 117))	('suppress', 'NegReg', (167, 175))	('Akt', 'Gene', (126, 129))
65928	28481871	However, alterations in other molecular pathways such as Wnt signaling also promote invasive processes, and it is likely that dysregulation of multiple signaling pathways contributes to GBM aggressiveness.	('promote', 'PosReg', (76, 83))	('aggressiveness', 'Phenotype', 'HP:0000718', (190, 204))	('GBM aggressiveness', 'Disease', 'MESH:D005910', (186, 204))	('GBM aggressiveness', 'Disease', (186, 204))	('alterations', 'Var', (9, 20))	('invasive processes', 'CPA', (84, 102))
65931	28481871	Signaling via the tetraspanin-like scaffolds Vangl1 and Vangl2 in mammals comprises a branch of non-canonical Wnt signaling associated with developmental PCP, and dysregulation of this pathway is associated with various disease states.	('developmental PCP', 'Disease', (140, 157))	('Vangl1', 'Gene', (45, 51))	('associated', 'Reg', (196, 206))	('dysregulation', 'Var', (163, 176))	('PCP', 'Chemical', '-', (154, 157))	('Vangl2', 'Gene', (56, 62))
65936	28481871	Vangl proteins localize to the leading edge of lamellapodia and to the base and arms of actin protrusions of migrating breast cancer cells, and VANGL1 knockdown in these cells reduces motility.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('VANGL1', 'Gene', (144, 150))	('VANGL1', 'Gene', '81839', (144, 150))	('breast cancer', 'Disease', (119, 132))	('Vangl', 'Chemical', '-', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('reduces', 'NegReg', (176, 183))	('motility', 'CPA', (184, 192))	('lamellapodia', 'Disease', (47, 59))	('lamellapodia', 'Disease', 'None', (47, 59))	('knockdown', 'Var', (151, 160))
65938	28481871	Vangl1 and/or Vangl2 dysregulation has been reported in several cancer types, including GBM.	('Vangl1', 'Gene', (0, 6))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('dysregulation', 'Var', (21, 34))	('reported', 'Reg', (44, 52))	('GBM', 'Disease', (88, 91))	('Vangl2', 'Gene', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
65943	28481871	Loss of Nrdp1 has been associated with breast cancer, prostate cancer, colon cancer and recently GBM.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('Nrdp1', 'Gene', (8, 13))	('prostate cancer', 'Disease', (54, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))	('GBM', 'Disease', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('Loss', 'Var', (0, 4))	('associated', 'Reg', (23, 33))	('breast cancer', 'Disease', (39, 52))
65944	28481871	In glioma cell lines, re-expression of Nrdp1 has been reported to reduce BRUCE levels and increase apoptosis in response to temozolomide treatment, and may reduce cell migration in a subset of gliomas via ErbB3 suppression.	('cell migration', 'CPA', (163, 177))	('glioma', 'Disease', (3, 9))	('ErbB3', 'Gene', (205, 210))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('gliomas', 'Disease', (193, 200))	('glioma', 'Disease', (193, 199))	('response to temozolomide treatment', 'MPA', (112, 146))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('reduce', 'NegReg', (156, 162))	('ErbB3', 'Gene', '2065', (205, 210))	('BRUCE', 'Gene', '57448', (73, 78))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('gliomas', 'Disease', 'MESH:D005910', (193, 200))	('apoptosis', 'CPA', (99, 108))	('temozolomide', 'Chemical', 'MESH:D000077204', (124, 136))	('suppression', 'NegReg', (211, 222))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('reduce', 'NegReg', (66, 72))	('BRUCE', 'Gene', (73, 78))	('increase', 'PosReg', (90, 98))	('re-expression', 'Var', (22, 35))	('gliomas', 'Phenotype', 'HP:0009733', (193, 200))	('Nrdp1', 'Gene', (39, 44))
65946	28481871	Here we report that VANGL1 and VANGL2 are overexpressed and NRDP1 is suppressed in brain tumors relative to normal brain tissue, and that restoration of Nrdp1 to GBM cell lines reduces cellular motility and invasiveness.	('brain tumor', 'Phenotype', 'HP:0030692', (83, 94))	('brain tumors', 'Disease', 'MESH:D001932', (83, 95))	('VANGL2', 'Gene', (31, 37))	('overexpressed', 'PosReg', (42, 55))	('restoration', 'Var', (138, 149))	('VANGL1', 'Gene', (20, 26))	('VANGL1', 'Gene', '81839', (20, 26))	('NRDP1', 'Gene', '10193', (60, 65))	('invasiveness', 'CPA', (207, 219))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cellular motility', 'CPA', (185, 202))	('reduces', 'NegReg', (177, 184))	('brain tumors', 'Phenotype', 'HP:0030692', (83, 95))	('Nrdp1', 'Gene', (153, 158))	('VANGL2', 'Gene', '57216', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('NRDP1', 'Gene', (60, 65))	('brain tumors', 'Disease', (83, 95))
65953	28481871	Conversely, shRNA-mediated suppression of the low endogenous levels of NRDP1 in T98G (Figs.	('T98G', 'Var', (80, 84))	('NRDP1', 'Gene', '10193', (71, 76))	('suppression', 'NegReg', (27, 38))	('low endogenous levels', 'MPA', (46, 67))	('T98G', 'CellLine', 'CVCL:0556', (80, 84))	('NRDP1', 'Gene', (71, 76))
65958	28481871	We observed that when seeded on brain slices, U251 cells with restored Nrdp1 disseminated less efficiently than control cells, as determined histologically and by anti-GFP staining (Figs.	('less', 'NegReg', (90, 94))	('U251', 'CellLine', 'CVCL:0021', (46, 50))	('disseminated', 'CPA', (77, 89))	('restored', 'Var', (62, 70))	('Nrdp1', 'Gene', (71, 76))
65961	28481871	Likewise, levels of EGFR and phosphorylation of signaling intermediates Akt and Erk are not altered upon Nrdp1 restoration (Fig.	('Nrdp1', 'Gene', (105, 110))	('Akt', 'Gene', (72, 75))	('Erk', 'Gene', (80, 83))	('restoration', 'Var', (111, 122))	('EGFR', 'MPA', (20, 24))	('Erk', 'Gene', '2048', (80, 83))	('Akt', 'Gene', '207', (72, 75))	('phosphorylation', 'MPA', (29, 44))
65965	28481871	S4F and S4G) and phospho-JNK (Figs.	('JNK', 'Gene', (25, 28))	('JNK', 'Gene', '5599', (25, 28))	('S4G', 'Var', (8, 11))
65968	28481871	The Vangl proteins are critical for PCP, and loss-of-function Vangl mutants lead to developmental defects in multiple tissues.	('Vangl', 'Gene', (62, 67))	('loss-of-function', 'NegReg', (45, 61))	('Vangl', 'Chemical', '-', (4, 9))	('Vangl', 'Chemical', '-', (62, 67))	('developmental defects', 'Disease', (84, 105))	('developmental defects', 'Disease', 'MESH:D003147', (84, 105))	('mutants', 'Var', (68, 75))	('PCP', 'Chemical', '-', (36, 39))
65972	28481871	Dysregulation of this pathway is also associated with decreased patient survival times (Fig.	('Dysregulation', 'Var', (0, 13))	('patient', 'Species', '9606', (64, 71))	('decreased', 'NegReg', (54, 63))	('patient survival times', 'CPA', (64, 86))
65977	28481871	S7A and S7B) nor suppressed Vangl protein levels (Fig.	('suppressed', 'NegReg', (17, 27))	('S7B', 'Var', (8, 11))	('Vangl', 'Chemical', '-', (28, 33))	('Vangl protein levels', 'MPA', (28, 48))
65985	28481871	Dvl ubiquitination is suppressed by Nrdp1 knockdown (Fig.	('Nrdp1', 'Gene', (36, 41))	('suppressed', 'NegReg', (22, 32))	('Dvl', 'Gene', '1855', (0, 3))	('Dvl', 'Gene', (0, 3))	('knockdown', 'Var', (42, 51))
65987	28481871	S7E and S7F), indicating that the ubiquitin ligase activity of Nrdp1 is necessary for Dvl ubiquitination.	('Dvl', 'Gene', '1855', (86, 89))	('Dvl', 'Gene', (86, 89))	('Nrdp1', 'Gene', (63, 68))	('S7F', 'Var', (8, 11))
65992	28481871	Polyubiquitination consists of ubiquitin monomers chained through any of seven lysines or the N-terminal amino group, most commonly utilizing K48, K63 or K11ref.	('K11ref', 'Var', (154, 160))	('lysines', 'Chemical', 'MESH:D008239', (79, 86))	('chained', 'Reg', (50, 57))	('Polyubiquitination', 'MPA', (0, 18))	('K63', 'Var', (147, 150))	('K48', 'Var', (142, 145))	('ubiquitin monomers', 'Protein', (31, 49))
65993	28481871	To determine the ubiquitin linkage on Dvl2 promoted by Nrdp1, we conducted ubiquitination assays using ubiquitin mutants where K48, K63, or K11 is mutated to arginine, thus preventing polyubiquitination through the mutated lysine.	('Dvl2', 'Gene', '1856', (38, 42))	('K48', 'Var', (127, 130))	('lysine', 'Chemical', 'MESH:D008239', (223, 229))	('preventing', 'NegReg', (173, 183))	('arginine', 'Chemical', 'MESH:D001120', (158, 166))	('mutated', 'Var', (215, 222))	('Nrdp1', 'Gene', (55, 60))	('K11', 'Var', (140, 143))	('Dvl2', 'Gene', (38, 42))	('polyubiquitination', 'MPA', (184, 202))	('K63', 'Var', (132, 135))
65994	28481871	We observed that only the K63R mutant cannot form polyubiquitin chains on Dvl2 (Fig.	('form polyubiquitin chains', 'MPA', (45, 70))	('K63R', 'Var', (26, 30))	('Dvl2', 'Gene', (74, 78))	('K63R', 'Mutation', 'p.K63R', (26, 30))	('Dvl2', 'Gene', '1856', (74, 78))
65996	28481871	This complements our observation that Nrdp1 does not promote endogenous Dvl2 degradation; unlike K48 and K11-linked ubiquitin chains, K63-linked poyubiquitination is not typically a degradation marker, but promotes context-dependent regulation of protein activity and complexes.	('context-dependent regulation', 'MPA', (215, 243))	('Dvl2', 'Gene', (72, 76))	('Dvl2', 'Gene', '1856', (72, 76))	('Nrdp1', 'Gene', (38, 43))	('complexes', 'MPA', (268, 277))	('promotes', 'PosReg', (206, 214))	('K63-linked', 'Var', (134, 144))	('activity', 'MPA', (255, 263))	('protein', 'Protein', (247, 254))
65997	28481871	These observations suggest that Nrdp1-mediated K63-linked polyubiquitination of Dvl proteins alters Dvl function to suppress GBM cell motility.	('Dvl', 'Gene', (100, 103))	('GBM cell motility', 'CPA', (125, 142))	('Nrdp1-mediated', 'Gene', (32, 46))	('Dvl', 'Gene', '1855', (100, 103))	('Dvl', 'Gene', (80, 83))	('K63-linked', 'Var', (47, 57))	('suppress', 'NegReg', (116, 124))	('Dvl', 'Gene', '1855', (80, 83))	('alters', 'Reg', (93, 99))
66000	28481871	Using Dvl1 mutants with the lysines in each domain mutated to arginines (Fig.	('mutants', 'Var', (11, 18))	('lysines', 'Protein', (28, 35))	('lysines', 'Chemical', 'MESH:D008239', (28, 35))	('Dvl1', 'Gene', (6, 10))	('arginines', 'Chemical', 'MESH:D001120', (62, 71))	('mutated', 'Var', (51, 58))
66007	28481871	S9B), suggesting that ubiquitination of these residues could reduce the affinity of the DEP domain for PA by steric hindrance.	('affinity', 'Interaction', (72, 80))	('DEP', 'Protein', (88, 91))	('reduce', 'NegReg', (61, 67))	('ubiquitination', 'Var', (22, 36))	('PA', 'Chemical', 'MESH:D010712', (103, 105))
66010	28481871	However, in the presence of Vangl2 and Nrdp1, Dvl1 binding to PA is significantly decreased, suggesting that Nrdp1-mediated ubiquitination inhibits Dvl function by preventing its association with the plasma membrane.	('association', 'Interaction', (179, 190))	('binding', 'Interaction', (51, 58))	('Dvl', 'Gene', (148, 151))	('PA', 'Chemical', 'MESH:D010712', (62, 64))	('Dvl', 'Gene', (46, 49))	('ubiquitination', 'MPA', (124, 138))	('Nrdp1-mediated', 'Var', (109, 123))	('Dvl', 'Gene', '1855', (148, 151))	('Dvl', 'Gene', '1855', (46, 49))	('preventing', 'NegReg', (164, 174))	('inhibits', 'NegReg', (139, 147))	('decreased', 'NegReg', (82, 91))
66018	28481871	5C and 5D), suggesting that polyubiquitinated Dvl cannot form the active Fzd-Dvl complexes necessary for directed migration.	('polyubiquitinated', 'Var', (28, 45))	('Dvl', 'Gene', (46, 49))	('Dvl', 'Gene', '1855', (46, 49))	('Dvl', 'Gene', (77, 80))	('Fzd', 'Chemical', '-', (73, 76))	('Dvl', 'Gene', '1855', (77, 80))
66019	28481871	Likewise, restoration of Nrdp1 to T98G cells suppresses Wnt5a-induced accumulation of phospho-Dvl2, implying that Nrdp1 interferes with Fzd-induced Dvl signaling in GBM cells (Fig.	('Dvl2', 'Gene', (94, 98))	('restoration', 'Var', (10, 21))	('Dvl', 'Gene', (94, 97))	('Dvl', 'Gene', (148, 151))	('Fzd', 'Chemical', '-', (136, 139))	('T98G', 'CellLine', 'CVCL:0556', (34, 38))	('Nrdp1', 'Gene', (25, 30))	('Dvl', 'Gene', '1855', (94, 97))	('Dvl2', 'Gene', '1856', (94, 98))	('Dvl', 'Gene', '1855', (148, 151))	('Nrdp1', 'Gene', (114, 119))	('suppresses', 'NegReg', (45, 55))	('interferes', 'NegReg', (120, 130))
66020	28481871	To demonstrate that Nrdp1-mediated Vangl-dependent ubiquitination of Dvl is relevant in GBM cell lines, we sought to knockdown Vangl.	('Dvl', 'Gene', (69, 72))	('ubiquitination', 'MPA', (51, 65))	('Dvl', 'Gene', '1855', (69, 72))	('Nrdp1-mediated', 'Gene', (20, 34))	('Vangl', 'Chemical', '-', (127, 132))	('Vangl', 'Chemical', '-', (35, 40))	('knockdown', 'Var', (117, 126))
66022	28481871	S10A), and VANGL1 expression in these cell lines can be decreased with two independent shRNAs (Fig.	('S10A', 'Var', (0, 4))	('VANGL1', 'Gene', '81839', (11, 17))	('VANGL1', 'Gene', (11, 17))	('decreased', 'NegReg', (56, 65))	('expression', 'MPA', (18, 28))	('S10A', 'SUBSTITUTION', 'None', (0, 4))
66023	28481871	In T98G cells, VANGL1 knockdown significantly decreases Nrdp1-mediated Dvl2 ubiquitination (Figs.	('VANGL1', 'Gene', '81839', (15, 21))	('VANGL1', 'Gene', (15, 21))	('T98G', 'CellLine', 'CVCL:0556', (3, 7))	('knockdown', 'Var', (22, 31))	('Dvl2', 'Gene', (71, 75))	('decreases', 'NegReg', (46, 55))	('Dvl2', 'Gene', '1856', (71, 75))
66025	28481871	VANGL1 knockdown is sufficient to inhibit migration in A1207 and T98G cells (Fig.	('migration', 'CPA', (42, 51))	('VANGL1', 'Gene', (0, 6))	('T98G', 'CellLine', 'CVCL:0556', (65, 69))	('VANGL1', 'Gene', '81839', (0, 6))	('inhibit', 'NegReg', (34, 41))	('knockdown', 'Var', (7, 16))
66027	28481871	However, in the presence of Nrdp1, VANGL1 knockdown has no additional effect on cell migration, implying that Nrdp1 and Vangl1 regulate GBM migration through the same pathway.	('regulate', 'Reg', (127, 135))	('cell migration', 'CPA', (80, 94))	('VANGL1', 'Gene', (35, 41))	('VANGL1', 'Gene', '81839', (35, 41))	('Nrdp1', 'Gene', (110, 115))	('GBM migration', 'CPA', (136, 149))	('Vangl1', 'Gene', (120, 126))	('knockdown', 'Var', (42, 51))
66029	28481871	Although dysregulation of NRDP1, VANGL1 and WNT5A in GBM has been reported in small sample sizes, our study finds that in large, publicly available microarray datasets the collective dysregulation of Vangl-dependent non-canonical Wnt signaling components NRDP1, VANGL1, VANGL2, WNT5A and FZD7 is a nearly ubiquitous event in GBMs of all molecular subtypes and lower grade astrocytomas and oligodendrogliomas.	('FZD7', 'Gene', (288, 292))	('NRDP1', 'Gene', (255, 260))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (389, 407))	('Vangl', 'Chemical', '-', (200, 205))	('astrocytomas', 'Disease', (372, 384))	('VANGL1', 'Gene', (33, 39))	('WNT5A', 'Gene', '7474', (44, 49))	('WNT5A', 'Gene', (278, 283))	('VANGL1', 'Gene', '81839', (262, 268))	('VANGL2', 'Gene', (270, 276))	('oligodendrogliomas', 'Disease', (389, 407))	('VANGL2', 'Gene', '57216', (270, 276))	('astrocytomas', 'Disease', 'MESH:D001254', (372, 384))	('VANGL1', 'Gene', (262, 268))	('WNT5A', 'Gene', '7474', (278, 283))	('glioma', 'Phenotype', 'HP:0009733', (400, 406))	('dysregulation', 'Var', (183, 196))	('NRDP1', 'Gene', '10193', (26, 31))	('gliomas', 'Phenotype', 'HP:0009733', (400, 407))	('FZD7', 'Gene', '8324', (288, 292))	('NRDP1', 'Gene', '10193', (255, 260))	('VANGL1', 'Gene', '81839', (33, 39))	('WNT5A', 'Gene', (44, 49))	('NRDP1', 'Gene', (26, 31))
66030	28481871	The correlation of aberrant expression of these components with decreased patient survival is strong evidence that aberrant PCP activation promotes glioma cell invasiveness, the primary causes of relapse in GBM patients.	('patient', 'Species', '9606', (74, 81))	('patients', 'Species', '9606', (211, 219))	('glioma cell invasiveness', 'Disease', 'MESH:D005910', (148, 172))	('PCP', 'Gene', (124, 127))	('glioma cell invasiveness', 'Disease', (148, 172))	('PCP', 'Chemical', '-', (124, 127))	('activation promotes', 'PosReg', (128, 147))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('aberrant', 'Var', (115, 123))	('aberrant', 'Var', (19, 27))	('patient', 'Species', '9606', (211, 218))
66032	28481871	Upon pathway activation, Dvl binds to the negatively charged plasma membrane phospholipid PA via positively charged residues (K409, K456, R461, R464, K465, K472, K482) in the DEP domain; mutation of these lysine residues to glutamate reduces the PA binding ability of Dvl and Fzd-dependent membrane recruitment.	('K465', 'Var', (150, 154))	('reduces', 'NegReg', (234, 241))	('lysine', 'Chemical', 'MESH:D008239', (205, 211))	('K482', 'Chemical', '-', (162, 166))	('R464', 'Var', (144, 148))	('Dvl', 'Gene', (25, 28))	('K472', 'Chemical', '-', (156, 160))	('K456', 'Var', (132, 136))	('R461', 'Var', (138, 142))	('phospholipid', 'Chemical', 'MESH:D010743', (77, 89))	('K472', 'Var', (156, 160))	('Dvl', 'Gene', '1855', (268, 271))	('Fzd', 'Chemical', '-', (276, 279))	('K456', 'Chemical', '-', (132, 136))	('K465', 'Chemical', '-', (150, 154))	('PA', 'Chemical', 'MESH:D010712', (90, 92))	('Fzd-dependent membrane recruitment', 'MPA', (276, 310))	('K409', 'Var', (126, 130))	('Dvl', 'Gene', '1855', (25, 28))	('glutamate', 'Chemical', 'MESH:D018698', (224, 233))	('Dvl', 'Gene', (268, 271))	('K409', 'Chemical', '-', (126, 130))	('mutation', 'Var', (187, 195))	('PA', 'Chemical', 'MESH:D010712', (246, 248))	('K482', 'Var', (162, 166))
66035	28481871	The mutated lysine in the Dvl1-DEP-6KR mutant not in the polybasic face, K434, participates in canonical Wnt/beta-catenin signaling and likely does not contribute to Nrdp1-mediated negative regulation of Dvl.	('mutated', 'Var', (4, 11))	('lysine', 'Protein', (12, 18))	('DEP-6', 'Gene', (31, 36))	('lysine', 'Chemical', 'MESH:D008239', (12, 18))	('beta-catenin', 'Gene', (109, 121))	('Dvl', 'Gene', '1855', (26, 29))	('Dvl', 'Gene', (204, 207))	('Dvl', 'Gene', (26, 29))	('DEP-6', 'Gene', '64798', (31, 36))	('K434', 'Chemical', '-', (73, 77))	('participates', 'Reg', (79, 91))	('Dvl', 'Gene', '1855', (204, 207))	('beta-catenin', 'Gene', '1499', (109, 121))
66040	28481871	The HECT E3 ligase Huwe1 inhibits canonical Wnt signaling by preventing formation of Dvl oligomers via K63-linked polyubiquitination of Dvl, while the RING E3 ligase PDZRN3 promotes non-canonical Wnt signaling by K63-linked polyubiquitination of the DIX domain to regulate Dvl3-Fzd4 complex endocytosis.	('K63-linked', 'Var', (213, 223))	('Dvl3', 'Gene', '1857', (273, 277))	('Dvl', 'Gene', '1855', (136, 139))	('PDZRN3', 'Gene', (166, 172))	('canonical Wnt signaling', 'MPA', (34, 57))	('non-canonical Wnt signaling', 'MPA', (182, 209))	('preventing', 'NegReg', (61, 71))	('Dvl', 'Gene', (273, 276))	('promotes', 'PosReg', (173, 181))	('Huwe1', 'Gene', '10075', (19, 24))	('Dvl', 'Gene', '1855', (85, 88))	('Fzd4', 'Gene', (278, 282))	('formation', 'MPA', (72, 81))	('Huwe1', 'Gene', (19, 24))	('PDZRN3', 'Gene', '23024', (166, 172))	('Dvl', 'Gene', (136, 139))	('Dvl3', 'Gene', (273, 277))	('regulate', 'Reg', (264, 272))	('Dvl', 'Gene', (85, 88))	('Dvl', 'Gene', '1855', (273, 276))	('K63-linked', 'Var', (103, 113))	('inhibits', 'NegReg', (25, 33))	('Fzd4', 'Gene', '8322', (278, 282))
66042	28481871	Nrdp1 has been previously linked to cell polarity through its interaction with the Ser/Thr kinase MARK2 (Par-1b) in breast epithelial cells, where disrupting MARK2-dependent phosphorylation of Nrdp1 prevents proper apical-basal polarity.	('MARK2', 'Gene', (158, 163))	('Nrdp1', 'Gene', (0, 5))	('interaction', 'Interaction', (62, 73))	('disrupting', 'Var', (147, 157))	('Par-1b', 'Gene', '2011', (105, 111))	('Par-1b', 'Gene', (105, 111))	('linked', 'Reg', (26, 32))	('prevents', 'NegReg', (199, 207))	('MARK2', 'Gene', '2011', (98, 103))	('MARK2', 'Gene', (98, 103))	('Nrdp1', 'Gene', (193, 198))	('MARK2', 'Gene', '2011', (158, 163))
66046	28481871	In breast cancer, aberrant ErbB3 signaling is associated with loss of Nrdp1 protein despite unchanged mRNA levels.	('loss', 'NegReg', (62, 66))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('aberrant', 'Var', (18, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('ErbB3', 'Gene', (27, 32))	('Nrdp1', 'Gene', (70, 75))	('protein', 'Protein', (76, 83))	('ErbB3', 'Gene', '2065', (27, 32))	('mRNA levels', 'MPA', (102, 113))
66050	28481871	However, VANGL1 knockdown does not change NRDP1 transcript levels in GMB cell lines (Fig.	('NRDP1', 'Gene', (42, 47))	('knockdown', 'Var', (16, 25))	('NRDP1', 'Gene', '10193', (42, 47))	('VANGL1', 'Gene', '81839', (9, 15))	('VANGL1', 'Gene', (9, 15))	('transcript levels', 'MPA', (48, 65))
66053	28481871	In summary, this study is the first to demonstrate that Nrdp1 regulates Wnt signaling, and we propose that loss of Nrdp1 in aggressive GBM tumors contributes to aberrant activation of a Vangl-dependent non-canonical Wnt pathway to promote tumor invasion.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('promote', 'PosReg', (231, 238))	('activation', 'PosReg', (170, 180))	('Wnt', 'MPA', (72, 75))	('aggressive GBM tumors', 'Disease', 'MESH:D005910', (124, 145))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('loss', 'Var', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('aggressive GBM tumors', 'Disease', (124, 145))	('tumor', 'Disease', (139, 144))	('Nrdp1', 'Gene', (115, 120))	('Vangl-dependent non-canonical Wnt pathway', 'Pathway', (186, 227))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (239, 244))	('Vangl', 'Chemical', '-', (186, 191))
66056	28481871	HEK293T cells were from ATCC, and T98G, U87-MG, A1207, and U251 cells were gifts from Dr. Paul Knoepfler.	('U251', 'CellLine', 'CVCL:0021', (59, 63))	('U87-MG', 'Var', (40, 46))	('T98G', 'CellLine', 'CVCL:0556', (34, 38))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('T98G', 'Var', (34, 38))	('U87-MG', 'CellLine', 'CVCL:0022', (40, 46))
66058	28481871	Antibodies employed were anti-Vangl2 N-13, anti-Muc4 P-20, anti-Rac1, anti-EGFR (1005) from Santa Cruz, anti-FLAG M2, anti-tubulin, anti-actin AC-15 from Sigma, anti-HA 12CA5 for Ub-HA from Roche, anti-Myc 9E10 from Calbiochem, anti-V5 from Invitrogen, anti-RhoA from BD Biosciences, anti-FLRF/RNF41/Nrdp1 from Bethyl Laboratories, anti-HA C29F4 for Fzd7-HA western blots, anti-Dvl2, anti-phospho-JNK (T183/Y185), anti-phospho-Erk (T202/Y204), anti-phospho-Akt (S473), anti-phospho-beta-catenin (Ser33/37/Thr41), anti-phospho-beta-catenin (Ser552), and anti-beta-catenin from Cell Signaling.	('JNK', 'Gene', (397, 400))	('Dvl2', 'Gene', '1856', (378, 382))	('Myc', 'Gene', '4609', (202, 205))	('beta-catenin', 'Gene', (526, 538))	('JNK', 'Gene', '5599', (397, 400))	('beta-catenin', 'Gene', '1499', (526, 538))	('beta-catenin', 'Gene', (558, 570))	('beta-catenin', 'Gene', '1499', (558, 570))	('Erk', 'Gene', '2048', (427, 430))	('Rac1', 'Gene', '5879', (64, 68))	('Muc4', 'Gene', '4585', (48, 52))	('RNF41', 'Gene', (294, 299))	('P-20', 'Gene', (53, 57))	('RhoA', 'Gene', (258, 262))	('Akt', 'Gene', (457, 460))	('Muc4', 'Gene', (48, 52))	('Erk', 'Gene', (427, 430))	('Myc', 'Gene', (202, 205))	('T202/Y204', 'Var', (432, 441))	('beta-catenin', 'Gene', (482, 494))	('Akt', 'Gene', '207', (457, 460))	('Dvl2', 'Gene', (378, 382))	('T183/Y185', 'Var', (402, 411))	('RNF41', 'Gene', '10193', (294, 299))	('FLRF', 'Gene', '10193', (289, 293))	('P-20', 'Gene', '51673', (53, 57))	('beta-catenin', 'Gene', '1499', (482, 494))	('Rac1', 'Gene', (64, 68))	('RhoA', 'Gene', '387', (258, 262))	('FLRF', 'Gene', (289, 293))
66060	28481871	HA-tagged ubiquitin (#17608), HA-tagged K48R and K63R ubiquitin mutants (#17604 and #17606), Wnt5a (#35911), and mouse Fzd7 (#42259) were from Addgene.	('#35911', 'Var', (100, 106))	('K48R', 'Mutation', 'p.K48R', (40, 44))	('#17608', 'Var', (21, 27))	('K63R', 'Mutation', 'p.K63R', (49, 53))	('ubiquitin', 'Protein', (54, 63))	('K63R', 'Var', (49, 53))	('mouse', 'Species', '10090', (113, 118))	('#17604', 'Var', (73, 79))	('K48R', 'Var', (40, 44))
66061	28481871	K11 in HA-tagged ubiquitin was replaced with arginine using site-directed mutagenesis to generate the K11R mutant.	('K11', 'Var', (0, 3))	('K11R', 'Var', (102, 106))	('arginine', 'Chemical', 'MESH:D001120', (45, 53))	('K11R', 'SUBSTITUTION', 'None', (102, 106))
66064	28481871	K409, K434, K458, K465, K472, and K482 in FLAG-Dvl1 were replaced with arginines using site-directed mutagenesis to generate FLAG-Dvl1-DEP-6KR.	('arginines', 'Chemical', 'MESH:D001120', (71, 80))	('K472', 'Var', (24, 28))	('K434', 'Chemical', '-', (6, 10))	('K482', 'Chemical', '-', (34, 38))	('K465', 'Chemical', '-', (18, 22))	('K409', 'Var', (0, 4))	('K465', 'Var', (18, 22))	('DEP-6', 'Gene', (135, 140))	('K482', 'Var', (34, 38))	('DEP-6', 'Gene', '64798', (135, 140))	('K409', 'Chemical', '-', (0, 4))	('K434', 'Var', (6, 10))	('K472', 'Chemical', '-', (24, 28))	('K458', 'Chemical', '-', (12, 16))	('K458', 'Var', (12, 16))	('FLAG-Dvl1', 'Gene', (42, 51))
66070	28481871	Expression analysis was conducted using the REMBRANDT dataset (https://gdoc.georgetown.edu/gdoc/, access date: 07-06-2016) (X201962_s_at NRDP1, X229997_at VANGL1, X226029_at VANGL2, X213425_at WNT5A and X203706_s_at FZD7).	('VANGL2', 'Gene', (174, 180))	('X226029_at', 'Var', (163, 173))	('FZD7', 'Gene', '8324', (216, 220))	('NRDP1', 'Gene', (137, 142))	('FZD7', 'Gene', (216, 220))	('X213425_at', 'Var', (182, 192))	('VANGL1', 'Gene', (155, 161))	('WNT5A', 'Gene', (193, 198))	('VANGL2', 'Gene', '57216', (174, 180))	('VANGL1', 'Gene', '81839', (155, 161))	('NRDP1', 'Gene', '10193', (137, 142))	('X201962_s_at', 'Var', (124, 136))	('X203706_s_at', 'Var', (203, 215))	('WNT5A', 'Gene', '7474', (193, 198))
66072	28481871	Levels for VANGL1 (Hs01572998_m1), WNT5A (Hs00998537_m1), and NRDP1/RNF41 (Hs00195064_m1) were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH, 4352934E) levels for each sample.	('GAPDH', 'Gene', '2597', (151, 156))	('WNT5A', 'Gene', (35, 40))	('Hs00195064_m1', 'Var', (75, 88))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (109, 149))	('VANGL1', 'Gene', (11, 17))	('VANGL1', 'Gene', '81839', (11, 17))	('GAPDH', 'Gene', (151, 156))	('NRDP1', 'Gene', (62, 67))	('WNT5A', 'Gene', '7474', (35, 40))	('Hs01572998_m1', 'Var', (19, 32))	('NRDP1', 'Gene', '10193', (62, 67))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (109, 149))	('RNF41', 'Gene', '10193', (68, 73))	('Hs00998537_m1', 'Var', (42, 55))	('RNF41', 'Gene', (68, 73))
66091	28918048	Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo.	('TRAIL resistance', 'CPA', (83, 99))	('knockdown', 'Var', (49, 58))	('miR-1', 'Gene', '79187', (40, 45))	('133a', 'Chemical', '-', (44, 48))	('suppressed', 'NegReg', (72, 82))	('glioblastoma', 'Disease', (103, 115))	('miR-1', 'Gene', (40, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
66115	28918048	We also monitored the expression of death receptors DR4 and DR5, and the results showed DR5 was downregulated in M059J and M059K cells, whereas it was upregulated in A172 and T98G cells when compared with U87 cells (Figure 1C).	('T98G', 'CellLine', 'CVCL:0556', (175, 179))	('DR4', 'Gene', (52, 55))	('upregulated', 'PosReg', (151, 162))	('M059K', 'Var', (123, 128))	('DR5', 'Gene', (88, 91))	('downregulated', 'NegReg', (96, 109))	('DR4', 'Gene', '8797', (52, 55))	('M059J', 'Var', (113, 118))
66116	28918048	In addition, DR4 expression was decreased in A172 and T98G cells and no obvious change was seen in other cells when compared with U87 cells (Figure S2).	('A172', 'Var', (45, 49))	('expression', 'MPA', (17, 27))	('T98G', 'Var', (54, 58))	('DR4', 'Gene', '8797', (13, 16))	('DR4', 'Gene', (13, 16))	('T98G', 'CellLine', 'CVCL:0556', (54, 58))	('decreased', 'NegReg', (32, 41))
66117	28918048	Collectively, the expression of DR5, not DR4, positively correlated with TRAIL-induced apoptosis, suggesting that activating DR5 expression may be an effective strategy to lowering TRAIL resistance in GBM cells.	('DR5', 'Gene', (125, 128))	('TRAIL-induced apoptosis', 'CPA', (73, 96))	('correlated', 'Reg', (57, 67))	('DR4', 'Gene', '8797', (41, 44))	('lowering', 'NegReg', (172, 180))	('activating', 'Var', (114, 124))	('DR4', 'Gene', (41, 44))	('TRAIL resistance', 'MPA', (181, 197))
66122	28918048	As expected, the expression of all miRNAs was increased in M059J cells yet significantly decreased in A172 cells when compared with U87 cells, of which miR-133a showed the most dramatic change (Figure 1D).	('M059J', 'Var', (59, 64))	('133a', 'Chemical', '-', (156, 160))	('miR-1', 'Gene', (152, 157))	('increased', 'PosReg', (46, 55))	('expression', 'MPA', (17, 27))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', (152, 155))	('miR-1', 'Gene', '79187', (152, 157))	('decreased', 'NegReg', (89, 98))
66124	28918048	Co-transfection of miR-133a significantly suppressed the luciferase activity of the DR5-WT reporter, but not that of DR5-Mu reporter, in U87, A172, and M059J cells (Figure 2A).	('DR5-WT', 'Var', (84, 90))	('miR-1', 'Gene', '79187', (19, 24))	('luciferase', 'Enzyme', (57, 67))	('133a', 'Chemical', '-', (23, 27))	('miR-1', 'Gene', (19, 24))	('suppressed', 'NegReg', (42, 52))	('activity', 'MPA', (68, 76))
66126	28918048	Although miR-133a expression in M059J cells is much higher than that in A172 cells, the promoted effect of anti-miR-133a on luciferase activity in both cells was unobvious.	('miR-1', 'Gene', '79187', (112, 117))	('miR-1', 'Gene', (9, 14))	('133a', 'Chemical', '-', (116, 120))	('133a', 'Chemical', '-', (13, 17))	('miR-1', 'Gene', (112, 117))	('expression', 'MPA', (18, 28))	('higher', 'PosReg', (52, 58))	('M059J', 'Var', (32, 37))	('miR-1', 'Gene', '79187', (9, 14))
66137	28918048	Although the unspecific off-target effects are unavoidable, the modified miR-133a mimics used in this study could reduce the off-target effects.	('modified', 'Var', (64, 72))	('miR-1', 'Gene', (73, 78))	('133a', 'Chemical', '-', (77, 81))	('off-target effects', 'MPA', (125, 143))	('reduce', 'NegReg', (114, 120))	('miR-1', 'Gene', '79187', (73, 78))
66151	28918048	Moreover, P-IkappaBalpha expression was improved by DR5 knockdown in U87 and A172 cells (Figure 5D).	('IkappaBalpha', 'Gene', '4792', (12, 24))	('DR5', 'Gene', (52, 55))	('expression', 'MPA', (25, 35))	('IkappaBalpha', 'Gene', (12, 24))	('improved', 'PosReg', (40, 48))	('knockdown', 'Var', (56, 65))
66172	28918048	Aberrant expression of miRNA has been documented regarding its influence on drug resistance and carcinogenesis.	('Aberrant expression', 'Var', (0, 19))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('drug resistance', 'CPA', (76, 91))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('influence', 'Reg', (63, 72))	('carcinogenesis', 'Disease', (96, 110))
66191	28918048	Downregulated by miR-133a (Figure 2), DR5 directed TRAIL resistance, and its knockdown may protect glioma cells against TRAIL-induced apoptosis (Figure 5).	('DR5', 'Gene', (38, 41))	('knockdown', 'Var', (77, 86))	('glioma', 'Disease', (99, 105))	('Downregulated', 'NegReg', (0, 13))	('miR-1', 'Gene', '79187', (17, 22))	('protect', 'PosReg', (91, 98))	('TRAIL-induced apoptosis', 'CPA', (120, 143))	('133a', 'Chemical', '-', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('miR-1', 'Gene', (17, 22))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('TRAIL resistance', 'CPA', (51, 67))
66194	28918048	To elucidate the in vitro effect of miR-133a on TRAIL resistance, a xenograft mouse model was applied and the results revealed that Sh133a promoted the TRAIL-induced apoptosis, activated DR5 expression, and formed smaller xenografts (Figure 6).	('promoted', 'PosReg', (139, 147))	('DR5', 'Protein', (187, 190))	('133a', 'Chemical', '-', (40, 44))	('miR-1', 'Gene', '79187', (36, 41))	('activated', 'PosReg', (177, 186))	('133a', 'Chemical', '-', (134, 138))	('TRAIL-induced apoptosis', 'CPA', (152, 175))	('Sh133a', 'Var', (132, 138))	('miR-1', 'Gene', (36, 41))	('mouse', 'Species', '10090', (78, 83))
66198	28918048	Silence of this miRNA may sensitize glioma cells to TRAIL-induced apoptosis on GBM patients.	('glioma', 'Disease', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('sensitize', 'Reg', (26, 35))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('patients', 'Species', '9606', (83, 91))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('Silence', 'Var', (0, 7))
66237	28380429	Consistent with its role as a glioblastoma growth regulator, Ccl5 knockdown in M-GBM cells reduces M-GBM cell survival in vitro, and increases mouse glioblastoma survival in vivo.	('glioblastoma', 'Disease', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('mouse', 'Species', '10090', (143, 148))	('glioblastoma', 'Disease', (30, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (30, 42))	('Ccl5', 'Gene', '20304', (61, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('M-GBM cell survival', 'CPA', (99, 118))	('reduces', 'NegReg', (91, 98))	('increases', 'PosReg', (133, 142))	('Ccl5', 'Gene', (61, 65))	('knockdown', 'Var', (66, 75))
66247	28380429	Consistent with an ecosystem paradigm in which non-neoplastic cells attracted by cancer cells in turn support neoplastic cell growth, inhibition of chemokine expression or chemokine receptor function has been shown to attenuate both low-grade and high-grade glioma growth in numerous experimental preclinical model systems in vivo.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('inhibition', 'Var', (134, 144))	('glioma growth', 'Disease', (258, 271))	('glioma growth', 'Disease', 'MESH:D005910', (258, 271))	('glioma', 'Phenotype', 'HP:0009733', (258, 264))	('chemokine receptor', 'Gene', '7852', (172, 190))	('cancer', 'Disease', (81, 87))	('chemokine receptor', 'Gene', (172, 190))	('attenuate', 'NegReg', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('chemokine', 'Protein', (148, 157))
66250	28380429	Similarly, colony stimulating factor-1 (CSF-1) creates a supportive glioma microenvironment, such that silencing CSF-1-receptor signaling on macrophages is sufficient to reduce high-grade glioma growth in mice.	('silencing', 'Var', (103, 112))	('colony stimulating factor-1', 'Gene', (11, 38))	('glioma', 'Disease', 'MESH:D005910', (188, 194))	('glioma', 'Disease', (68, 74))	('CSF-1-receptor', 'Gene', (113, 127))	('colony stimulating factor-1', 'Gene', '12977', (11, 38))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('glioma growth', 'Disease', 'MESH:D005910', (188, 201))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('high-grade', 'Disease', (177, 187))	('CSF-1-receptor', 'Gene', '12978', (113, 127))	('CSF-1', 'Gene', (113, 118))	('CSF-1', 'Gene', '12977', (113, 118))	('glioma growth', 'Disease', (188, 201))	('reduce', 'NegReg', (170, 176))	('CSF-1', 'Gene', (40, 45))	('CSF-1', 'Gene', '12977', (40, 45))	('mice', 'Species', '10090', (205, 209))	('glioma', 'Disease', (188, 194))
66255	28380429	Since the NF1 protein, neurofibromin, functions as a negative regulator of RAS, specifically K-RAS in astroglial cells, and NF1 mutation/loss characterizes the mesenchymal GBM (M-GBM) molecular subtype, we sought to determine whether Ccl5 expression creates a unique autocrine circuit for mesenchymal glioblastoma growth.	('NF1', 'Gene', (124, 127))	('Ccl5', 'Gene', (234, 238))	('mutation/loss', 'Var', (128, 141))	('Ccl5', 'Gene', '20304', (234, 238))	('mesenchymal glioblastoma growth', 'Disease', (289, 320))	('NF1', 'Gene', '18015', (124, 127))	('NF1', 'Gene', '18015', (10, 13))	('mesenchymal glioblastoma growth', 'Disease', 'MESH:D005909', (289, 320))	('glioblastoma', 'Phenotype', 'HP:0012174', (301, 313))	('K-RAS', 'Gene', '16653', (93, 98))	('K-RAS', 'Gene', (93, 98))	('neurofibromin', 'Gene', '18015', (23, 36))	('NF1', 'Gene', (10, 13))	('neurofibromin', 'Gene', (23, 36))
66257	28380429	Leveraging Nf1-deficient murine M-GBM models, we further demonstrate that Ccl5 shRNA-mediated knockdown increases glioblastoma cell apoptosis in vitro, as well as extends mouse glioblastoma survival in vivo.	('glioblastoma', 'Disease', (177, 189))	('knockdown', 'Var', (94, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('Nf1', 'Gene', (11, 14))	('glioblastoma', 'Disease', 'MESH:D005909', (177, 189))	('increases', 'PosReg', (104, 113))	('extends', 'PosReg', (163, 170))	('Ccl5', 'Gene', '20304', (74, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('Nf1', 'Gene', '18015', (11, 14))	('glioblastoma', 'Disease', (114, 126))	('Ccl5', 'Gene', (74, 78))	('murine', 'Species', '10090', (25, 31))	('mouse', 'Species', '10090', (171, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
66263	28380429	This relative enrichment of CCL5 expression in the mesenchymal subtype, which frequently exhibits loss of function mutations in the NF1 tumor suppressor gene, prompted us to focus on murine models characterized by Nf1 loss.	('mutations', 'Var', (115, 124))	('murine', 'Species', '10090', (183, 189))	('loss of function', 'NegReg', (98, 114))	('Nf1', 'Gene', (214, 217))	('CCL5', 'Gene', (28, 32))	('NF1', 'Gene', '18015', (132, 135))	('Nf1', 'Gene', '18015', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('NF1', 'Gene', (132, 135))
66267	28380429	Next, we reduced Ccl5 levels in 1861 cells by shRNA-mediated knockdown (KD).	('knockdown', 'Var', (61, 70))	('reduced', 'NegReg', (9, 16))	('Ccl5', 'Gene', (17, 21))	('Ccl5', 'Gene', '20304', (17, 21))
66282	28380429	Expression of WT, but not mutant, NF1-GRD reduced Ccl5 levels in 1861 cells (Figure 4B), demonstrating that neurofibromin negatively regulates Ccl5 expression.	('reduced', 'NegReg', (42, 49))	('NF1', 'Gene', '18015', (34, 37))	('Ccl5', 'Gene', '20304', (143, 147))	('Ccl5', 'Gene', '20304', (50, 54))	('Ccl5', 'Gene', (50, 54))	('neurofibromin', 'Gene', (108, 121))	('neurofibromin', 'Gene', '18015', (108, 121))	('NF1', 'Gene', (34, 37))	('mutant', 'Var', (26, 32))	('Ccl5', 'Gene', (143, 147))
66286	28380429	In addition, AKT inhibition in 1861 cells reduced mTOR activity (Figure 4F, 4G), and mTOR inhibition using rapamycin (Figure 4F, 4G) reduced Ccl5 expression (Figure 4H).	('mTOR', 'Gene', '56717', (85, 89))	('reduced', 'NegReg', (42, 49))	('mTOR', 'Gene', (50, 54))	('Ccl5', 'Gene', (141, 145))	('Ccl5', 'Gene', '20304', (141, 145))	('inhibition', 'Var', (17, 27))	('AKT', 'Gene', '11651', (13, 16))	('mTOR', 'Gene', '56717', (50, 54))	('AKT', 'Gene', (13, 16))	('mTOR', 'Gene', (85, 89))	('rapamycin', 'Chemical', 'MESH:D020123', (107, 116))	('reduced', 'NegReg', (133, 140))
66288	28380429	As a complementary approach, we employed shRNA knockdown of Raptor, a molecule critical for the function of mTOR complex-1 (Figure 4I).	('mTOR', 'Gene', (108, 112))	('Raptor', 'Gene', '74370', (60, 66))	('Raptor', 'Gene', (60, 66))	('mTOR', 'Gene', '56717', (108, 112))	('knockdown', 'Var', (47, 56))
66302	28380429	Similarly, Ccl5 KD in Cd44 KD cells (Figure 6B) did not change cell growth (Figure 6C), establishing that the growth-promoting effects of Ccl5 require CD44 expression on M-GBM cells.	('Cd44', 'Gene', '12505', (22, 26))	('Ccl5', 'Gene', (11, 15))	('Ccl5', 'Gene', '20304', (11, 15))	('CD44', 'Var', (151, 155))	('Cd44', 'Gene', (22, 26))	('Ccl5', 'Gene', (138, 142))	('Ccl5', 'Gene', '20304', (138, 142))	('growth-promoting', 'MPA', (110, 126))
66305	28380429	We observed no further reduction of cell proliferation in Ccl5 KD cells following Cd44 knockdown (Figure 6D-6F), suggesting that this pro-survival pathway is specific to the interaction between Ccl5 and CD44, and is not regulated by other CD44 ligands.	('Ccl5', 'Gene', (58, 62))	('Ccl5', 'Gene', '20304', (58, 62))	('pro-survival pathway', 'Pathway', (134, 154))	('Cd44', 'Gene', '12505', (82, 86))	('Cd44', 'Gene', (82, 86))	('Ccl5', 'Gene', (194, 198))	('Ccl5', 'Gene', '20304', (194, 198))	('interaction', 'Interaction', (174, 185))	('knockdown', 'Var', (87, 96))
66317	28380429	First, one of the main CCL5 receptors, CCR5, is expressed in U87 and U251 glioblastoma cell lines, such that its knockdown inhibits U87 growth in nude mice.	('glioblastoma', 'Disease', (74, 86))	('CCR5', 'Gene', (39, 43))	('U87', 'Gene', (132, 135))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('U87', 'Gene', '641648', (132, 135))	('U251', 'CellLine', 'CVCL:0021', (69, 73))	('U87', 'Gene', (61, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('knockdown', 'Var', (113, 122))	('inhibits', 'NegReg', (123, 131))	('U87', 'Gene', '641648', (61, 64))	('nude mice', 'Species', '10090', (146, 155))
66323	28380429	CD44 expression is increased in GBM compared to low-grade gliomas and high levels of CD44 are associated with worse survival of GBM patients.	('expression', 'MPA', (5, 15))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('GBM', 'Disease', (32, 35))	('increased', 'PosReg', (19, 28))	('CD44', 'Gene', (0, 4))	('gliomas', 'Disease', (58, 65))	('gliomas', 'Phenotype', 'HP:0009733', (58, 65))	('high', 'Var', (70, 74))	('gliomas', 'Disease', 'MESH:D005910', (58, 65))	('patients', 'Species', '9606', (132, 140))
66324	28380429	Inhibiting CD44 function using monoclonal antibodies or RNA silencing reduced GBM growth in vivo and prolonged mouse survival.	('reduced', 'NegReg', (70, 77))	('Inhibiting', 'Var', (0, 10))	('mouse', 'Species', '10090', (111, 116))	('RNA', 'MPA', (56, 59))	('mouse survival', 'CPA', (111, 125))	('prolonged', 'PosReg', (101, 110))	('GBM growth in vivo', 'CPA', (78, 96))	('CD44', 'Protein', (11, 15))	('function', 'MPA', (16, 24))
66329	28380429	This pro-survival effect is specific to Ccl5, and does not appear to involve other CD44 ligands, since Cd44 knockdown in Ccl5 KD cells does not further reduce cell growth.	('knockdown', 'Var', (108, 117))	('Ccl5', 'Gene', (121, 125))	('Ccl5', 'Gene', '20304', (121, 125))	('Ccl5', 'Gene', (40, 44))	('Ccl5', 'Gene', '20304', (40, 44))	('Cd44', 'Gene', '12505', (103, 107))	('Cd44', 'Gene', (103, 107))
66333	28380429	For example, CD44 protects chronic lymphocytic leukemia cells from spontaneous and induced cell death by increasing expression of the MCL-1 pro-survival protein, while CD44 activation in breast cancer cells induces c-Jun mediated survival.	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('expression', 'MPA', (116, 126))	('increasing', 'PosReg', (105, 115))	('c-Jun', 'Gene', '16476', (215, 220))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (35, 55))	('CD44', 'Var', (13, 17))	('lymphocytic leukemia', 'Disease', (35, 55))	('activation', 'PosReg', (173, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (27, 55))	('induces', 'PosReg', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('c-Jun', 'Gene', (215, 220))	('MCL-1', 'Gene', (134, 139))	('CD44', 'Gene', (168, 172))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('MCL-1', 'Gene', '17210', (134, 139))	('breast cancer', 'Disease', (187, 200))
66334	28380429	It has been suggested in GBM that CD44 also inhibits the Hippo-mediated apoptotic signaling pathway to achieve resistance to reactive oxygen species- or cytotoxic agent-induced stress.	('Hippo-mediated apoptotic signaling pathway', 'Pathway', (57, 99))	('CD44', 'Var', (34, 38))	('Hippo', 'Chemical', '-', (57, 62))	('inhibits', 'NegReg', (44, 52))	('achieve', 'PosReg', (103, 110))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (125, 148))
66341	28380429	Third, pharmacological inhibition of RAS downstream effector activation (AKT/mTOR) suppressed Ccl5 expression in M-GBM cells.	('AKT', 'Gene', (73, 76))	('inhibition', 'Var', (23, 33))	('Ccl5', 'Gene', (94, 98))	('Ccl5', 'Gene', '20304', (94, 98))	('mTOR', 'Gene', '56717', (77, 81))	('mTOR', 'Gene', (77, 81))	('suppressed', 'NegReg', (83, 93))	('AKT', 'Gene', '11651', (73, 76))
66346	28380429	The regulation of chemokines by oncogenic signaling pathways suggests that other brain cancer-associated mutations might similarly modulate chemokine production.	('modulate', 'Reg', (131, 139))	('brain cancer', 'Phenotype', 'HP:0030692', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (105, 114))	('chemokine production', 'MPA', (140, 160))	('brain cancer', 'Disease', (81, 93))	('brain cancer', 'Disease', 'MESH:D001932', (81, 93))
66351	28380429	Since it is possible that attenuated Ccl5 expression alters the functional status of tumor-associated macrophages/microglia, current studies are focused on identifying potential changes in the tumor microenvironment conferred by reduced glioblastoma tumor cell Ccl5 production in vivo.	('alters', 'Reg', (53, 59))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (237, 249))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (237, 255))	('tumor', 'Disease', (250, 255))	('glioblastoma tumor', 'Disease', (237, 255))	('Ccl5', 'Gene', '20304', (261, 265))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('Ccl5', 'Gene', '20304', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('Ccl5', 'Gene', (261, 265))	('attenuated', 'Var', (26, 36))	('reduced', 'NegReg', (229, 236))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Ccl5', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
66374	28030802	Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies.	('translocation', 'Var', (134, 147))	('gene amplification', 'Var', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('activating', 'MPA', (109, 119))
66375	28030802	With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (55, 58))	('tied', 'Reg', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('FGF', 'Gene', (55, 58))	('aberrations', 'Var', (60, 71))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
66376	28030802	Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy.	('FGF', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (14, 17))
66379	28030802	As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('FGF', 'Gene', (102, 105))	('FGF', 'Gene', (136, 139))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (102, 105))	('inhibitors', 'Var', (107, 117))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
66382	28030802	We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (78, 81))	('FGF', 'Gene', (78, 81))	('inhibitors', 'Var', (83, 93))
66384	28030802	Many prior studies indicate that alterations in FGFR signaling are associated with a broad range of congenital craniofacial developmental disorders.	('congenital craniofacial developmental disorders', 'Disease', 'MESH:D019465', (100, 147))	('congenital craniofacial developmental disorders', 'Disease', (100, 147))	('alterations', 'Var', (33, 44))	('associated', 'Reg', (67, 77))	('FGF', 'Gene', (48, 51))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (48, 51))
66385	28030802	Relatively recently, we have come to understand that somatic mutations of FGFR also have a role in oncologic evolution which makes this pathway of interest when exploring the realm of cancer-directed therapy.	('cancer', 'Disease', (184, 190))	('FGF', 'Gene', (74, 77))	('oncologic evolution', 'Disease', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (61, 70))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (74, 77))	('role', 'Reg', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
66388	28030802	We ultimately need to re-evaluate how we can better develop strategies to bring direct FGFR inhibitors into the clinical setting.	('FGF', 'Gene', (87, 90))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (87, 90))	('inhibitors', 'Var', (92, 102))
66392	28030802	The members differ from one another in their ligand affinities and tissue distribution with variations in splicing of FGFR1-3 accounting for some additional diversity.	('ligand affinities', 'Interaction', (45, 62))	('FGFR1', 'Gene', '2260', (118, 123))	('variations', 'Var', (92, 102))	('FGFR1', 'Gene', (118, 123))
66395	28030802	Upon ligand binding, FGFRs dimerize and trigger a cascade of downstream signaling pathways, including the mitogen activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), the phosphoinositide-3-kinase (PI3K)/Akt pathways, and DAG-PKC and IP3-Ca2+ signaling branches via PLCgamma activation.	('dimerize', 'Var', (27, 35))	('IP3', 'Chemical', 'MESH:D015544', (271, 274))	('MAPK', 'Gene', (140, 144))	('Ca2+', 'Chemical', 'MESH:D000069285', (275, 279))	('trigger', 'Reg', (40, 47))	('PLCgamma', 'Enzyme', (303, 311))	('FGF', 'Gene', (21, 24))	('Akt', 'Gene', '207', (241, 244))	('activation', 'PosReg', (312, 322))	('binding', 'Interaction', (12, 19))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (21, 24))	('mitogen activated protein kinase', 'Pathway', (106, 138))	('MAPK', 'Gene', '5594', (140, 144))	('Akt', 'Gene', (241, 244))
66397	28030802	There are several proposed mechanisms for FGFR related oncogenesis including: (i) activating or "driver" mutations resulting in cell growth and survival; (ii) neo-angiogenesis; and (iii) acquired resistance to other cancer therapy.	('cell growth', 'CPA', (128, 139))	('oncogenesis', 'Disease', (55, 66))	('activating', 'PosReg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('neo-angiogenesis', 'CPA', (159, 175))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('FGF', 'Gene', (42, 45))	('acquired resistance', 'CPA', (187, 206))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (42, 45))
66399	28030802	Receptor overexpression can be a result of gene amplification or changes in post-transcriptional processing; point mutations may result in constitutive receptor activation or decreased sensitivity to ligand binding; translocations can produce fusion proteins with constitutive activity; and isoform switching and alternative splicing can reduce specificity to FGFs.	('overexpression', 'PosReg', (9, 23))	('point mutations', 'Var', (109, 124))	('sensitivity to ligand binding', 'MPA', (185, 214))	('result', 'Reg', (129, 135))	('fusion proteins', 'Protein', (243, 258))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (360, 363))	('specificity', 'MPA', (345, 356))	('changes', 'Reg', (65, 72))	('FGF', 'Gene', (360, 363))	('reduce', 'NegReg', (338, 344))	('alternative splicing', 'Var', (313, 333))	('activation', 'PosReg', (161, 171))	('constitutive', 'Protein', (139, 151))	('translocations', 'Var', (216, 230))	('post-transcriptional processing', 'MPA', (76, 107))	('decreased', 'NegReg', (175, 184))
66401	28030802	Using next generation sequencing (NGS) to detect FGFR anomalies, a comprehensive review of a cohort of nearly 5,000 cancer patients found aberrations in 7.1% of malignancies.	('anomalies', 'Disease', 'MESH:D000014', (54, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (49, 52))	('cancer', 'Disease', (116, 122))	('aberrations', 'Var', (138, 149))	('malignancies', 'Disease', (161, 173))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (123, 131))	('anomalies', 'Disease', (54, 63))	('FGF', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
66403	28030802	Amplification of the chromosomal region 8p11-12, the genomic location of FGFR1, has been detected in 10% of breast cancers (predominantly in estrogen receptor (ER) positive cancers) and this finding has been related to higher FGFR1 expression levels correlating to worse prognosis.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('FGFR1', 'Gene', '2260', (226, 231))	('estrogen receptor', 'Gene', (141, 158))	('ER', 'Gene', '2099', (160, 162))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('expression', 'MPA', (232, 242))	('FGFR1', 'Gene', (73, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('higher', 'PosReg', (219, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Disease', (173, 180))	('FGFR1', 'Gene', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('estrogen receptor', 'Gene', '2099', (141, 158))	('detected', 'Reg', (89, 97))	('Amplification', 'Var', (0, 13))	('FGFR1', 'Gene', '2260', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
66404	28030802	Recently, it has also been reported that FGFR1 is amplified in as many as 19% of squamous non-small cell lung cancers (SqCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (105, 117))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (94, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (90, 117))	('squamous non-small cell lung cancers', 'Disease', (81, 117))	('squamous non-small cell lung cancers', 'Disease', 'MESH:D002289', (81, 117))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('amplified', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))
66405	28030802	Moreover, preclinical studies have shown that a subset of FGFR1-amplified small cell lung cancer is extremely sensitive to FGFR inhibition by PD173074, a specific FGFR1 inhibitor.	('inhibition', 'NegReg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('PD173074', 'Var', (142, 150))	('FGFR1', 'Gene', '2260', (163, 168))	('FGFR1', 'Gene', '2260', (58, 63))	('FGF', 'Gene', (163, 166))	('FGF', 'Gene', (123, 126))	('small cell lung cancer', 'Disease', 'MESH:D055752', (74, 96))	('FGF', 'Gene', (58, 61))	('small cell lung cancer', 'Disease', (74, 96))	('FGFR1', 'Gene', (163, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (163, 166))	('FGFR1', 'Gene', (58, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (123, 126))	('PD173074', 'Chemical', 'MESH:C115711', (142, 150))	('sensitive', 'Reg', (110, 119))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (58, 61))
66406	28030802	FGFR1 amplifications have also been reported in oral squamous cell carcinoma, ovarian cancer, bladder cancer and rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', (113, 129))	('FGFR1', 'Gene', (0, 5))	('ovarian cancer', 'Disease', (78, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 76))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (113, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (113, 129))	('oral squamous cell carcinoma', 'Disease', (48, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('amplifications', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR1', 'Gene', '2260', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('reported', 'Reg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
66410	28030802	Amplification and activating mutations in FGFR4 have been identified in 7-8% of rhabdomyosarcoma patients and FGFR inhibitors are potentially effective in a rhabdomyosarcoma mouse model expressing mutated FGFR4.	('mutated', 'Var', (197, 204))	('activating', 'PosReg', (18, 28))	('FGF', 'Gene', (110, 113))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (42, 45))	('mouse', 'Species', '10090', (174, 179))	('FGF', 'Gene', (205, 208))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (110, 113))	('rhabdomyosarcoma', 'Disease', (80, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (205, 208))	('mutations', 'Var', (29, 38))	('rhabdomyosarcoma', 'Disease', (157, 173))	('patients', 'Species', '9606', (97, 105))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (80, 96))	('Amplification', 'Var', (0, 13))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (157, 173))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (80, 96))	('FGF', 'Gene', (42, 45))	('identified', 'Reg', (58, 68))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (157, 173))
66415	28030802	Inhibition of this axis is thus hypothesized to result in a disruption of bile acid homeostasis.	('bile acid homeostasis', 'MPA', (74, 95))	('result', 'Reg', (48, 54))	('bile acid', 'Chemical', 'MESH:D001647', (74, 83))	('Inhibition', 'Var', (0, 10))	('disruption', 'MPA', (60, 70))
66416	28030802	The same review mentioned above also noted that gene mutations and rearrangements affecting FGF/FGFR signaling were less common than amplification.	('FGF', 'Gene', (92, 95))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (92, 95))	('FGF', 'Gene', (96, 99))	('rearrangements', 'Var', (67, 81))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))
66417	28030802	Mutations in FGFR 2 are implicated in a broad spectrum of malignant disease.	('malignant disease', 'Disease', 'MESH:D009369', (58, 75))	('FGFR 2', 'Gene', (13, 19))	('FGFR 2', 'Gene', '2263', (13, 19))	('Mutations', 'Var', (0, 9))	('malignant disease', 'Disease', (58, 75))	('implicated', 'Reg', (24, 34))
66418	28030802	Mutations are present in 12% of endometrial carcinomas and FGFR2 mutant endometrial cancer cell lines are highly sensitive to FGFR tyrosine kinase inhibitors, implicating FGFR2 as an innovative therapeutic target in endometrial carcinoma.	('FGFR2', 'Gene', (59, 64))	('endometrial cancer', 'Disease', (72, 90))	('sensitive', 'MPA', (113, 122))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('FGFR2', 'Gene', '2263', (171, 176))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (32, 54))	('endometrial carcinoma', 'Disease', (216, 237))	('FGFR2', 'Gene', '2263', (59, 64))	('mutant', 'Var', (65, 71))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('FGF', 'Gene', (126, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (216, 237))	('tyrosine', 'Chemical', 'MESH:D014443', (131, 139))	('FGF', 'Gene', (171, 174))	('FGF', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (126, 129))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (32, 53))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (216, 237))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('endometrial carcinomas', 'Disease', (32, 54))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (32, 53))	('FGFR2', 'Gene', (171, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (171, 174))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (59, 62))
66419	28030802	Also, approximately 10% of cases of gastric cancer are associated with FGFR2 amplification and/or mutation; in particular amplification is suggestive of a poor prognosis and more widespread disease.	('mutation', 'Var', (98, 106))	('gastric cancer', 'Disease', (36, 50))	('associated', 'Reg', (55, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('amplification', 'Var', (77, 90))	('amplification', 'Var', (122, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
66420	28030802	Gastric cancer cell lines with FGFR2 amplifications show evidence of ligand-independent signaling and are highly sensitive to FGFR inhibitors.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (126, 129))	('cancer', 'Disease', (8, 14))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (31, 34))	('ligand-independent signaling', 'MPA', (69, 97))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGF', 'Gene', (126, 129))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('FGF', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('amplifications', 'Var', (37, 51))
66421	28030802	In breast cancer, single nucleotide polymorphisms (SNPs) in FGFR2 were found to be strongly associated with evidence of postmenopausal disease.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('postmenopausal disease', 'Phenotype', 'HP:0008209', (120, 142))	('postmenopausal disease', 'Disease', (120, 142))	('single nucleotide polymorphisms', 'Var', (18, 49))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('associated', 'Reg', (92, 102))
66422	28030802	FGFR2 amplification is also detected in 5% of triple-negative breast cancers, providing the possibility of specific targeted therapy when many other options are less efficacious by the nature of the disease profile.	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('detected', 'Reg', (28, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
66423	28030802	Recently, several novel FGFR2 mutations have been identified in lung cancer, both in cases of adenocarcinoma and squamous cell carcinoma.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('FGFR2', 'Gene', '2263', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('identified', 'Reg', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('FGFR2', 'Gene', (24, 29))
66426	28030802	As aforementioned, FGFR mutations do not always result in "driver" mutations alone.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (19, 22))	('mutations', 'Var', (24, 33))	('FGF', 'Gene', (19, 22))	('result', 'Reg', (48, 54))
66427	28030802	As seen 10% of melanoma, missense mutations of FGFR2 have been identified in BRAF-inhibitor treatment resistance.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('BRAF', 'Gene', '673', (77, 81))	('identified', 'Reg', (63, 73))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (77, 81))	('treatment resistance', 'MPA', (92, 112))	('missense mutations', 'Var', (25, 43))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))
66428	28030802	FGFR3 mutations are found in approximately 70% of non-muscle-invasive bladder cancers and 10-20% of invasive bladder cancers.	('invasive bladder', 'Phenotype', 'HP:0100645', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (61, 85))	('bladder cancers', 'Phenotype', 'HP:0009725', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('FGFR3', 'Gene', (0, 5))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (100, 124))	('invasive bladder', 'Phenotype', 'HP:0100645', (100, 116))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('invasive bladder cancers', 'Disease', (61, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (50, 77))	('found', 'Reg', (20, 25))	('invasive bladder cancers', 'Disease', (100, 124))	('bladder cancers', 'Phenotype', 'HP:0009725', (109, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('mutations', 'Var', (6, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
66429	28030802	The presence of an FGFR3 mutation strongly relates to low-grade, non-muscle-invasive tumors with a better prognosis, however the clinical viability of FGFR3 as a target for cancer directed therapy in this population is unclear and remains controversial.	('relates', 'Reg', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('low-grade', 'Disease', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (173, 179))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('FGFR3', 'Gene', (19, 24))	('tumors', 'Disease', (85, 91))
66430	28030802	Interestingly, in patients with non-invasive bladder cancer after resection, the presence of an FGFR3 mutation in cells obtained from urinalysis at routine follow-up was predictive of disease recurrence.	('mutation', 'Var', (102, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FGFR3', 'Gene', (96, 101))	('patients', 'Species', '9606', (18, 26))	('presence', 'Var', (81, 89))	('invasive bladder', 'Phenotype', 'HP:0100645', (36, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
66431	28030802	FGFR3 mutations have also been identified in many other cancer types, including 3% of squamous cell lung carcinoma, cervical cancers, multiple myeloma, prostate cancer and spermatocytic seminomas.	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (172, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell lung carcinoma', 'Disease', (86, 114))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (56, 62))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (172, 195))	('multiple myeloma', 'Disease', 'MESH:D009101', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('cancer', 'Disease', (125, 131))	('mutations', 'Var', (6, 15))	('spermatocytic seminomas', 'Disease', (172, 195))	('multiple myeloma', 'Disease', (134, 150))	('prostate cancer', 'Disease', (152, 167))	('identified', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cervical cancers', 'Disease', (116, 132))	('cervical cancers', 'Disease', 'MESH:D002583', (116, 132))	('FGFR3', 'Gene', (0, 5))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('multiple myeloma', 'Phenotype', 'HP:0006775', (134, 150))
66432	28030802	In head and neck squamous cell carcinoma (HNSCC) that was positive for human papilloma virus (HPV, 42.5% of 120 tumor samples), genomic analysis using parallel sequencing technology revealed nearly 18% of tumors with mutations in FGFR2 or FGFR 3, which was notably different than in HPV negative samples.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('HPV', 'Species', '10566', (283, 286))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('papilloma', 'Phenotype', 'HP:0012740', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', (205, 211))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('FGFR2', 'Gene', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('human papilloma virus', 'Species', '10566', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('FGFR 3', 'Gene', '2261', (239, 245))	('FGFR2', 'Gene', '2263', (230, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('FGFR 3', 'Gene', (239, 245))	('HPV', 'Species', '10566', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (205, 210))	('mutations', 'Var', (217, 226))
66433	28030802	Interestingly, HPV negative cases that had FGFR3 mutations were not as responsive to FGFR inhibition as the single HPV positive case studied, suggesting further need for study in HNSCC based on HPV status.	('mutations', 'Var', (49, 58))	('FGF', 'Gene', (43, 46))	('FGF', 'Gene', (85, 88))	('HPV', 'Species', '10566', (15, 18))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (43, 46))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (85, 88))	('HPV', 'Species', '10566', (194, 197))	('HPV', 'Species', '10566', (115, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))
66434	28030802	FGFR3-activating mutations are also found at a high frequency in epidermal nevi and seborrhoeic keratosis, which are benign skin conditions and do not progress to malignancy.	('seborrhoeic keratosis', 'Phenotype', 'HP:0031287', (84, 105))	('seborrhoeic keratosis', 'Disease', 'MESH:D007642', (84, 105))	('FGFR3-activating', 'Gene', (0, 16))	('epidermal nevi', 'Phenotype', 'HP:0010816', (65, 79))	('malignancy', 'Disease', 'MESH:D009369', (163, 173))	('epidermal nevi', 'Disease', (65, 79))	('malignancy', 'Disease', (163, 173))	('seborrhoeic keratosis', 'Disease', (84, 105))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('mutations', 'Var', (17, 26))
66437	28030802	In a comprehensive survey of gene fusions across different solid tumor histologies, the authors described a wide-ranging distribution of FGFR1, FGFR2, and FGFR3 fusions across 8 of 20 tumor types analyzed.	('FGFR2', 'Gene', '2263', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('FGFR1', 'Gene', (137, 142))	('tumor', 'Disease', (184, 189))	('FGFR3', 'Gene', (155, 160))	('FGFR1', 'Gene', '2260', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('fusions', 'Var', (161, 168))	('FGFR2', 'Gene', (144, 149))
66442	28030802	Pre-clinical evidence suggests that FGFR inhibitors are able to reduce growth and induce apoptosis in cell lines harboring FGFR1 gene rearrangements.	('rearrangements', 'Var', (134, 148))	('induce', 'Reg', (82, 88))	('FGF', 'Gene', (36, 39))	('reduce', 'NegReg', (64, 70))	('apoptosis', 'CPA', (89, 98))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (36, 39))	('FGF', 'Gene', (123, 126))	('FGFR1', 'Gene', (123, 128))	('growth', 'CPA', (71, 77))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (123, 126))	('reduce growth', 'Phenotype', 'HP:0001510', (64, 77))	('FGFR1', 'Gene', '2260', (123, 128))
66443	28030802	Intrahepatic cholangiocarcinoma demonstrates FGFR2 fusions in 13.6% of cases that are mutually exclusive with KRAS/BRAF mutations, and in vivo cellular studies confirm the oncogenic potential of this aberration.	('BRAF', 'Gene', '673', (115, 119))	('Intrahepatic cholangiocarcinoma', 'Disease', (0, 31))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 31))	('FGFR2', 'Gene', (45, 50))	('BRAF', 'Gene', (115, 119))	('FGFR2', 'Gene', '2263', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('fusions', 'Var', (51, 58))
66447	28030802	Fusion aberrations have been described in FGFR 1-3 genes with multiple partners (examples include TACC1, TACC2, TACC3, BAIAP2L1, NPM1, AFF3) across a wide spectrum of tumor histologies.	('NPM1', 'Gene', (129, 133))	('TACC1', 'Gene', (98, 103))	('TACC2', 'Gene', '10579', (105, 110))	('TACC2', 'Gene', (105, 110))	('FGFR 1', 'Gene', (42, 48))	('BAIAP2L1', 'Gene', (119, 127))	('Fusion aberrations', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('NPM1', 'Gene', '4869', (129, 133))	('FGFR 1', 'Gene', '2260', (42, 48))	('BAIAP2L1', 'Gene', '55971', (119, 127))	('TACC1', 'Gene', '6867', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('AFF3', 'Gene', (135, 139))	('tumor', 'Disease', (167, 172))	('AFF3', 'Gene', '3899', (135, 139))
66448	28030802	The TACC3 gene (transforming acidic coiled-coil containing protein) was first identified as a component of FGFR3-TACC3 fusion in glioblastoma multiforme (GBM) and bladder urothelial tumors, this fusion protein is constitutively active and has been shown to affect mitosis by altering chromosomal segregation patterns.	('affect', 'Reg', (257, 263))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('glioblastoma multiforme', 'Disease', (129, 152))	('altering', 'Reg', (275, 283))	('bladder urothelial tumors', 'Disease', (163, 188))	('fusion', 'Var', (119, 125))	('bladder urothelial tumors', 'Disease', 'MESH:D001749', (163, 188))	('mitosis', 'Disease', 'None', (264, 271))	('chromosomal segregation patterns', 'CPA', (284, 316))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('FGFR3-TACC3', 'Gene', (107, 118))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (129, 152))	('bladder urothelial tumors', 'Phenotype', 'HP:0009725', (163, 188))	('mitosis', 'Disease', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
66449	28030802	In an analysis of nearly 600 cases of lung adenocarcinoma patients without any smoking history, investigators found an FGFR3-TACC3 fusion in a tissue sample from a patient that previously did not have any known oncogenic alteration.	('FGFR3-TACC3', 'Gene', (119, 130))	('patients', 'Species', '9606', (58, 66))	('patient', 'Species', '9606', (58, 65))	('patient', 'Species', '9606', (164, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('fusion', 'Var', (131, 137))	('lung adenocarcinoma', 'Disease', (38, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
66451	28030802	In vitro, these cells with an FGFR3-TACC3 fusion demonstrated sensitivity to pan-FGFR inhibitors, suggesting a possible subset of lung adenocarcinoma patients that may benefit from targeting this pathway.	('FGF', 'Gene', (81, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('FGF', 'Gene', (30, 33))	('fusion', 'Var', (42, 48))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (30, 33))	('patients', 'Species', '9606', (150, 158))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (81, 84))	('lung adenocarcinoma', 'Disease', (130, 149))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
66452	28030802	It is also worth mentioning that we described the first 3 cases of cervical cancer harboring the FGFR-TACC3 fusion, noting that one patient received treatment with FGFR targeted therapy and achieved stable disease for 4 cycles.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FGF', 'Gene', (164, 167))	('fusion', 'Var', (108, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (164, 167))	('patient', 'Species', '9606', (132, 139))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FGF', 'Gene', (97, 100))
66453	28030802	However, ligand-dependent signaling may also occur and would suggest that ectopic expression of FGFs can promote cancer.	('promote', 'PosReg', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('ectopic expression', 'Var', (74, 92))	('FGF', 'Gene', (96, 99))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
66458	28030802	Early development of FGFR inhibitors exhibits antitumor activity and present very specific toxicity profiles.	('inhibitors', 'Var', (26, 36))	('FGF', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (21, 24))	('toxicity', 'Disease', (91, 99))	('tumor', 'Disease', (50, 55))
66459	28030802	Prior studies also indicate that FGFR inhibitors enhance tumor sensitivity to conventional anticancer drugs such as 5-fluorouracil, irinotecan, paclitaxel, and etoposide in human cancer cells acquiring anti-apoptotic potential based on aberrant FGFR activation.	('irinotecan', 'Chemical', 'MESH:D000077146', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('FGF', 'Gene', (33, 36))	('activation', 'PosReg', (250, 260))	('FGF', 'Gene', (245, 248))	('cancer', 'Disease', (95, 101))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (33, 36))	('inhibitors', 'Var', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (57, 62))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('human', 'Species', '9606', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('etoposide', 'Chemical', 'MESH:D005047', (160, 169))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (116, 130))	('enhance', 'PosReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Disease', (179, 185))
66468	28030802	Pan-FGFR inhibitors such as lenvatinib (E7080), ponatinib (AP24534), regorafenib (BAY 73-4506), dovitinib (TKI258), lucitanib (E3810), cediranib (AZD2171), intedanib (BIBF 1120), brivanib (BMS-540215), and others are currently being studied in clinical trials.	('intedanib', 'Chemical', 'MESH:C530716', (156, 165))	('AP24534', 'Chemical', 'MESH:C545373', (59, 66))	('brivanib', 'Chemical', 'MESH:C509922', (179, 187))	('lucitanib', 'Chemical', 'MESH:C000595232', (116, 125))	('cediranib', 'Chemical', 'MESH:C500926', (135, 144))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (4, 7))	('AZD2171', 'Chemical', 'MESH:C500926', (146, 153))	('regorafenib', 'Chemical', 'MESH:C559147', (69, 80))	('E7080', 'Chemical', 'MESH:C531958', (40, 45))	('BAY 73-4506', 'Chemical', 'MESH:C559147', (82, 93))	('TKI258', 'Chemical', 'MESH:C500007', (107, 113))	('FGF', 'Gene', (4, 7))	('dovitinib', 'Chemical', 'MESH:C500007', (96, 105))	('lenvatinib', 'Chemical', 'MESH:C531958', (28, 38))	('E7080', 'Var', (40, 45))	('E3810', 'Var', (127, 132))	('ponatinib', 'Chemical', 'MESH:C545373', (48, 57))	('BIBF', 'Chemical', '-', (167, 171))
66475	28030802	Interestingly, despite the high potency against FGFRs, one Phase II trial in advanced urothelial carcinoma using dovitinib to treat FGFR3 mutated versus FGFR wild-type cancer failed to show a meaningful overall response rate and the study was terminated after concluding that dovitinib has limited single-agent activity in this population.	('FGF', 'Gene', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('dovitinib', 'Chemical', 'MESH:C500007', (276, 285))	('FGF', 'Gene', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutated', 'Var', (138, 145))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (132, 135))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (86, 106))	('dovitinib', 'Chemical', 'MESH:C500007', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (153, 156))	('cancer', 'Disease', (168, 174))	('FGF', 'Gene', (48, 51))	('urothelial carcinoma', 'Disease', (86, 106))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (48, 51))
66478	28030802	Lenvatinib (E7080, Eisai) is another multikinase inhibitor, inhibiting FGFR1-4 as well as VEGFR1-3, RET, KIT and PDGFR-beta.	('inhibiting', 'NegReg', (60, 70))	('RET', 'Gene', '5979', (100, 103))	('FGFR1', 'Gene', (71, 76))	('PDGFR-beta', 'Gene', (113, 123))	('VEGFR1', 'Gene', '2321', (90, 96))	('KIT', 'Gene', (105, 108))	('FGFR1', 'Gene', '2260', (71, 76))	('E7080', 'Chemical', 'MESH:C531958', (12, 17))	('VEGFR1', 'Gene', (90, 96))	('RET', 'Gene', (100, 103))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('E7080', 'Var', (12, 17))	('PDGFR-beta', 'Gene', '5159', (113, 123))
66491	28030802	Ongoing Phase II/III clinical trials include a comparison of lenvatinib with sorafenib in hepatocellular carcinoma (NCT01761266), lenvatinib with everolimus in renal cell carcinoma (NCT02454478), and as monotherapy in unresectable biliary cancer (NCT02579616).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('biliary cancer', 'Disease', (231, 245))	('lenvatinib', 'Chemical', 'MESH:C531958', (61, 71))	('renal cell carcinoma', 'Disease', (160, 180))	('hepatocellular carcinoma', 'Disease', (90, 114))	('NCT01761266', 'Var', (116, 127))	('everolimus', 'Chemical', 'MESH:D000068338', (146, 156))	('lenvatinib', 'Chemical', 'MESH:C531958', (130, 140))	('biliary cancer', 'Disease', 'MESH:D001661', (231, 245))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('sorafenib', 'Chemical', 'MESH:D000077157', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
66496	28030802	These include compounds like AZD4547, BGJ398, JNJ42756493, and PD173074.	('BGJ398', 'Var', (38, 44))	('JNJ42756493', 'Var', (46, 57))	('PD173074', 'Var', (63, 71))	('AZD4547', 'Var', (29, 36))	('PD173074', 'Chemical', 'MESH:C115711', (63, 71))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('JNJ42756493', 'Chemical', 'MESH:C000604580', (46, 57))	('BGJ398', 'Chemical', 'MESH:C568950', (38, 44))
66497	28030802	AZD4547 is a small-molecule compound that is a selective FGFR (FGFR 1-3) inhibitor, delivered orally in capsule form.	('FGFR 1', 'Gene', '2260', (63, 69))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (63, 66))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGF', 'Gene', (57, 60))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (57, 60))	('FGF', 'Gene', (63, 66))	('FGFR 1', 'Gene', (63, 69))	('AZD4547', 'Var', (0, 7))
66499	28030802	Oral administration of AZD4547 has also resulted in prolonged survival of FGFR3-TACC3-transformed glioma xenografts by 28 days compared with mice treated with the vehicle control.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('prolonged', 'PosReg', (52, 61))	('survival', 'CPA', (62, 70))	('FGFR3-TACC3-transformed', 'Gene', (74, 97))	('mice', 'Species', '10090', (141, 145))	('AZD4547', 'Var', (23, 30))	('glioma', 'Disease', (98, 104))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))
66500	28030802	Furthermore, inhibition with AZD4547 resulted in a significant dose-dependent tumor growth inhibition and survival of gastric cancer carrying an FGFR2 gene amplification both in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (118, 132))	('FGFR2', 'Gene', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('survival', 'CPA', (106, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('FGFR2', 'Gene', '2263', (145, 150))	('AZD4547', 'Var', (29, 36))	('inhibition', 'NegReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('tumor', 'Disease', (78, 83))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))
66501	28030802	Other pre-clinical studies on xenograft models transplanted with transformed cells derived from FGFR1 amplified NSCLC cancer patients have shown that AZD4547 stops tumor growth and promotes regression.	('tumor', 'Disease', (164, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('stops', 'NegReg', (158, 163))	('NSCLC cancer', 'Disease', (112, 124))	('regression', 'CPA', (190, 200))	('promotes', 'PosReg', (181, 189))	('AZD4547', 'Var', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('FGFR1', 'Gene', (96, 101))	('FGFR1', 'Gene', '2260', (96, 101))	('NSCLC cancer', 'Disease', 'MESH:D009369', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (150, 157))	('patients', 'Species', '9606', (125, 133))
66504	28030802	The increase in serum phosphate concentration observed in this phase I study provides evidence that AZD4547 at this dose leads to pharmacologic target inhibition.	('pharmacologic target inhibition', 'MPA', (130, 161))	('AZD4547', 'Var', (100, 107))	('AZD4547', 'Chemical', 'MESH:C572463', (100, 107))	('increase in serum phosphate concentration', 'Phenotype', 'HP:0002905', (4, 45))	('serum phosphate concentration', 'MPA', (16, 45))	('phosphate', 'Chemical', 'MESH:D010710', (22, 31))	('increase', 'PosReg', (4, 12))	('increase in serum phosphate', 'Phenotype', 'HP:0002905', (4, 31))
66506	28030802	Expansion cohorts to further assess safety and tolerability required tumors with FGFR 1 amplification as confirmed through FISH (FGFR: Centromeric ratio >= 2).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FGF', 'Gene', (81, 84))	('FGF', 'Gene', (129, 132))	('amplification', 'Var', (88, 101))	('FGFR 1', 'Gene', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('FGFR 1', 'Gene', '2260', (81, 87))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (81, 84))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (129, 132))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
66507	28030802	In a cohort of 15 patients with FGFR1 amplified SqCLC, the most common adverse events (AEs) were dermatologic and GI related.	('amplified', 'Var', (38, 47))	('FGFR1', 'Gene', (32, 37))	('SqCLC', 'MPA', (48, 53))	('FGFR1', 'Gene', '2260', (32, 37))	('patients', 'Species', '9606', (18, 26))	('AEs', 'Chemical', '-', (87, 90))
66512	28030802	Of note, partial response (PR, by RECIST criteria) was observed in tumors with a high burden of FGFR aberration including one SqCLC patient with FGFR1 amplification and another patient with FGFR2 amplified gastroesophageal cancer.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (145, 148))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('gastroesophageal cancer', 'Disease', (206, 229))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (206, 229))	('FGF', 'Gene', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR1', 'Gene', '2260', (145, 150))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (190, 193))	('FGFR2', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FGF', 'Gene', (145, 148))	('patient', 'Species', '9606', (132, 139))	('tumors', 'Disease', (67, 73))	('FGFR2', 'Gene', '2263', (190, 195))	('FGF', 'Gene', (96, 99))	('FGFR1', 'Gene', (145, 150))	('patient', 'Species', '9606', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('amplification', 'Var', (151, 164))
66514	28030802	AZD4547 is currently under a Phase II clinical trial to assess its activity in patients with FGFR1 or FGFR2 amplified breast, squamous lung, and stomach cancer whose cancers have progressed following previous chemotherapy (NCT01795768).	('cancers', 'Disease', (166, 173))	('stomach cancer', 'Disease', 'MESH:D013274', (145, 159))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('amplified', 'Var', (108, 117))	('stomach cancer', 'Phenotype', 'HP:0012126', (145, 159))	('stomach cancer', 'Disease', (145, 159))	('squamous lung', 'Disease', (126, 139))	('breast', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('patients', 'Species', '9606', (79, 87))	('FGFR1', 'Gene', (93, 98))	('FGFR2', 'Gene', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('squamous lung', 'Disease', 'MESH:D002294', (126, 139))	('FGFR1', 'Gene', '2260', (93, 98))	('FGFR2', 'Gene', '2263', (102, 107))
66515	28030802	285 patients with advanced cancer were screened, identifying FGFR1 amplification in 18% (20/111) HER2 negative breast cancer, 9.5% (4/42) NSCLC, and FGFR2 amplification in 7.6% (10/132) gastroesophageal (GC).	('negative', 'NegReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('HER2', 'Gene', '2064', (97, 101))	('FGFR1', 'Gene', '2260', (61, 66))	('FGFR2', 'Gene', '2263', (149, 154))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('gastroesophageal', 'Disease', 'MESH:D005764', (186, 202))	('breast cancer', 'Disease', (111, 124))	('gastroesophageal', 'Disease', (186, 202))	('amplification', 'Var', (155, 168))	('amplification', 'Var', (67, 80))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('HER2', 'Gene', (97, 101))	('cancer', 'Disease', (118, 124))	('FGFR1', 'Gene', (61, 66))	('NSCLC', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('FGFR2', 'Gene', (149, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
66521	28030802	A recently completed Phase II trial aimed to evaluate the safety and efficacy of AZD4547 versus paclitaxel in advanced gastric or gastro-oesophageal junction cancer; no results have been reported (NTC01457846).	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastro-oesophageal junction cancer', 'Disease', (130, 164))	('AZD4547', 'Var', (81, 88))	('gastro-oesophageal junction cancer', 'Disease', 'MESH:D005764', (130, 164))	('AZD4547', 'Chemical', 'MESH:C572463', (81, 88))	('advanced gastric', 'Disease', (110, 126))
66522	28030802	AZD4547 is also undergoing a Phase I/II clinical trial in combination with fulvestrant versus fulvestrant alone in ER+ breast cancer patients with FGFR1 amplification (NTC01202591).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('breast cancer', 'Disease', (119, 132))	('fulvestrant', 'Chemical', 'MESH:D000077267', (94, 105))	('patients', 'Species', '9606', (133, 141))	('amplification', 'Var', (153, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('ER', 'Gene', '2099', (115, 117))	('FGFR1', 'Gene', (147, 152))	('FGFR1', 'Gene', '2260', (147, 152))	('fulvestrant', 'Chemical', 'MESH:D000077267', (75, 86))
66524	28030802	Of the 94 enrolled patients initially, partial responses were seen in 4 FGFR3 mutated bladder cancers, 2 FGFR1 amplified SqCLC, and a reduction in tumor burden was seen in FGFR2 fusion cholangiocarcinoma as well as in FGFR1 amplified breast cancer.	('FGFR1', 'Gene', (105, 110))	('FGFR2', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('mutated', 'Var', (78, 85))	('tumor', 'Disease', (147, 152))	('FGFR2', 'Gene', '2263', (172, 177))	('cholangiocarcinoma', 'Disease', (185, 203))	('FGFR1', 'Gene', '2260', (218, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('patients', 'Species', '9606', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('bladder cancers', 'Phenotype', 'HP:0009725', (86, 101))	('breast cancer', 'Disease', (234, 247))	('FGFR1', 'Gene', '2260', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('FGFR1', 'Gene', (218, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('reduction', 'NegReg', (134, 143))	('bladder cancers', 'Disease', 'MESH:D001749', (86, 101))	('FGFR3', 'Gene', (72, 77))	('bladder cancers', 'Disease', (86, 101))
66525	28030802	Investigators used FISH to screen for FGFR1 amplification, and in the cohort of 17 SqCLC (expansion arm) patients there were 4/17 PRs (2 after data cutoff date) and 3 patients with SD.	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (167, 175))	('PRs', 'Disease', (130, 133))	('amplification', 'Var', (44, 57))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('SD', 'Chemical', '-', (181, 183))
66529	28030802	Trials that are actively recruiting for study of BGJ398 alone exist for non-muscle invasive urothelial carcinoma (NCT02657486), recurrent glioblastoma (NCT01975701), and advanced cholangiocarcinoma (NCT02150967).	('NCT02657486', 'Var', (114, 125))	('BGJ398', 'Chemical', 'MESH:C568950', (49, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('invasive urothelial carcinoma', 'Disease', (83, 112))	('BGJ398', 'Gene', (49, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('glioblastoma', 'Disease', (138, 150))	('NCT02150967', 'Var', (199, 210))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('NCT01975701', 'Var', (152, 163))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (83, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Disease', (179, 197))
66531	28030802	JNJ-42756493 (Janssen) is another pan-FGFR inhibitor that is orally bioavailable.	('JNJ-42756493', 'Var', (0, 12))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (38, 41))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (0, 12))	('FGF', 'Gene', (38, 41))
66536	28030802	All patients that responded demonstrated FGFR2 or FGFR3 translocations, and of the responses identified, 3 of the patients with partial responses harbored an FGFR3-TACC3 fusion alteration.	('FGFR3-TACC3', 'Gene', (158, 169))	('FGFR3', 'Gene', (50, 55))	('FGFR2', 'Gene', (41, 46))	('FGFR2', 'Gene', '2263', (41, 46))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (114, 122))	('translocations', 'Var', (56, 70))
66542	28030802	An FGFR2-IIIb-specific antibody, GP369, has been shown to inhibit the proliferation of human cancer cell lines and tumor xenografts with amplified or activated FGFR2 signaling.	('FGFR2', 'Gene', (3, 8))	('FGFR2', 'Gene', '2263', (3, 8))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', (115, 120))	('proliferation', 'CPA', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inhibit', 'NegReg', (58, 65))	('FGFR2', 'Gene', (160, 165))	('FGFR2', 'Gene', '2263', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('GP369', 'Var', (33, 38))
66543	28030802	BAY1187982 (Bayer) also falls under the spectrum of exploiting the antibody/antigen relationship as a human anti-FGFR2-Ab that is conjugated to a cytotoxic agent (antibody-drug conjugate).	('FGFR2', 'Gene', (113, 118))	('falls', 'Phenotype', 'HP:0002527', (24, 29))	('fall', 'Phenotype', 'HP:0002527', (24, 28))	('human', 'Species', '9606', (102, 107))	('BAY1187982', 'Var', (0, 10))	('FGFR2', 'Gene', '2263', (113, 118))	('BAY1187982', 'Chemical', 'MESH:C000621819', (0, 10))
66546	28030802	Antibodies targeting FGFR3 have also been shown to have significant inhibitory effect on cell proliferation in bladder cancer cells and t (4; 14)-positive multiple myeloma.	('multiple myeloma', 'Disease', 'MESH:D009101', (155, 171))	('bladder cancer', 'Disease', (111, 125))	('Antibodies', 'Var', (0, 10))	('inhibitory effect', 'NegReg', (68, 85))	('multiple myeloma', 'Disease', (155, 171))	('FGFR3', 'Gene', (21, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('multiple myeloma', 'Phenotype', 'HP:0006775', (155, 171))
66547	28030802	MFGR1877S (Genentech) is a human anti-FGFR3 monoclonal antibody that demonstrated activity in preclinical models of urothelial carcinoma harboring FGFR3 overexpression.	('overexpression', 'PosReg', (153, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('MFGR1877S', 'Var', (0, 9))	('anti-FGFR3', 'Gene', (33, 43))	('human', 'Species', '9606', (27, 32))	('FGFR3', 'Gene', (147, 152))	('urothelial carcinoma', 'Disease', (116, 136))	('activity', 'MPA', (82, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
66548	28030802	Subsequently there have been two Phase I trials completed, one in solid tumors (NCT01363024) and one in t(4; 14)-positive multiple myeloma (NCT01122875).	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('solid tumors', 'Disease', (66, 78))	('NCT01363024', 'Var', (80, 91))	('multiple myeloma', 'Phenotype', 'HP:0006775', (122, 138))	('multiple myeloma', 'Disease', 'MESH:D009101', (122, 138))	('multiple myeloma', 'Disease', (122, 138))
66554	28030802	A subsequent Phase II trial is currently recruiting and is looking to evaluate FP-1039 in solid tumors alone, or in combination with docetaxel, or paclitaxel and carboplatin (NCT01868022).	('solid tumors', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('carboplatin', 'Chemical', 'MESH:D016190', (162, 173))	('solid tumors', 'Disease', (90, 102))	('docetaxel', 'Chemical', 'MESH:D000077143', (133, 142))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('FP-1039', 'Var', (79, 86))
66555	28030802	Given the broad scope of malignancies with FGF/FGFR pathway aberrations, proof of concept has been demonstrated for its role as a driver for oncogenesis, as a downstream key player in angiogenesis, and as a pathway responsible for acquired resistance to other anti-cancer therapies.	('FGF', 'Gene', (43, 46))	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('FGF', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('oncogenesis', 'CPA', (141, 152))	('malignancies', 'Disease', (25, 37))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (43, 46))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (47, 50))	('aberrations', 'Var', (60, 71))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))
66556	28030802	Pre-clinical and clinical studies have shown that cancers harboring FGF/FGFR pathway aberrations are likely to be sensitive to FGFR inhibitors across various histologies.	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (72, 75))	('cancers', 'Disease', (50, 57))	('FGF', 'Gene', (68, 71))	('FGF', 'Gene', (127, 130))	('aberrations', 'Var', (85, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (68, 71))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('sensitive', 'Reg', (114, 123))	('FGF', 'Gene', (72, 75))
66560	28030802	As aforementioned, a recent study used next generation sequencing (NGS) to characterize frequencies of FGFR aberrations in nearly 5,000 solid tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (103, 106))	('aberrations', 'Var', (108, 119))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('FGF', 'Gene', (103, 106))
66561	28030802	They found that 7.1% of malignancies demonstrated detectable abnormalities with the most common being gene amplification, followed by mutations, then rearrangements.	('gene amplification', 'Var', (102, 120))	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('mutations', 'Var', (134, 143))	('malignancies', 'Disease', (24, 36))
66563	28030802	Within the cohort of malignancies analyzed, urothelial carcinoma exhibited the highest percentage of FGFR aberrancy (largely mutation, then amplification, followed by fusion) at 32%.	('FGF', 'Gene', (101, 104))	('malignancies', 'Disease', 'MESH:D009369', (21, 33))	('aberrancy', 'Var', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (101, 104))	('urothelial carcinoma', 'Disease', (44, 64))	('malignancies', 'Disease', (21, 33))	('amplification', 'Var', (140, 153))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (44, 64))	('mutation', 'Var', (125, 133))
66565	28030802	Notably there was no evaluation of FGF ligand dependent signaling, highlighting that a subset of patients with FGF/FGFR pathway aberrations may still benefit from FGFR targeted therapy but were not characterized in this study.	('FGF', 'Gene', (115, 118))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (35, 38))	('aberrations', 'Var', (128, 139))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (163, 166))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (111, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (115, 118))	('FGF', 'Gene', (35, 38))	('benefit', 'PosReg', (150, 157))	('FGF', 'Gene', (163, 166))	('FGF', 'Gene', (111, 114))	('patients', 'Species', '9606', (97, 105))
66567	28030802	Ultimately, when evaluating all FGF/FGFR aberrations (mutations, amplifications, rearrangements, etc.)	('rearrangements', 'Var', (81, 95))	('FGF', 'Gene', (32, 35))	('FGF', 'Gene', (36, 39))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (36, 39))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (32, 35))
66569	28030802	Much of the pre-clinical and early clinical data come from trials in patient populations unselected for FGF/FGFR pathway abnormalities.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (104, 107))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (108, 111))	('abnormalities', 'Var', (121, 134))	('patient', 'Species', '9606', (69, 76))	('FGF', 'Gene', (108, 111))	('FGF', 'Gene', (104, 107))
66570	28030802	The true response rates or clinical benefits for those whose cancers harbor FGF/FGFR abnormalities may be higher than observed in unselected patient populations.	('FGF', 'Gene', (76, 79))	('FGF', 'Gene', (80, 83))	('response', 'CPA', (9, 17))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (76, 79))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (80, 83))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('patient', 'Species', '9606', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('higher', 'PosReg', (106, 112))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('clinical benefits', 'CPA', (27, 44))	('abnormalities', 'Var', (85, 98))
66571	28030802	Many ongoing Phase I/II trials can be commended for aiming to select patients with specific FGF/FGFR alterations, and at this stage (appropriately so) there exist a variety in the methods including FISH, chromogenic in situ hybridization (CISH), quantitative real-time PCR, and NGS.	('alterations', 'Var', (101, 112))	('FGF', 'Gene', (92, 95))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (92, 95))	('FGF', 'Gene', (96, 99))	('patients', 'Species', '9606', (69, 77))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))
66575	28030802	We must additionally consider that FGF/FGFR pathway alterations likely vary in their role depending on tumor histology and interactions with other oncogenic pathways.	('interactions', 'Interaction', (123, 135))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('alterations', 'Var', (52, 63))	('tumor', 'Disease', (103, 108))	('FGF', 'Gene', (39, 42))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (39, 42))	('FGF', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
66578	28030802	It was later found out that EGFR expression by IHC in colorectal cancer did not correlate with response to therapy, and subsequent investigation led to the identification of the KRAS mutation conferring resistance.	('KRAS', 'Gene', (178, 182))	('EGFR', 'Gene', '1956', (28, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('EGFR', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('mutation', 'Var', (183, 191))	('colorectal cancer', 'Disease', (54, 71))
66584	28030802	As further studies unfold, we need to utilize multiplex molecular testing such as NGS to screen tumors harboring specific molecular aberrations of interest and increase the likelihood of detecting actionable FGF/FGFR alterations in each patient.	('FGF', 'Gene', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('patient', 'Species', '9606', (237, 244))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (208, 211))	('FGF', 'Gene', (212, 215))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (212, 215))	('alterations', 'Var', (217, 228))
66587	28030802	There are some studies that have identified a high concordance for actionable mutations between paired plasma and tumor specimens, especially for metastatic disease in non-small cell lung cancer, breast cancer, and colorectal cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (215, 232))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('colorectal cancer', 'Disease', (215, 232))	('metastatic disease', 'Disease', (146, 164))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (114, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
66592	28030802	The accessibility of testing would likely allow for frequent monitoring of tumor evolution, and the presence of novel molecular alterations while actively receiving anti-cancer treatment may predict upcoming resistance to therapy.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('alterations', 'Var', (128, 139))	('cancer', 'Disease', (170, 176))	('predict', 'Reg', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('resistance', 'CPA', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
66593	28030802	Already this has been described in a small cohort of patients with colorectal cancer initially demonstrating KRAS wild-type tumors, which subsequently were noted to have molecular alterations (via serum analysis) including KRAS, NRAS, EGFR, and BRAF after treatment with anti-EGFR therapies.	('EGFR', 'Gene', '1956', (276, 280))	('NRAS', 'Gene', '4893', (229, 233))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', '1956', (235, 239))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('KRAS', 'Disease', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NRAS', 'Gene', (229, 233))	('tumors', 'Disease', (124, 130))	('EGFR', 'Gene', (276, 280))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('KRAS', 'Var', (109, 113))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('EGFR', 'Gene', (235, 239))	('colorectal cancer', 'Disease', (67, 84))
66596	28030802	Ideally, we could use this approach to monitor treatment response, disease recurrence, as well as pick up resistant clones in patients that have an FGFR alteration being treated with an FGFR inhibitor.	('alteration', 'Var', (153, 163))	('FGF', 'Gene', (186, 189))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (148, 151))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (186, 189))	('patients', 'Species', '9606', (126, 134))	('FGF', 'Gene', (148, 151))
66597	28030802	New trial designs and approaches are being developed in order to capture the many malignancies that may harbor an FGF/FGFR aberration.	('FGF', 'Gene', (118, 121))	('aberration', 'Var', (123, 133))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (114, 117))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (118, 121))	('malignancies', 'Disease', (82, 94))	('FGF', 'Gene', (114, 117))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
66603	28030802	Thus far we have discussed the use of FGFR inhibitors assuming that FGF/FGFR is the primary driver for oncogenesis in certain histologies or in certain molecular aberrations such as FGFR3 fusion in bladder cancer.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (38, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('fusion', 'Var', (188, 194))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (72, 75))	('bladder cancer', 'Disease', (198, 212))	('FGF', 'Gene', (182, 185))	('FGF', 'Gene', (68, 71))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (68, 71))	('FGF', 'Gene', (38, 41))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (182, 185))	('FGF', 'Gene', (72, 75))
66605	28030802	Additionally we must appreciate the evolving nature of cancer cells and the likelihood of resistance to FGFR inhibitors directly either by (i) compensatory signaling or (ii) via intrinsic gatekeeper mutations in the FGFR receptors themselves.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gatekeeper', 'Species', '111938', (188, 198))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (216, 219))	('FGF', 'Gene', (216, 219))	('mutations', 'Var', (199, 208))	('FGF', 'Gene', (104, 107))	('compensatory signaling', 'MPA', (143, 165))	('cancer', 'Disease', (55, 61))
66606	28030802	Recently, acquired resistance to EGFR specific inhibitors in NSCLC mutant cell lines has been hypothesized to relate to the activation of the FGFR1-FGF2 autocrine loop.	('FGF2', 'Gene', '2247', (148, 152))	('activation', 'PosReg', (124, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('FGFR1', 'Gene', '2260', (142, 147))	('EGFR', 'Gene', '1956', (33, 37))	('FGF2', 'Gene', (148, 152))	('FGFR1', 'Gene', (142, 147))	('NSCLC', 'Disease', (61, 66))	('mutant', 'Var', (67, 73))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
66613	28030802	This effect was appreciated in cell lines and xenograft mouse models of KRAS-mutant lung adenocarcinoma and KRAS-mutant pancreatic carcinoma, but was not as significant in KRAS wild-type lung cancer cells or KRAS mutant colon cancer.	('KRAS-mutant', 'Var', (108, 119))	('KRAS-mutant', 'Var', (72, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (120, 140))	('mouse', 'Species', '10090', (56, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('lung adenocarcinoma', 'Disease', (84, 103))	('colon cancer', 'Disease', 'MESH:D015179', (220, 232))	('pancreatic carcinoma', 'Disease', (120, 140))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('colon cancer', 'Disease', (220, 232))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
66617	28030802	Secondly, they hypothesize that a combination of MEK and FGFR inhibition would likely be a valid approach in the treatment of KRAS-mutant lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('MEK', 'Gene', (49, 52))	('FGF', 'Gene', (57, 60))	('MEK', 'Gene', '5609', (49, 52))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (57, 60))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('inhibition', 'NegReg', (62, 72))	('KRAS-mutant', 'Var', (126, 137))
66622	28030802	In breast cancer, FGFR1 amplification has been associated with endocrine resistance and poor prognosis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('endocrine resistance', 'MPA', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('FGFR1', 'Gene', (18, 23))	('amplification', 'Var', (24, 37))	('FGFR1', 'Gene', '2260', (18, 23))	('associated', 'Reg', (47, 57))
66625	28030802	In the development of a novel targeted therapy, we must also recognize the inevitability of acquiring resistance to the drug - either from up-regulation of compensatory pathways or innate mutations rendering the FGFR receptor resistant.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (212, 215))	('nevi', 'Phenotype', 'HP:0003764', (76, 80))	('up-regulation', 'PosReg', (139, 152))	('FGF', 'Gene', (212, 215))	('mutations', 'Var', (188, 197))
66626	28030802	In a study using FGFR3-mutant cell lines, the investigators identified EGFR signaling as a key mechanism in limiting FGFR3 inhibition.	('FGFR3-mutant', 'Var', (17, 29))	('FGFR3', 'Gene', (117, 122))	('EGFR', 'Gene', '1956', (71, 75))	('inhibition', 'NegReg', (123, 133))	('EGFR', 'Gene', (71, 75))
66627	28030802	In partially dependent FGFR3 cell lines, inhibiting FGFR3 resulted in a temporary down regulation of MAPK signaling that was bypassed by a prompt up regulation in EGFR signaling.	('inhibiting', 'Var', (41, 51))	('MAPK', 'Gene', '5594', (101, 105))	('EGFR', 'Gene', '1956', (163, 167))	('MAPK', 'Gene', (101, 105))	('EGFR', 'Gene', (163, 167))	('FGFR3', 'Gene', (52, 57))	('down regulation', 'NegReg', (82, 97))
66628	28030802	In EGFR dependent cell lines, they also identified that EGFR downstream signaling dominated, even in the presence of an activating FGFR3 mutation.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('mutation', 'Var', (137, 145))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('FGFR3', 'Gene', (131, 136))	('activating', 'PosReg', (120, 130))
66629	28030802	More recently, in SqCLC cell lines with FGFR1 amplification, investigators identified clonal cell populations that were resistant to treatment with AZD4547 or BAY1163877.	('BAY1163877', 'Chemical', '-', (159, 169))	('amplification', 'Var', (46, 59))	('AZD4547', 'Var', (148, 155))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('BAY1163877', 'Var', (159, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (148, 155))
66631	28030802	In these AZD4547 treated cells, MET amplification was thought to lead to resistance through ErbB3 activation.	('resistance', 'MPA', (73, 83))	('activation', 'PosReg', (98, 108))	('lead to', 'Reg', (65, 72))	('AZD4547', 'Chemical', 'MESH:C572463', (9, 16))	('MET amplification', 'Var', (32, 49))	('ErbB3', 'Gene', (92, 97))	('ErbB3', 'Gene', '2065', (92, 97))
66635	28030802	In discussing innate mutations, the "gatekeeper" mutation is responsible for the most common type of kinase inhibitor resistance, these are mutations of a residue located in the ATP binding pocket of the RTK.	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('gatekeeper', 'Species', '111938', (37, 47))	('RTK', 'Gene', (204, 207))	('mutations', 'Var', (140, 149))	('RTK', 'Gene', '5979', (204, 207))
66643	28030802	A similar pattern of drug development and understanding has unfolded in the targeted treatment of EGFR mutant NSCLC or ALK-rearranged NSCLC.	('EGFR', 'Gene', (98, 102))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('ALK', 'Gene', '238', (119, 122))	('mutant', 'Var', (103, 109))	('ALK', 'Gene', (119, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('EGFR', 'Gene', '1956', (98, 102))	('NSCLC', 'Disease', (134, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
66644	28030802	In treating EGFR mutant NSCLC, the first generation EGFR tyrosine kinase inhibitors gefinitib and erlotinib (approved in 2003 and 2004 respectively), followed by the second-generation afatinib, have been widely used in treatment of advanced disease.	('NSCLC', 'Disease', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('erlotinib', 'Chemical', 'MESH:D000069347', (98, 107))	('EGFR', 'Gene', '1956', (12, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('afatinib', 'Chemical', 'MESH:D000077716', (184, 192))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('gefinitib', 'Chemical', '-', (84, 93))	('EGFR', 'Gene', (12, 16))	('mutant', 'Var', (17, 23))
66645	28030802	In fact, the most common acquired EGFR mutation leading to decreased survival has been found to be the "gatekeeper" mutation T790M, with nearly 50-60% of resistant cases demonstrating this anomaly.	('gatekeeper', 'Species', '111938', (104, 114))	('anomaly', 'Disease', (189, 196))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))	('decreased', 'NegReg', (59, 68))	('anomaly', 'Disease', 'MESH:D000014', (189, 196))	('T790M', 'Mutation', 'rs121434569', (125, 130))	('EGFR', 'Gene', '1956', (34, 38))	('survival', 'MPA', (69, 77))
66647	28030802	Continued development of EGFR inhibitor therapy led to the accelerated approval of the third generation EGFR inhibitor osimertinib for patients with metastatic EGFR T790M mutation-positive NSCLC that have progressed on or after previous EGFR inhibitor therapy.	('T790M mutation-positive', 'Var', (165, 188))	('NSCLC', 'Disease', (189, 194))	('EGFR', 'Gene', '1956', (237, 241))	('osimertinib', 'Chemical', 'MESH:C000603933', (119, 130))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (135, 143))	('EGFR', 'Gene', (104, 108))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('EGFR', 'Gene', (237, 241))	('EGFR', 'Gene', '1956', (160, 164))	('T790M', 'Mutation', 'rs121434569', (165, 170))	('EGFR', 'Gene', (160, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (104, 108))
66650	28030802	As observed in the aforementioned stories, resistance to ALK blockade also emerges in time by multiple mechanisms including: ALK kinase mutations (30%) at L1196M (gatekeeper), F1174L, and G1202R, as well as activation of alternate oncogenes with resulting bypass signaling.	('gatekeeper', 'Species', '111938', (163, 173))	('F1174L', 'Var', (176, 182))	('ALK', 'Gene', (57, 60))	('ALK', 'Gene', '238', (125, 128))	('G1202R', 'Var', (188, 194))	('G1202R', 'Mutation', 'rs1057519783', (188, 194))	('F1174L', 'Mutation', 'rs863225281', (176, 182))	('mutations', 'Var', (136, 145))	('L1196M', 'Mutation', 'rs1057519784', (155, 161))	('ALK', 'Gene', '238', (57, 60))	('ALK', 'Gene', (125, 128))
66652	28030802	With ceritinib, there already exists some emerging data that ALK-G1202R and F1174V/C mutations confer some resistance to therapy.	('resistance to therapy', 'MPA', (107, 128))	('F1174V', 'Var', (76, 82))	('ALK', 'Gene', (61, 64))	('F1174V', 'SUBSTITUTION', 'None', (76, 82))	('ceritinib', 'Chemical', 'MESH:C586847', (5, 14))	('ALK', 'Gene', '238', (61, 64))	('G1202R', 'Mutation', 'rs1057519783', (65, 71))
66655	28030802	Several pre-clinical studies have highlighted a significant gatekeeper mutation (FGFR1 V561M, FGFR2 V564I, FGFR3 V555M, FGFR4 V550M) that renders targeted therapy ineffective.	('V561M', 'Mutation', 'p.V561M', (87, 92))	('FGFR1', 'Gene', (81, 86))	('FGFR2', 'Gene', (94, 99))	('V564I', 'Var', (100, 105))	('FGFR2', 'Gene', '2263', (94, 99))	('gatekeeper', 'Species', '111938', (60, 70))	('V550M', 'Mutation', 'rs774571806', (126, 131))	('FGFR1', 'Gene', '2260', (81, 86))	('V555M', 'Mutation', 'rs199544087', (113, 118))	('FGFR3', 'Gene', (107, 112))	('V555M', 'Var', (113, 118))	('V561M', 'Var', (87, 92))	('V564I', 'Mutation', 'rs1057519797', (100, 105))
66656	28030802	Preclinical cellular models harboring the FGFR3 V555M mutation have demonstrated resistance to AZD4547.	('resistance', 'MPA', (81, 91))	('FGFR3', 'Gene', (42, 47))	('V555M', 'Mutation', 'rs199544087', (48, 53))	('AZD4547', 'Chemical', 'MESH:C572463', (95, 102))	('V555M', 'Var', (48, 53))
66657	28030802	Recently, the FGFR1 V561M gatekeeper mutation was characterized at a structural and kinetic level where a 38-fold increase in autophosphorylation of the receptor was demonstrated.	('increase', 'PosReg', (114, 122))	('gatekeeper', 'Species', '111938', (26, 36))	('V561M', 'Var', (20, 25))	('FGFR1', 'Gene', (14, 19))	('autophosphorylation', 'MPA', (126, 145))	('FGFR1', 'Gene', '2260', (14, 19))	('V561M', 'Mutation', 'p.V561M', (20, 25))
66658	28030802	Interestingly, the mutated receptor still maintained affinity for AZD4547.	('affinity', 'MPA', (53, 61))	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('AZD4547', 'Var', (66, 73))	('mutated', 'Var', (19, 26))
66659	28030802	Subsequent generations of FGFR inhibitors will need to be able to circumvent these cellular defense mechanisms, and there exist two compounds FIIN-2 and FIIN-3 developed in preclinical studies that have demonstrated potency against wild type FGFR1-4 as well as receptors with gatekeeper mutations.	('FGF', 'Gene', (26, 29))	('FGFR1', 'Gene', '2260', (242, 247))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (242, 245))	('gatekeeper', 'Species', '111938', (276, 286))	('potency', 'MPA', (216, 223))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (26, 29))	('mutations', 'Var', (287, 296))	('FGF', 'Gene', (242, 245))	('FGFR1', 'Gene', (242, 247))
66662	28030802	When designing clinical trials, we should exclude tumors with the aforementioned gatekeeper mutations of FGFR known to confer possible resistance to currently available selective FGFR inhibitors.	('FGF', 'Gene', (105, 108))	('gatekeeper', 'Species', '111938', (81, 91))	('mutations', 'Var', (92, 101))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (105, 108))	('FGF', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))
66681	28030802	Already in other known targetable mutations discussed above, such as EGFR in colorectal cancer or BCR-ABL1 in CML, the use of next generation sequencing (NGS) has proved invaluable in identifying not only actionable mutations, but also for screening "gatekeeper" mutations that may confer resistance to therapy.	('EGFR', 'Gene', '1956', (69, 73))	('colorectal cancer', 'Disease', (77, 94))	('EGFR', 'Gene', (69, 73))	('BCR-ABL1', 'Gene', (98, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('CML', 'Disease', 'MESH:D015464', (110, 113))	('CML', 'Phenotype', 'HP:0005506', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gatekeeper', 'Species', '111938', (251, 261))	('mutations', 'Var', (216, 225))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('CML', 'Disease', (110, 113))
66682	28030802	As selective FGFR inhibitors get closer to routine clinical use, we can learn from the past especially with regards to patient selection as it predicts response to therapy.	('FGF', 'Gene', (13, 16))	('patient', 'Species', '9606', (119, 126))	('inhibitors', 'Var', (18, 28))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (13, 16))
66686	28030802	The use of massive parallel DNA sequencing technology allows for noting differences in disease response based on FGFR mutation or fusion in lung, which may be important in a minority of lung cancers and this detail would be easily missed with FISH or IHC.	('fusion', 'Var', (130, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (186, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('FGF', 'Gene', (113, 116))	('lung cancers', 'Disease', (186, 198))	('mutation', 'Var', (118, 126))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('lung cancers', 'Disease', 'MESH:D008175', (186, 198))
66688	28030802	This is an ideal platform to discover unusual responders to FGFR inhibitor therapy with the goal of identifying new and relevant FGF/FGFR alterations, especially with the addition of rare tumors that might otherwise not have enrolled in a clinical trial.	('tumors', 'Disease', (188, 194))	('FGF', 'Gene', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('FGF', 'Gene', (60, 63))	('FGF', 'Gene', (133, 136))	('alterations', 'Var', (138, 149))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (60, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (129, 132))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
66689	28030802	Despite the advances in drug design to include the second-generation selective FGFR inhibitors, the biology of FGF/FGFR signaling is complex and we have seen that response to therapy is dependent on a multitude of factors.	('FGF', 'Gene', (115, 118))	('inhibitors', 'Var', (84, 94))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (79, 82))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (111, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (115, 118))	('FGF', 'Gene', (79, 82))	('FGF', 'Gene', (111, 114))
66690	28030802	At the present time, targeting FGFR fusion aberrations has demonstrated the best response; we see this in bladder cancer with encouraging results.	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('aberrations', 'Var', (43, 54))	('FGF', 'Gene', (31, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (31, 34))
66692	28030802	This is of interest given that the tumors in which FGFR3-TACC3 mutations have been identified (2.6% of urothelial carcinoma cases, 1.2-8.3% of GBM) are on the more aggressive end of the spectrum with overall limited treatment options.	('mutations', 'Var', (63, 72))	('urothelial carcinoma', 'Disease', (103, 123))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('FGFR3-TACC3', 'Gene', (51, 62))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (103, 123))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
66757	28143434	Compared to recently published studies in gliomas, more and higher b values are used in our study, as more b values in segment of low b values can improve the accuracy of the pseudodiffusion, while higher b values can better eliminate the perfusion-related diffusion; thus it can in turn generate a more realistic molecular diffusion coefficient value.	('pseudodiffusion', 'MPA', (175, 190))	('perfusion-related diffusion', 'MPA', (239, 266))	('improve', 'PosReg', (147, 154))	('glioma', 'Phenotype', 'HP:0009733', (42, 48))	('eliminate', 'NegReg', (225, 234))	('molecular diffusion coefficient value', 'MPA', (314, 351))	('accuracy', 'MPA', (159, 167))	('gliomas', 'Disease', 'MESH:D005910', (42, 49))	('b values', 'Var', (107, 115))	('gliomas', 'Phenotype', 'HP:0009733', (42, 49))	('gliomas', 'Disease', (42, 49))
66799	26912794	Moreover, integrin expression studies have underlined potential roles for the laminin receptors alpha2beta1, alpha3beta1, alpha6beta1, and alpha6beta4 in glioma invasion.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('alpha6beta1', 'Var', (122, 133))	('laminin', 'Protein', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('alpha6beta4', 'Var', (139, 150))	('alpha2beta1', 'Protein', (96, 107))	('glioma', 'Disease', (154, 160))	('alpha3beta1', 'Var', (109, 120))
66854	26912794	Blebbistatin also caused a large decrease in velocity in both migration modes (Figure 5C).	('velocity', 'MPA', (45, 53))	('decrease', 'NegReg', (33, 41))	('Blebbistatin', 'Var', (0, 12))	('rat', 'Species', '10116', (65, 68))	('Blebbistatin', 'Chemical', 'MESH:C472645', (0, 12))
66864	26912794	Instead, the Arp2/3 inhibitor CK666 caused an increase in the linear migration velocity on thick lines, whereas it inhibited 2D random motion (Figure 5C and Supplemental Movies S14 and S15).	('rat', 'Species', '10116', (72, 75))	('CK666', 'Var', (30, 35))	('increase', 'PosReg', (46, 54))	('linear migration velocity on thick lines', 'CPA', (62, 102))	('Arp2/3', 'Gene', '10097;10096', (13, 19))	('CK666', 'Chemical', 'MESH:C543733', (30, 35))	('Arp2/3', 'Gene', (13, 19))	('inhibited', 'NegReg', (115, 124))
66865	26912794	On 2D surfaces at low cell densities, CK666 treatment caused an indentation of lamellipodia and a decrease in velocity (Figure 5, B and C).	('indentation of lamellipodia', 'CPA', (64, 91))	('velocity', 'MPA', (110, 118))	('decrease', 'NegReg', (98, 106))	('CK666', 'Var', (38, 43))	('CK666', 'Chemical', 'MESH:C543733', (38, 43))
66866	26912794	In contrast, at high densities on the large lines that activated the linear migration mode, CK666 addition caused sharper spindle shapes, better alignment in antiparallel arrays even in the reservoir (Figure 5D), and higher velocities of migration.	('CK666', 'Var', (92, 97))	('CK666', 'Chemical', 'MESH:C543733', (92, 97))	('migration', 'CPA', (238, 247))	('higher', 'PosReg', (217, 223))	('alignment', 'MPA', (145, 154))	('better', 'PosReg', (138, 144))	('linear migration', 'CPA', (69, 85))	('rat', 'Species', '10116', (79, 82))	('velocities', 'MPA', (224, 234))	('rat', 'Species', '10116', (241, 244))	('spindle shapes', 'CPA', (122, 136))
66868	26912794	After SMIFH2 addition, on 2D surfaces at low cell densities, glioma cells developed large lamellipodia all around their periphery and were not able to polarize in any direction (Figure 5, B and C, and Supplemental Movie S14).	('glioma cells', 'Disease', 'MESH:D005910', (61, 73))	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('SMIFH2', 'Chemical', '-', (6, 12))	('SMIFH2', 'Gene', (6, 12))	('addition', 'Var', (13, 21))	('glioma cells', 'Disease', (61, 73))
66869	26912794	On the linear patterns, SMIFH2 addition blocked all process extension and migration (Figure 5, A and C, and Supplemental Movie S15).	('SMIFH2', 'Gene', (24, 30))	('blocked', 'NegReg', (40, 47))	('rat', 'Species', '10116', (77, 80))	('process extension', 'CPA', (52, 69))	('migration', 'CPA', (74, 83))	('SMIFH2', 'Chemical', '-', (24, 30))	('addition', 'Var', (31, 39))
66890	26912794	In both cell lines, knockdown of FHOD3 reduced the migration speed on linear patterns (Figure 7B and Supplemental Figure S6E) by a factor of two, whereas the effects of knocking down mDia1 or mDia2 were not significant compared with control conditions.	('mDia1', 'Gene', '13367', (183, 188))	('rat', 'Species', '10116', (54, 57))	('FHOD3', 'Gene', (33, 38))	('reduced', 'NegReg', (39, 46))	('mDia2', 'Gene', (192, 197))	('knockdown', 'Var', (20, 29))	('migration speed on linear patterns', 'CPA', (51, 85))	('mDia1', 'Gene', (183, 188))	('mDia2', 'Gene', '56419', (192, 197))
66891	26912794	However, the speed on 2D substrates was affected by FHOD3 and mDia1 knockdown, as observed by).	('mDia1', 'Gene', '13367', (62, 67))	('affected', 'Reg', (40, 48))	('speed', 'MPA', (13, 18))	('FHOD3', 'Gene', (52, 57))	('rat', 'Species', '10116', (30, 33))	('mDia1', 'Gene', (62, 67))	('knockdown', 'Var', (68, 77))
66892	26912794	In addition, we observed that FHOD3-knockdown cells moved slowly and stayed close to each other instead of spreading and exploring their environment as did control and most of the mDia1- and mDia2-knockdown cells.	('FHOD3-knockdown', 'Var', (30, 45))	('mDia1', 'Gene', '13367', (180, 185))	('mDia2', 'Gene', '56419', (191, 196))	('mDia2', 'Gene', (191, 196))	('FHOD3-knockdown', 'Gene', (30, 45))	('mDia1', 'Gene', (180, 185))	('slowly', 'NegReg', (58, 64))	('spreading', 'CPA', (107, 116))
66894	26912794	In the case of mDia1 knockdown, a minor population of mDia1-knockdown cells moved extremely slowly (mean speed, <10 mum/h), whereas the majority of the knockdown population moved at approximately the same speed as the control (mean speed, >20 mum/h; Supplemental Figure S6G).	('slowly', 'NegReg', (92, 98))	('mDia1', 'Gene', (54, 59))	('mDia1', 'Gene', '13367', (15, 20))	('mum', 'Gene', '56925', (243, 246))	('mDia1', 'Gene', '13367', (54, 59))	('mum', 'Gene', (243, 246))	('mum', 'Gene', '56925', (116, 119))	('knockdown', 'Var', (21, 30))	('mDia1', 'Gene', (15, 20))	('mum', 'Gene', (116, 119))	('moved', 'MPA', (76, 81))
66895	26912794	The consistently lower migration velocity in the FHOD3-knockdown cells indicated that it had a major role in the migration process.	('migration velocity', 'CPA', (23, 41))	('lower', 'NegReg', (17, 22))	('rat', 'Species', '10116', (26, 29))	('FHOD3-knockdown', 'Var', (49, 64))	('rat', 'Species', '10116', (116, 119))	('FHOD3-knockdown', 'Gene', (49, 64))
66903	26912794	We tested the involvement of three formins:mDia1, mDia2, and FHOD3:in this process and found that only FHOD3 knockdown led to a consistent inhibition of the linear migration.	('mDia1', 'Gene', (43, 48))	('inhibition', 'NegReg', (139, 149))	('linear migration', 'CPA', (157, 173))	('FHOD3', 'Gene', (103, 108))	('tested', 'Reg', (3, 9))	('mDia1', 'Gene', '13367', (43, 48))	('knockdown', 'Var', (109, 118))	('mDia2', 'Gene', (50, 55))	('mDia2', 'Gene', '56419', (50, 55))	('formins', 'Chemical', '-', (35, 42))	('rat', 'Species', '10116', (167, 170))
66937	26912794	Although Arp2/3 activity is present in the linear migration mode, inhibition of Arp2/3 increases cell velocity, indicating that Arp2/3-dependent extensions detract from directed migration and could be involved in sensing the environment.	('Arp2/3', 'Gene', (80, 86))	('Arp2/3', 'Gene', (128, 134))	('increases', 'PosReg', (87, 96))	('Arp2/3', 'Gene', (9, 15))	('detract', 'NegReg', (156, 163))	('cell velocity', 'CPA', (97, 110))	('rat', 'Species', '10116', (53, 56))	('inhibition', 'Var', (66, 76))	('rat', 'Species', '10116', (181, 184))	('Arp2/3', 'Gene', '10097;10096', (80, 86))	('Arp2/3', 'Gene', '10097;10096', (128, 134))	('directed migration', 'CPA', (169, 187))	('Arp2/3', 'Gene', '10097;10096', (9, 15))
66938	26912794	Consistent with that hypothesis, inhibition of Arp2/3 activity causes better alignment of the glioma cells along the lines and parallel to each other.	('inhibition', 'Var', (33, 43))	('glioma cells', 'Disease', (94, 106))	('Arp2/3', 'Gene', '10097;10096', (47, 53))	('better', 'PosReg', (70, 76))	('Arp2/3', 'Gene', (47, 53))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('activity', 'MPA', (54, 62))	('alignment', 'CPA', (77, 86))	('glioma cells', 'Disease', 'MESH:D005910', (94, 106))
66939	26912794	Similarly, Arp2/3 inhibition accelerates migration of leukocytes in confined conditions, and hence the Arp2/3 lamellipodial protrusions are not required for this other type of confined migration.	('accelerates', 'PosReg', (29, 40))	('migration', 'CPA', (41, 50))	('Arp2/3', 'Gene', '10097;10096', (103, 109))	('rat', 'Species', '10116', (44, 47))	('Arp2/3', 'Gene', '10097;10096', (11, 17))	('Arp2/3', 'Gene', (11, 17))	('rat', 'Species', '10116', (188, 191))	('inhibition', 'Var', (18, 28))	('rat', 'Species', '10116', (35, 38))	('Arp2/3', 'Gene', (103, 109))
66940	26912794	However, upon Arp2/3 inhibition, instead of forming sharp spindles, leukocytes switch to a blebbing motility.	('inhibition', 'Var', (21, 31))	('switch', 'Reg', (79, 85))	('blebbing motility', 'CPA', (91, 108))	('Arp2/3', 'Gene', (14, 20))	('Arp2/3', 'Gene', '10097;10096', (14, 20))
66941	26912794	In glioma cells, at the subcellular level, the inhibition of Arp2/3 increases the formation of parallel actin cables, reinforcing the sharp, spindle shape of the cells.	('increases', 'PosReg', (68, 77))	('formation', 'MPA', (82, 91))	('glioma cells', 'Disease', (3, 15))	('inhibition', 'Var', (47, 57))	('sharp', 'CPA', (134, 139))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('Arp2/3', 'Gene', '10097;10096', (61, 67))	('glioma cells', 'Disease', 'MESH:D005910', (3, 15))	('Arp2/3', 'Gene', (61, 67))
66954	26912794	Similarly,) found that fibroblast migration on thin lines is unaffected or potentiated by Rac knockdown.	('knockdown', 'Var', (94, 103))	('Rac', 'Gene', (90, 93))	('fibroblast migration', 'CPA', (23, 43))	('potentiated', 'PosReg', (75, 86))	('rat', 'Species', '10116', (37, 40))	('Rac', 'Gene', '207', (90, 93))
66955	26912794	Low Rac1 GTPase activity could cause partial inhibition of the Arp2/3 complex, which would increase the velocity of linear migration.	('Arp2/3', 'Gene', (63, 69))	('velocity', 'MPA', (104, 112))	('increase', 'PosReg', (91, 99))	('Rac1', 'Gene', '5879', (4, 8))	('Rac1', 'Gene', (4, 8))	('activity', 'MPA', (16, 24))	('rat', 'Species', '10116', (126, 129))	('Arp2/3', 'Gene', '10097;10096', (63, 69))	('Low', 'Var', (0, 3))
66979	26912794	Poly-l-lysine (0.01% solution), (-)-blebbistatin, latrunculin A, nocodazole, and CK666 were from Sigma-Aldrich.	('CK666', 'Var', (81, 86))	('Poly-l-lysine', 'Chemical', '-', (0, 13))	('CK666', 'Chemical', 'MESH:C543733', (81, 86))	('-)-blebbistatin', 'Var', (33, 48))	('(-)-blebbistatin', 'Chemical', 'MESH:C472645', (32, 48))	('latrunculin A', 'Chemical', 'MESH:C037067', (50, 63))	('nocodazole', 'Chemical', 'MESH:D015739', (65, 75))	('Poly-l-lysine', 'Var', (0, 13))
67019	26739692	Early reports showed that cells exposed to TTFields exhibited increase time in mitosis .	('mitosis', 'Disease', 'None', (79, 86))	('TTFields', 'Chemical', '-', (43, 51))	('mitosis', 'Disease', (79, 86))	('TTFields', 'Var', (43, 51))	('increase', 'PosReg', (62, 70))
67023	26739692	Since this is triggered by the capture of metaphase spindle microtubules by the kinetochores of chromosomes subsequent to metaphase plate formation (see below), this suggests that in the presence of TTFields metaphase spindle formation and function are normal.	('metaphase spindle formation', 'CPA', (208, 235))	('TTFields', 'Var', (199, 207))	('presence', 'Var', (187, 195))	('TTFields', 'Chemical', '-', (199, 207))
67026	26739692	TTFields have also been shown to cause tumor regression in animal models and human cancers.	('TTFields', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('TTFields', 'Chemical', '-', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
67034	26739692	These data suggest that beyond their effects on the malignant cells, TTFields may contribute to tumor regression by both starving the tumor and reducing intratumoral immune privilege.	('tumor', 'Disease', (158, 163))	('reducing', 'NegReg', (144, 152))	('TTFields', 'Var', (69, 77))	('TTFields', 'Chemical', '-', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (134, 139))
67057	26739692	Proteins that are important to mitotic progression that have high dipole moments have been suggested to be targets of TTFields perturbation, include the alpha/beta-tubulin monomeric subunit of microtubule and the mitotic septin complex.	('dipole', 'Chemical', '-', (66, 72))	('alpha/beta-tubulin', 'Protein', (153, 171))	('TTFields', 'Chemical', '-', (118, 126))	('perturbation', 'Var', (127, 139))	('dipole moments', 'MPA', (66, 80))
67060	26739692	Therefore, it is possible that TTFields interfere with a critical mitotic function performed by microtubules , including the formation of the metaphase and anaphase spindles and their respective mechanical functions, or the astral microtubules that help regulate the CCF.	('TTFields', 'Var', (31, 39))	('TTFields', 'Chemical', '-', (31, 39))	('mechanical functions', 'CPA', (195, 215))	('interfere', 'NegReg', (40, 49))
67064	26739692	The perturbation of the septin complex is particularly enticing because of its known roles in the regulation of CCF function and actin bundle cross-linking and organization of structures such as the cellular submembranous actin cytoskeleton that is required for its rigidity .	('rigidity', 'Phenotype', 'HP:0002063', (266, 274))	('rigidity', 'Disease', 'MESH:D009127', (266, 274))	('perturbation', 'Var', (4, 16))	('rigidity', 'Disease', (266, 274))
67065	26739692	Short hairpin RNA-driven depletion of septin 7 resulted in mitotic blebbing with similarities to that seen with TTFields treatment , and an increase in cell size .	('septin 7', 'Gene', '989', (38, 46))	('mitotic blebbing', 'CPA', (59, 75))	('septin 7', 'Gene', (38, 46))	('cell size', 'CPA', (152, 161))	('depletion', 'Var', (25, 34))	('increase', 'PosReg', (140, 148))	('TTFields', 'Chemical', '-', (112, 120))
67066	26739692	These observations strongly suggests a mechanism of action where TTFields perturb mitosis by interfering with normal septin localization and function during mitosis, leading membrane blebbing and aberrant mitotic exit.	('septin', 'Protein', (117, 123))	('perturb mitosis', 'Disease', (74, 89))	('TTFields', 'Var', (65, 73))	('TTFields', 'Chemical', '-', (65, 73))	('localization', 'MPA', (124, 136))	('perturb mitosis', 'Disease', 'MESH:C536875', (74, 89))	('interfering', 'NegReg', (93, 104))	('mitosis', 'Disease', (82, 89))	('mitosis', 'Disease', 'None', (82, 89))	('function', 'MPA', (141, 149))	('mitosis', 'Disease', (157, 164))	('mitosis', 'Disease', 'None', (157, 164))	('mitotic exit', 'CPA', (205, 217))
67068	26739692	Likewise, cells exposed to TTFields subsequently exhibit decreased proliferation with a failure to enter S phase and increased levels of apoptosis beginning > 24 hours after TTFields exposure in a p53-dependent manner.	('TTFields', 'Var', (27, 35))	('increased', 'PosReg', (117, 126))	('apoptosis', 'MPA', (137, 146))	('TTFields', 'Chemical', '-', (27, 35))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('decreased', 'NegReg', (57, 66))	('levels', 'MPA', (127, 133))	('TTFields', 'Chemical', '-', (174, 182))
67112	26739692	Patients in the chemotherapy arm were observed to have a similar but less robust dichotomization; those who used > 4.1 and <= 4.1 mg/day dexamethasone had a mOS of 6.0 and 8.9 months, respectively.	('dexamethasone', 'Chemical', 'MESH:D003907', (137, 150))	('<= 4.1', 'Var', (123, 129))	('mOS', 'Gene', '17451', (157, 160))	('Patients', 'Species', '9606', (0, 8))	('mOS', 'Gene', (157, 160))
67161	26015297	A number of factors have been identified to be prognostic for survival in GB patients including age, performance status, neurological function, neurocognitive function, extent of surgical resection, MGMT promoter methylation and IDH1 mutation.	('MGMT', 'Gene', '4255', (199, 203))	('IDH1', 'Gene', (229, 233))	('mutation', 'Var', (234, 242))	('IDH1', 'Gene', '3417', (229, 233))	('patients', 'Species', '9606', (77, 85))	('MGMT', 'Gene', (199, 203))	('GB', 'Phenotype', 'HP:0012174', (74, 76))
67176	26015297	After receiving institutional research ethics approval, an electronic chart review was completed to collect the following baseline patient and tumor characteristics: age at treatment, body mass index (BMI), prior history of diabetes and use of diabetic medication, Eastern Co-operative Group (ECOG) performance status, and isocitrate dehydrogenase 1 (IDH-1) mutation status.	('diabetes', 'Disease', (224, 232))	('tumor', 'Disease', (143, 148))	('IDH-1', 'Gene', '3417', (351, 356))	('diabetes', 'Disease', 'MESH:D003920', (224, 232))	('diabetic', 'Disease', 'MESH:D003920', (244, 252))	('IDH-1', 'Gene', (351, 356))	('mutation', 'Var', (358, 366))	('isocitrate dehydrogenase 1', 'Gene', (323, 349))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('isocitrate dehydrogenase 1', 'Gene', '3417', (323, 349))	('diabetic', 'Disease', (244, 252))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('patient', 'Species', '9606', (131, 138))
67259	26015297	The mechanism of through which IDH-1 mutation effect tumor outcomes is not well understood.	('mutation', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('IDH-1', 'Gene', (31, 36))	('IDH-1', 'Gene', '3417', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('effect', 'Reg', (46, 52))	('tumor', 'Disease', (53, 58))
67260	26015297	One of the proposed mechanisms of relevance to our study is that GBM cells harboring the IDH mutation have impaired glucose oxidation leading to reduced production of energy and other substrates used for biosynthesis and resulting in slower growth rates.	('impaired glucose oxidation', 'Disease', (107, 133))	('reduced', 'NegReg', (145, 152))	('growth rates', 'MPA', (241, 253))	('GB', 'Phenotype', 'HP:0012174', (65, 67))	('slower', 'NegReg', (234, 240))	('impaired glucose oxidation', 'Phenotype', 'HP:0040270', (107, 133))	('IDH', 'Gene', (89, 92))	('mutation', 'Var', (93, 101))	('IDH', 'Gene', '3417', (89, 92))	('impaired glucose oxidation', 'Disease', 'MESH:D004194', (107, 133))
67261	26015297	Based on this proposed mechanism, higher glucose exposure may not drive metabolism in tumors with IDH-1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (104, 113))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('IDH-1', 'Gene', '3417', (98, 103))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('IDH-1', 'Gene', (98, 103))	('metabolism', 'MPA', (72, 82))
67262	26015297	However considering the small proportion of IDH-1 mutated tumors in our cohort, only 6 % of all evaluated tumors, the IDH mutations status of cases included in this study are unlikely to confound our findings.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('IDH', 'Gene', (118, 121))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mutated', 'Var', (50, 57))	('IDH', 'Gene', '3417', (118, 121))	('IDH', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('IDH-1', 'Gene', '3417', (44, 49))	('IDH-1', 'Gene', (44, 49))	('IDH', 'Gene', '3417', (44, 47))
67274	26030909	Cell movement, colony formation, and invasion in vitro were suppressed by sFRP4+TMZ treatment, which correlated with the switch of expression of markers from mesenchymal (Twist, Snail, N-cadherin) to epithelial (E-cadherin).	('suppressed', 'NegReg', (60, 70))	('colony formation', 'CPA', (15, 31))	('N-cadherin', 'Gene', (185, 195))	('sFRP4+TMZ', 'Var', (74, 83))	('Snail', 'Gene', '6615', (178, 183))	('Snail', 'Gene', (178, 183))	('N-cadherin', 'Gene', '1000', (185, 195))	('TMZ', 'Chemical', 'MESH:D000077204', (80, 83))	('E-cadherin', 'Gene', (212, 222))	('Cell movement', 'CPA', (0, 13))	('E-cadherin', 'Gene', '999', (212, 222))	('invasion in vitro', 'CPA', (37, 54))
67275	26030909	sFRP4 treatment elicited activation of the Wnt-Ca2 + pathway, which antagonizes the Wnt/ss-catenin pathway.	('Wnt', 'Chemical', '-', (84, 87))	('Wnt', 'Chemical', '-', (43, 46))	('ss-catenin', 'Chemical', '-', (88, 98))	('treatment', 'Var', (6, 15))	('Ca2', 'Gene', '760', (47, 50))	('sFRP4', 'Gene', (0, 5))	('activation', 'PosReg', (25, 35))	('Ca2', 'Gene', (47, 50))
67277	26030909	The efficacy of sFRP4+TMZ treatment was demonstrated in vivo using nude mice, which showed minimum tumor engraftment using CSCs pretreated with sFRP4+TMZ.	('tumor', 'Disease', (99, 104))	('mum', 'Gene', '56925', (95, 98))	('S', 'Chemical', 'MESH:D013455', (124, 125))	('nude mice', 'Species', '10090', (67, 76))	('TMZ', 'Chemical', 'MESH:D000077204', (22, 25))	('sFRP4+TMZ', 'Var', (144, 153))	('TMZ', 'Chemical', 'MESH:D000077204', (150, 153))	('mum', 'Gene', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
67290	26030909	Over-expression of sFRP4 has been associated with a decreased rate of proliferation, decreased anchorage-independent growth, and decreased invasiveness in the prostate cancer cell line, PC-3.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('decreased', 'NegReg', (85, 94))	('PC-3', 'CellLine', 'CVCL:0035', (186, 190))	('anchorage-independent growth', 'CPA', (95, 123))	('decreased', 'NegReg', (52, 61))	('sFRP4', 'Gene', (19, 24))	('decreased invasiveness in the prostate cancer', 'Disease', 'MESH:D011471', (129, 174))	('prostate cancer', 'Phenotype', 'HP:0012125', (159, 174))	('decreased invasiveness in the prostate cancer', 'Disease', (129, 174))	('Over-expression', 'Var', (0, 15))
67291	26030909	Silencing of the sFRP genes through hypermethylation of the promoter region has been detected in cancers such as hepatocarcinoma and GBM.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('sFRP genes', 'Gene', (17, 27))	('cancers', 'Disease', (97, 104))	('hepatocarcinoma', 'Disease', 'None', (113, 128))	('Silencing', 'NegReg', (0, 9))	('hypermethylation', 'Var', (36, 52))	('hepatocarcinoma', 'Disease', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('GBM', 'Disease', (133, 136))	('detected', 'Reg', (85, 93))	('S', 'Chemical', 'MESH:D013455', (0, 1))
67309	26030909	A similar pattern was observed using the BrdU cell proliferation assay, wherein S+T treatment was seen to inhibit proliferation up to 40% (Fig 2B).	('BrdU', 'Chemical', 'MESH:D001973', (41, 45))	('S+T', 'Chemical', '-', (80, 83))	('inhibit', 'NegReg', (106, 113))	('proliferation', 'CPA', (114, 127))	('S+T treatment', 'Var', (80, 93))
67311	26030909	This was further confirmed by labeling the spheroids for the CD133 marker by immunocytochemistry, which displayed a marked reduction of CD133 staining in S+T treated samples (Fig 2C).	('S+T treated', 'Var', (154, 165))	('CD133', 'Gene', (61, 66))	('S+T', 'Chemical', '-', (154, 157))	('staining', 'MPA', (142, 150))	('reduction', 'NegReg', (123, 132))	('CD133', 'Gene', (136, 141))	('CD133', 'Gene', '8842', (136, 141))	('CD133', 'Gene', '8842', (61, 66))
67317	26030909	The percentage of apoptotic cells increased in S, T, and S+T treated U87 and U373, thereby indicating the onset of apoptosis by changes in mitochondrial membrane potential (Fig 4).	('apoptotic cells', 'CPA', (18, 33))	('S+T', 'Var', (57, 60))	('mitochondrial membrane potential', 'MPA', (139, 171))	('S', 'Chemical', 'MESH:D013455', (57, 58))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('S+T', 'Chemical', '-', (57, 60))	('changes', 'Reg', (128, 135))
67323	26030909	The expression of the mesenchymal marker N-cadherin was observed to have reduced significantly in S+T treated GSCs, with a pronounced decrease in U87 GSCs.	('S', 'Chemical', 'MESH:D013455', (111, 112))	('N-cadherin', 'Gene', (41, 51))	('reduced', 'NegReg', (73, 80))	('expression', 'MPA', (4, 14))	('S+T', 'Var', (98, 101))	('decrease', 'NegReg', (134, 142))	('N-cadherin', 'Gene', '1000', (41, 51))	('S', 'Chemical', 'MESH:D013455', (98, 99))	('S+T', 'Chemical', '-', (98, 101))	('S', 'Chemical', 'MESH:D013455', (151, 152))
67324	26030909	A decrease in the stemness related marker CD133 was observed to be dramatic in S+T treated GSCs from U87 and U373 cell lines.	('S', 'Chemical', 'MESH:D013455', (79, 80))	('CD133', 'Gene', '8842', (42, 47))	('decrease', 'NegReg', (2, 10))	('S', 'Chemical', 'MESH:D013455', (92, 93))	('stemness', 'CPA', (18, 26))	('S+T', 'Var', (79, 82))	('S+T', 'Chemical', '-', (79, 82))	('CD133', 'Gene', (42, 47))
67326	26030909	Expectedly, treatment with S+T led to a significant decrease in expression of these three transcription factors in both cell lines as seen by RT-PCR (S3 Fig) and qPCR (Fig 6A and 6B).	('S', 'Chemical', 'MESH:D013455', (27, 28))	('expression', 'MPA', (64, 74))	('S+T', 'Var', (27, 30))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('decrease', 'NegReg', (52, 60))	('S+T', 'Chemical', '-', (27, 30))
67328	26030909	It was observed that expression of these markers reduced significantly upon treatment with S+T, and the level of ABCC2 was undetectable in S+T treated U87 GSCs (Fig 6A and 6B).	('S+T', 'Var', (139, 142))	('reduced', 'NegReg', (49, 56))	('ABCC2', 'Gene', (113, 118))	('ABCC2', 'Gene', '1244', (113, 118))	('S', 'Chemical', 'MESH:D013455', (139, 140))	('S+T', 'Chemical', '-', (91, 94))	('expression', 'MPA', (21, 31))	('S+T', 'Chemical', '-', (139, 142))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('S', 'Chemical', 'MESH:D013455', (91, 92))
67334	26030909	Treatment of U87 spheroids with S+T resulted in a substantial reduction in alpha-SMA, vimentin, and beta-catenin protein expression when compared to the untreated control U87 spheroid cells (Fig 7B).	('beta-catenin', 'Gene', (100, 112))	('S+T', 'Var', (32, 35))	('vimentin', 'Protein', (86, 94))	('beta-catenin', 'Gene', '1499', (100, 112))	('S+T', 'Chemical', '-', (32, 35))	('SMA', 'Gene', '6606', (81, 84))	('SMA', 'Gene', (81, 84))	('reduction', 'NegReg', (62, 71))
67342	26030909	In addition, in U87 GSCs treated with S+T, the colonies had a drastic decrease in size and the cell numbers in the colonies were meager (Fig 9A).	('S+T', 'Chemical', '-', (38, 41))	('meager', 'NegReg', (129, 135))	('S', 'Chemical', 'MESH:D013455', (38, 39))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('colonies', 'CPA', (47, 55))	('cell numbers', 'CPA', (95, 107))	('S+T', 'Var', (38, 41))	('decrease', 'NegReg', (70, 78))
67347	26030909	Staining with crystal violet revealed a clear inhibition of cell growth through the ECM in S+T treated cells (Fig 9B, panel 3).	('S+T', 'Var', (91, 94))	('inhibition', 'NegReg', (46, 56))	('S+T', 'Chemical', '-', (91, 94))	('cell growth', 'CPA', (60, 71))	('S', 'Chemical', 'MESH:D013455', (91, 92))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('crystal violet', 'Chemical', 'MESH:D005840', (14, 28))
67354	26030909	On the 10th day, upon harvest, there were significantly smaller volumes of subcutaneous tumors from the mice injected with S+T treated GSCs than that of untreated, S treated, and T treated groups (Fig 10B).	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (75, 94))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (75, 94))	('S+T', 'Chemical', '-', (123, 126))	('S+T treated', 'Var', (123, 134))	('mice', 'Species', '10090', (104, 108))	('smaller', 'NegReg', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('S', 'Chemical', 'MESH:D013455', (136, 137))	('subcutaneous tumors', 'Disease', (75, 94))	('S', 'Chemical', 'MESH:D013455', (123, 124))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('S', 'Chemical', 'MESH:D013455', (164, 165))
67372	26030909	We observed that GSCs treated with S+T had substantially increased anchorage and decreased sphere forming ability, wherein the cells could grow out of the spheres and adhere to form a monolayer.	('decreased', 'NegReg', (81, 90))	('S', 'Chemical', 'MESH:D013455', (18, 19))	('S+T', 'Chemical', '-', (35, 38))	('sphere forming ability', 'CPA', (91, 113))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('increased', 'PosReg', (57, 66))	('S+T', 'Var', (35, 38))	('anchorage', 'CPA', (67, 76))
67374	26030909	We observed that treatment with S+T decreased GSC invasiveness through ECM and migration through transwell chambers, which could be interlinked to the acquisition of epithelial traits by this drug combination.	('S+T', 'Var', (32, 35))	('S+T', 'Chemical', '-', (32, 35))	('migration through transwell chambers', 'CPA', (79, 115))	('S', 'Chemical', 'MESH:D013455', (32, 33))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('GSC invasiveness through ECM', 'CPA', (46, 74))	('decreased', 'NegReg', (36, 45))
67377	26030909	The pronounced reduction that we observed of the cytoskeletal proteins, vimentin, and alpha smooth muscle actin, and the adherens junction protein, ss-catenin, in S+T treated CSCs is clear testimony to the switch of the status from mesenchymal to epithelial.	('S', 'Chemical', 'MESH:D013455', (176, 177))	('vimentin', 'Protein', (72, 80))	('cytoskeletal proteins', 'MPA', (49, 70))	('S', 'Chemical', 'MESH:D013455', (163, 164))	('S+T', 'Chemical', '-', (163, 166))	('reduction', 'NegReg', (15, 24))	('ss-catenin', 'Chemical', '-', (148, 158))	('alpha smooth muscle actin', 'Protein', (86, 111))	('S+T', 'Var', (163, 166))
67379	26030909	The Snail family of transcription factors initiates the repression of E-cadherin by mediating histone modifications, which alter their protein stability and intracellular localization.	('intracellular localization', 'MPA', (157, 183))	('mediating', 'Reg', (84, 93))	('histone', 'MPA', (94, 101))	('Snail', 'Gene', (4, 9))	('Snail', 'Gene', '6615', (4, 9))	('protein stability', 'MPA', (135, 152))	('alter', 'Reg', (123, 128))	('modifications', 'Var', (102, 115))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', '999', (70, 80))
67382	26030909	The involvement of EMT-mediating transcription factors were clearly seen in our study where the expression of Snail, Slug, and Twist decreased to half in S+T treated GSCs.	('S', 'Chemical', 'MESH:D013455', (117, 118))	('S+T', 'Var', (154, 157))	('expression', 'MPA', (96, 106))	('Twist', 'Gene', (127, 132))	('S', 'Chemical', 'MESH:D013455', (110, 111))	('Slug', 'Gene', '6591', (117, 121))	('S+T', 'Chemical', '-', (154, 157))	('Slug', 'Gene', (117, 121))	('Snail', 'Gene', (110, 115))	('S', 'Chemical', 'MESH:D013455', (167, 168))	('S', 'Chemical', 'MESH:D013455', (154, 155))	('Snail', 'Gene', '6615', (110, 115))	('decreased', 'NegReg', (133, 142))
67383	26030909	In concordance, the expression of the functional epithelial marker E-cadherin had a two fold increase in S+T treated GSCs, and its mesenchymal counterpart N-cadherin decreased upon drug treatment.	('S+T', 'Var', (105, 108))	('expression', 'MPA', (20, 30))	('increase', 'PosReg', (93, 101))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('S+T', 'Chemical', '-', (105, 108))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('N-cadherin', 'Gene', (155, 165))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('N-cadherin', 'Gene', '1000', (155, 165))
67391	26030909	Hence, the decreased expression of drug efflux proteins ABCG2 and ABCC4 by S+T treatment may reflect the gain of epithelial characteristics, and that the two processes of EMT and chemo-resistance may be intertwined.	('ABCC4', 'Gene', '10257', (66, 71))	('S+T', 'Var', (75, 78))	('ABCG2', 'Gene', (56, 61))	('drug efflux', 'MPA', (35, 46))	('decreased', 'NegReg', (11, 20))	('expression', 'MPA', (21, 31))	('S+T', 'Chemical', '-', (75, 78))	('ABCG2', 'Gene', '9429', (56, 61))	('gain', 'PosReg', (105, 109))	('ABCC4', 'Gene', (66, 71))	('epithelial', 'MPA', (113, 123))
67482	24252689	The strong negative impact of the H/C location on outcome is influenced by several factors including inability to perform complete resection, the high frequency of the PMA variant in this location and the young age of the patients.	('PMA', 'Gene', (168, 171))	('patients', 'Species', '9606', (222, 230))	('variant', 'Var', (172, 179))
67483	24252689	Recent studies have shown a wide range of mechanisms for deregulating the ERK/MAPK pathway in PA, including NF1 deletion and mutation, KIAA1549/BRAF fusion, SRGAP3/RAF1 fusion and BRAF V600E activating mutation.	('NF1', 'Gene', '4763', (108, 111))	('BRAF', 'Gene', (180, 184))	('SRGAP3', 'Gene', '9901', (157, 163))	('ERK', 'Gene', '5594', (74, 77))	('deregulating', 'PosReg', (57, 69))	('KIAA1549', 'Gene', '57670', (135, 143))	('deletion', 'Var', (112, 120))	('BRAF', 'Gene', '673', (144, 148))	('ERK', 'Gene', (74, 77))	('RAF1', 'Gene', (164, 168))	('RAF1', 'Gene', '5894', (164, 168))	('BRAF', 'Gene', (144, 148))	('SRGAP3', 'Gene', (157, 163))	('V600E', 'Mutation', 'rs113488022', (185, 190))	('BRAF', 'Gene', '673', (180, 184))	('NF1', 'Gene', (108, 111))	('KIAA1549', 'Gene', (135, 143))	('mutation', 'Var', (125, 133))
67484	24252689	These findings suggest that PA exhibiting BRAF alterations might benefit from BRAF signalling pathway inhibitors.	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', '673', (78, 82))	('benefit', 'PosReg', (65, 72))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', (42, 46))	('alterations', 'Var', (47, 58))
67521	24252689	IC50 values of celecoxib were 90 muM for U118 (Figure 2a) and 110 muM and U87-MG (data not shown).	('muM', 'Gene', (33, 36))	('muM', 'Gene', '56925', (66, 69))	('U87-MG', 'Var', (74, 80))	('muM', 'Gene', (66, 69))	('U118', 'Var', (41, 45))	('muM', 'Gene', '56925', (33, 36))	('celecoxib', 'Chemical', 'MESH:D000068579', (15, 24))	('U87-MG', 'CellLine', 'CVCL:0022', (74, 80))
67531	24252689	As shown in Figure 3c, the co-treatment with fluvastatin (240 muM) and celecoxib (100 muM) for 24 h triggered apoptosis in U87-MG.	('celecoxib', 'Chemical', 'MESH:D000068579', (71, 80))	('muM', 'Gene', '56925', (62, 65))	('U87-MG', 'CellLine', 'CVCL:0022', (123, 129))	('muM', 'Gene', '56925', (86, 89))	('U87-MG', 'Var', (123, 129))	('muM', 'Gene', (62, 65))	('muM', 'Gene', (86, 89))	('apoptosis', 'CPA', (110, 119))	('fluvastatin', 'Chemical', 'MESH:D000077340', (45, 56))
67563	24252689	Fluvastatin was also identified as a drug that could target genes of interest and therefore we hypothesized that it could be another potential agent for the treatment of H/C PA. Our in vitro data confirmed our hypothesis showing activity with IC50 in the range of 500 muM to 900 muM for GBM.	('GBM', 'Phenotype', 'HP:0012174', (287, 290))	('muM', 'Gene', '56925', (279, 282))	('activity', 'MPA', (229, 237))	('muM', 'Gene', '56925', (268, 271))	('muM', 'Gene', (279, 282))	('C PA', 'Gene', (172, 176))	('IC50', 'Var', (243, 247))	('Fluvastatin', 'Chemical', 'MESH:D000077340', (0, 11))	('muM', 'Gene', (268, 271))	('C PA', 'Gene', '1357', (172, 176))
67569	24252689	Indeed, combining the IC50 celecoxib concentration with a concentration of fluvastatin below the single drug IC50 triggered massive cell death (approximately 99%), therefore strengthening the potential interest of this combination.	('IC50', 'Var', (22, 26))	('cell death', 'CPA', (132, 142))	('fluvastatin', 'Chemical', 'MESH:D000077340', (75, 86))	('celecoxib', 'Chemical', 'MESH:D000068579', (27, 36))
67570	24252689	Steady state plasma levels of celecoxib following twice daily 250 mg/m2 celecoxib intake in children led to peak concentrations of 1400 mug/L +/- 700 and 2800 mug/L +/- 1500 respectively if celecoxib was taken without or with food.	('2800 mug/L +/- 1500', 'Var', (154, 173))	('celecoxib', 'Gene', (72, 81))	('celecoxib', 'Chemical', 'MESH:D000068579', (30, 39))	('celecoxib', 'Chemical', 'MESH:D000068579', (72, 81))	('children', 'Species', '9606', (92, 100))	('celecoxib', 'Chemical', 'MESH:D000068579', (190, 199))
67598	24252689	After 48 hr (subconfluency), cells were treated with serial concentrations of fluvastatin (30; 60; 120; 240; 365; 490; 610; 730; 850; 975 muM), celecoxib (0; 26; 52; 65; 78; 91; 104; 117; 131; 183; 210; 236; 260; 288; 314 muM) and their combinations in 100 mul of culture media.	('muM', 'Gene', (222, 225))	('30;', 'Var', (91, 94))	('celecoxib', 'Chemical', 'MESH:D000068579', (144, 153))	('muM', 'Gene', '56925', (138, 141))	('muM', 'Gene', (138, 141))	('fluvastatin', 'Chemical', 'MESH:D000077340', (78, 89))	('muM', 'Gene', '56925', (222, 225))
67626	23934175	cMYC Expression in Infiltrating Gliomas: Associations with IDH1 Mutations, Clinicopathologic Features and Outcome Gliomas are among the most frequent adult primary brain tumors.	('IDH1', 'Gene', '3417', (59, 63))	('cMYC', 'Gene', (0, 4))	('Gliomas', 'Phenotype', 'HP:0009733', (32, 39))	('Gliomas', 'Disease', (114, 121))	('Gliomas', 'Disease', (32, 39))	('Associations', 'Interaction', (41, 53))	('cMYC', 'Gene', '4609', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Mutations', 'Var', (64, 73))	('brain tumors', 'Disease', (164, 176))	('brain tumors', 'Disease', 'MESH:D001932', (164, 176))	('brain tumors', 'Phenotype', 'HP:0030692', (164, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('IDH1', 'Gene', (59, 63))	('Gliomas', 'Disease', 'MESH:D005910', (114, 121))	('Gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('Gliomas', 'Disease', 'MESH:D005910', (32, 39))
67627	23934175	Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('correlate with', 'Reg', (48, 62))	('IDH1', 'Gene', (13, 17))	('glioblastomas', 'Disease', 'MESH:D005909', (73, 86))	('glioblastomas', 'Phenotype', 'HP:0012174', (73, 86))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('increased', 'PosReg', (91, 100))	('survival', 'CPA', (101, 109))	('glioblastomas', 'Disease', (73, 86))
67629	23934175	Recent genotyping studies also showed SNP variants near the cMYC gene locus, associate with an increased risk for development of IDH1/2 mutant gliomas suggesting a possible interaction between cMYC and IDH1.	('cMYC', 'Gene', '4609', (60, 64))	('IDH1/2', 'Gene', '3417;3418', (129, 135))	('IDH1', 'Gene', (129, 133))	('cMYC', 'Gene', (193, 197))	('glioma', 'Phenotype', 'HP:0009733', (143, 149))	('IDH1/2', 'Gene', (129, 135))	('cMYC', 'Gene', (60, 64))	('gliomas', 'Disease', (143, 150))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', (202, 206))	('gliomas', 'Disease', 'MESH:D005910', (143, 150))	('cMYC', 'Gene', '4609', (193, 197))	('IDH1', 'Gene', '3417', (202, 206))	('gliomas', 'Phenotype', 'HP:0009733', (143, 150))	('SNP variants', 'Var', (38, 50))
67632	23934175	cMYC expression associated with younger age as well as p53 immunopositivity (OR=3.6, p=0.0332) and mutant IDH1 (R132H) (OR=7.4, p=0.06) among malignant gliomas in our cohort.	('cMYC', 'Gene', (0, 4))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('gliomas', 'Phenotype', 'HP:0009733', (152, 159))	('R132H', 'Mutation', 'rs121913500', (112, 117))	('IDH1', 'Gene', '3417', (106, 110))	('malignant gliomas', 'Disease', (142, 159))	('cMYC', 'Gene', '4609', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('mutant', 'Var', (99, 105))	('IDH1', 'Gene', (106, 110))	('malignant gliomas', 'Disease', 'MESH:D005910', (142, 159))	('R132H', 'Var', (112, 117))	('associated', 'Reg', (16, 26))
67633	23934175	Independent analysis of the publically available TCGA glioblastoma dataset confirmed our strong association between cMYC and mutant IDH1 expression.	('IDH1', 'Gene', (132, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('expression', 'MPA', (137, 147))	('mutant', 'Var', (125, 131))	('cMYC', 'Gene', '4609', (116, 120))	('IDH1', 'Gene', '3417', (132, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('cMYC', 'Gene', (116, 120))	('glioblastoma', 'Disease', (54, 66))
67635	23934175	However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 (R132H) mutants in both univariate and multivariate analyses.	('IDH1', 'Gene', (114, 118))	('shortened', 'NegReg', (44, 53))	('time to malignant transformation', 'CPA', (54, 86))	('cMYC', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (114, 118))	('mutants', 'Var', (127, 134))	('R132H', 'Mutation', 'rs121913500', (120, 125))	('cMYC', 'Gene', '4609', (9, 13))
67636	23934175	In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas.	('IDH1', 'Gene', '3417', (185, 189))	('gliomas', 'Phenotype', 'HP:0009733', (128, 135))	('gliomas', 'Disease', (128, 135))	('gliomas', 'Disease', 'MESH:D005910', (128, 135))	('gliomas', 'Disease', (197, 204))	('gliomas', 'Phenotype', 'HP:0009733', (197, 204))	('gliomas', 'Disease', 'MESH:D005910', (197, 204))	('cMYC', 'Gene', '4609', (38, 42))	('mutant', 'Var', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('associated', 'Reg', (50, 60))	('IDH1', 'Gene', (185, 189))	('cMYC', 'Gene', (38, 42))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))
67641	23934175	Primary glioblastomas frequently show epidermal growth factor receptor amplifications and p16INK4A deletions.	('amplifications', 'Var', (71, 85))	('p16INK4A', 'Gene', '1029', (90, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('epidermal growth factor receptor', 'Gene', (38, 70))	('Primary glioblastomas', 'Disease', (0, 21))	('epidermal growth factor receptor', 'Gene', '1956', (38, 70))	('glioblastomas', 'Phenotype', 'HP:0012174', (8, 21))	('Primary glioblastomas', 'Disease', 'MESH:D005909', (0, 21))	('p16INK4A', 'Gene', (90, 98))
67642	23934175	Conversely, a mutation of IDH1, leading to an amino acid substitution at codon 32 of exon 4 (IDH1 (R132H)), is a robust marker of secondary glioblastomas and associated with younger age.	('R132H', 'Mutation', 'rs121913500', (99, 104))	('IDH1', 'Gene', (93, 97))	('IDH1', 'Gene', '3417', (93, 97))	('glioblastomas', 'Phenotype', 'HP:0012174', (140, 153))	('IDH1', 'Gene', (26, 30))	('glioblastomas', 'Disease', 'MESH:D005909', (140, 153))	('amino acid substitution', 'Var', (46, 69))	('mutation', 'Var', (14, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('glioblastomas', 'Disease', (140, 153))	('IDH1', 'Gene', '3417', (26, 30))
67644	23934175	Chromosomal arms 1p and 19q co-deletion, typical of oligodendrogliomas, and IDH1 mutations are important genetic aberrations strongly correlated with survival and therapeutic response in gliomas.	('IDH1', 'Gene', (76, 80))	('gliomas', 'Phenotype', 'HP:0009733', (63, 70))	('gliomas', 'Disease', (63, 70))	('gliomas', 'Disease', (187, 194))	('arms 1p', 'Gene', '3075', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('arms 1p', 'Gene', (12, 19))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (52, 70))	('IDH1', 'Gene', '3417', (76, 80))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('gliomas', 'Disease', 'MESH:D005910', (63, 70))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('mutations', 'Var', (81, 90))	('oligodendrogliomas', 'Disease', (52, 70))	('correlated with', 'Reg', (134, 149))
67653	23934175	Furthermore, recent genotyping studies showed SNP variants mapping to 8q24.21, near the cMYC gene locus, associated with increased risk for development of IDH1/2 mutant gliomas, which suggests an interaction in the pathogenesis of gliomas at the genetic level.	('glioma', 'Phenotype', 'HP:0009733', (231, 237))	('cMYC', 'Gene', '4609', (88, 92))	('gliomas', 'Disease', (169, 176))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('gliomas', 'Disease', (231, 238))	('SNP', 'Gene', (46, 49))	('gliomas', 'Disease', 'MESH:D005910', (231, 238))	('gliomas', 'Phenotype', 'HP:0009733', (231, 238))	('cMYC', 'Gene', (88, 92))	('IDH1/2', 'Gene', '3417;3418', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (169, 175))	('variants', 'Var', (50, 58))	('associated', 'Reg', (105, 115))	('IDH1/2', 'Gene', (155, 161))
67682	23934175	Compared to IDH1 (R132H) negative malignant gliomas, IDH1 (R132H) mutants co-expressed cMYC more frequently [63/97 (65%) vs. 22/25 (88%), Fisher's exact p=0.028] and intensely [mean=0.85 vs. 1.20, t-test p=0.022] (Figure 2A-B).	('mutants', 'Var', (66, 73))	('cMYC', 'Gene', (87, 91))	('R132H', 'Mutation', 'rs121913500', (59, 64))	('IDH1', 'Gene', (12, 16))	('R132H', 'Mutation', 'rs121913500', (18, 23))	('malignant gliomas', 'Disease', 'MESH:D005910', (34, 51))	('IDH1', 'Gene', (53, 57))	('gliomas', 'Phenotype', 'HP:0009733', (44, 51))	('IDH1', 'Gene', '3417', (53, 57))	('cMYC', 'Gene', '4609', (87, 91))	('IDH1', 'Gene', '3417', (12, 16))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))	('malignant gliomas', 'Disease', (34, 51))
67686	23934175	Among glioblastomas, strong p53 expression was also more frequent among IDH1 (R132H) mutants (7/8 (87.5%) vs. 21/87 (24%), Pearsons chi2=14.1, p=0.0002).	('p53', 'Gene', (28, 31))	('IDH1', 'Gene', (72, 76))	('p53', 'Gene', '7157', (28, 31))	('glioblastomas', 'Phenotype', 'HP:0012174', (6, 19))	('mutants', 'Var', (85, 92))	('IDH1', 'Gene', '3417', (72, 76))	('glioblastomas', 'Disease', 'MESH:D005909', (6, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (6, 18))	('glioblastomas', 'Disease', (6, 19))	('expression', 'MPA', (32, 42))	('R132H', 'Mutation', 'rs121913500', (78, 83))
67688	23934175	Among malignant gliomas, cMYC expression independently associated with both strong p53 (OR=3.6, p=0.0332) and mutant IDH1 (R132H) (OR=7.4, p=0.06) expression.	('cMYC', 'Gene', (25, 29))	('R132H', 'Mutation', 'rs121913500', (123, 128))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('IDH1', 'Gene', '3417', (117, 121))	('malignant gliomas', 'Disease', 'MESH:D005910', (6, 23))	('gliomas', 'Phenotype', 'HP:0009733', (16, 23))	('cMYC', 'Gene', '4609', (25, 29))	('associated', 'Reg', (55, 65))	('mutant', 'Var', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (16, 22))	('R132H', 'Var', (123, 128))	('IDH1', 'Gene', (117, 121))	('malignant gliomas', 'Disease', (6, 23))
67700	23934175	Previous reports indicate significant associations between IDH1 mutations and the alternative lengthening of telomeres (ALT) phenotype and ATRX loss in astrocytomas.	('IDH1', 'Gene', '3417', (59, 63))	('ATRX', 'Gene', '546', (139, 143))	('alternative lengthening of', 'CPA', (82, 108))	('astrocytomas', 'Disease', 'MESH:D001254', (152, 164))	('mutations', 'Var', (64, 73))	('astrocytoma', 'Phenotype', 'HP:0009592', (152, 163))	('IDH1', 'Gene', (59, 63))	('ATRX', 'Gene', (139, 143))	('loss', 'NegReg', (144, 148))	('astrocytomas', 'Disease', (152, 164))
67704	23934175	Thus we performed FISH analysis in a subset of our cohort using probes targeting the cMYC locus and Ch 8 centromere.	('cMYC', 'Gene', '4609', (85, 89))	('cMYC', 'Gene', (85, 89))	('probes', 'Var', (64, 70))
67708	23934175	Next, we evaluated public TCGA datasets for correlations between IDH1 mutations and cMYC mRNA expression or copy number alterations in glioblastoma.	('IDH1', 'Gene', '3417', (65, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('mutations', 'Var', (70, 79))	('mRNA expression', 'MPA', (89, 104))	('copy number alterations', 'Var', (108, 131))	('cMYC', 'Gene', (84, 88))	('glioblastoma', 'Disease', (135, 147))	('IDH1', 'Gene', (65, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('cMYC', 'Gene', '4609', (84, 88))
67709	23934175	cMYC copy number correlated with mRNA expression (Supplemental Figure S2).	('cMYC', 'Gene', (0, 4))	('copy number', 'Var', (5, 16))	('mRNA expression', 'MPA', (33, 48))	('cMYC', 'Gene', '4609', (0, 4))	('correlated', 'Reg', (17, 27))
67710	23934175	Similar to our immunohistochemical results, cMYC mRNA expression was significantly higher in IDH1-R132 mutants versus IDH1 wild type glioblastomas (median 0.9565 versus 0.0305, respectively; t-test p=0.0007)(Figure 3).	('IDH1', 'Gene', (93, 97))	('cMYC', 'Gene', '4609', (44, 48))	('IDH1', 'Gene', (118, 122))	('glioblastomas', 'Disease', 'MESH:D005909', (133, 146))	('mutants', 'Var', (103, 110))	('IDH1', 'Gene', '3417', (93, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('IDH1', 'Gene', '3417', (118, 122))	('glioblastomas', 'Disease', (133, 146))	('cMYC', 'Gene', (44, 48))	('higher', 'PosReg', (83, 89))	('glioblastomas', 'Phenotype', 'HP:0012174', (133, 146))
67711	23934175	All heterozygous cMYC deletions were detected in IDH1 wild types, while 7/14 (50%) of IDH1-R132 mutated and 23/203 (11%) of IDH1 wild types showed cMYC amplification (p<0.0001).	('cMYC', 'Gene', (147, 151))	('mutated', 'Var', (96, 103))	('IDH1', 'Gene', '3417', (49, 53))	('deletions', 'Var', (22, 31))	('IDH1', 'Gene', (86, 90))	('IDH1', 'Gene', (124, 128))	('cMYC', 'Gene', '4609', (17, 21))	('cMYC', 'Gene', '4609', (147, 151))	('IDH1', 'Gene', '3417', (124, 128))	('IDH1', 'Gene', '3417', (86, 90))	('cMYC', 'Gene', (17, 21))	('IDH1', 'Gene', (49, 53))
67713	23934175	Next we explored the prognostic significance of cMYC and IDH1 (R132H) expression.	('R132H', 'Var', (63, 68))	('cMYC', 'Gene', (48, 52))	('R132H', 'Mutation', 'rs121913500', (63, 68))	('IDH1', 'Gene', (57, 61))	('cMYC', 'Gene', '4609', (48, 52))	('IDH1', 'Gene', '3417', (57, 61))
67716	23934175	IDH1 (R132H) expression associated with improved survival compared to IDH1 (R132H) negative malignant gliomas [median 42 vs. 16 months, p=0.0026], irrespective of cMYC expression (Figure 4B), suggesting the impact of cMYC expression on survival depends on IDH1 mutation status.	('cMYC', 'Gene', (163, 167))	('IDH1', 'Gene', (256, 260))	('expression', 'Var', (13, 23))	('improved', 'PosReg', (40, 48))	('IDH1', 'Gene', (0, 4))	('survival', 'MPA', (49, 57))	('cMYC', 'Gene', (217, 221))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('IDH1', 'Gene', '3417', (256, 260))	('cMYC', 'Gene', '4609', (163, 167))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('IDH1', 'Gene', '3417', (0, 4))	('IDH1', 'Gene', (70, 74))	('malignant gliomas', 'Disease', 'MESH:D005910', (92, 109))	('R132H', 'Mutation', 'rs121913500', (6, 11))	('cMYC', 'Gene', '4609', (217, 221))	('malignant gliomas', 'Disease', (92, 109))	('IDH1', 'Gene', '3417', (70, 74))	('R132H', 'Mutation', 'rs121913500', (76, 81))
67719	23934175	However, both age (RR=22.3, p=0.0107) and cMYC expression (RR=51.6, p=0.0251), but not strong p53 expression (RR=0.5, p=0.1785), were associated with increased risk of death among IDH1 (R132H) mutants in malignant gliomas.	('cMYC', 'Gene', (42, 46))	('IDH1', 'Gene', (180, 184))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('IDH1', 'Gene', '3417', (180, 184))	('death', 'Disease', 'MESH:D003643', (168, 173))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('death', 'Disease', (168, 173))	('mutants', 'Var', (193, 200))	('malignant gliomas', 'Disease', (204, 221))	('cMYC', 'Gene', '4609', (42, 46))	('R132H', 'Mutation', 'rs121913500', (186, 191))	('malignant gliomas', 'Disease', 'MESH:D005910', (204, 221))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))
67721	23934175	Interestingly, cMYC expression correlated with reduced time to malignant transformation in IDH1 (R132H) mutants (p=0.02) (Figure 5A).	('cMYC', 'Gene', '4609', (15, 19))	('time to malignant transformation', 'CPA', (55, 87))	('mutants', 'Var', (104, 111))	('IDH1', 'Gene', (91, 95))	('cMYC', 'Gene', (15, 19))	('R132H', 'Mutation', 'rs121913500', (97, 102))	('IDH1', 'Gene', '3417', (91, 95))	('reduced', 'NegReg', (47, 54))
67722	23934175	Next we evaluated the impact of cMYC mRNA expression or gene amplification and IDH1 mutations on survival in the glioblastoma TCGA dataset.	('glioblastoma', 'Disease', (113, 125))	('IDH1', 'Gene', '3417', (79, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('cMYC', 'Gene', '4609', (32, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('mutations', 'Var', (84, 93))	('cMYC', 'Gene', (32, 36))	('IDH1', 'Gene', (79, 83))
67723	23934175	As previously reported, IDH1 (R132) mutations correlated with increased progression-free and overall survival.	('increased', 'PosReg', (62, 71))	('IDH1', 'Gene', '3417', (24, 28))	('overall survival', 'CPA', (93, 109))	('mutations', 'Var', (36, 45))	('IDH1', 'Gene', (24, 28))	('progression-free', 'CPA', (72, 88))
67724	23934175	Despite trends similar to our cohort, we detected no association with progression-free or overall survival once stratifying by both IDH1 mutation and cMYC mRNA expression (using the 75% quartile as cut-off).	('cMYC', 'Gene', (150, 154))	('IDH1', 'Gene', (132, 136))	('mutation', 'Var', (137, 145))	('IDH1', 'Gene', '3417', (132, 136))	('cMYC', 'Gene', '4609', (150, 154))	('overall', 'MPA', (90, 97))
67725	23934175	We also detected a non significant trend between cMYC amplification and improved survival among IDH1-R132 mutant glioblastomas (p=0.07) (Supplemental Figure S3).	('IDH1', 'Gene', '3417', (96, 100))	('mutant', 'Var', (106, 112))	('glioblastomas', 'Phenotype', 'HP:0012174', (113, 126))	('cMYC', 'Gene', (49, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('improved', 'PosReg', (72, 80))	('glioblastomas', 'Disease', 'MESH:D005909', (113, 126))	('cMYC', 'Gene', '4609', (49, 53))	('survival', 'MPA', (81, 89))	('glioblastomas', 'Disease', (113, 126))	('IDH1', 'Gene', (96, 100))
67726	23934175	TCGA analyses were limited by sample size as only 14/185 (7.6%) glioblastomas had IDH1 mutations.	('glioblastomas', 'Phenotype', 'HP:0012174', (64, 77))	('glioblastomas', 'Disease', 'MESH:D005909', (64, 77))	('glioblastomas', 'Disease', (64, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (82, 86))	('mutations', 'Var', (87, 96))
67727	23934175	These findings suggest that although the clinical significance of cMYC nuclear protein levels is difficult to separate from other well established glioma prognostic factors (age, tumor grade, IDH1 mutations), it may be an adverse prognostic factor in the smaller subset of IDH1 mutant gliomas.	('gliomas', 'Disease', 'MESH:D005910', (285, 292))	('glioma', 'Phenotype', 'HP:0009733', (285, 291))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('IDH1', 'Gene', '3417', (273, 277))	('IDH1', 'Gene', '3417', (192, 196))	('glioma', 'Disease', (147, 153))	('mutant', 'Var', (278, 284))	('cMYC', 'Gene', (66, 70))	('gliomas', 'Phenotype', 'HP:0009733', (285, 292))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('cMYC', 'Gene', '4609', (66, 70))	('gliomas', 'Disease', (285, 292))	('glioma', 'Disease', (285, 291))	('IDH1', 'Gene', (273, 277))	('glioma', 'Disease', 'MESH:D005910', (285, 291))	('IDH1', 'Gene', (192, 196))	('tumor', 'Disease', (179, 184))
67729	23934175	Our main finding is the association of cMYC expression with mutant IDH1 (R132H) expression and strong p53 nuclear labeling in malignant gliomas.	('malignant gliomas', 'Disease', (126, 143))	('cMYC', 'Gene', '4609', (39, 43))	('association', 'Interaction', (24, 35))	('R132H', 'Var', (73, 78))	('IDH1', 'Gene', (67, 71))	('malignant gliomas', 'Disease', 'MESH:D005910', (126, 143))	('p53', 'Gene', '7157', (102, 105))	('gliomas', 'Phenotype', 'HP:0009733', (136, 143))	('R132H', 'Mutation', 'rs121913500', (73, 78))	('IDH1', 'Gene', '3417', (67, 71))	('cMYC', 'Gene', (39, 43))	('expression', 'MPA', (80, 90))	('p53', 'Gene', (102, 105))	('mutant', 'Var', (60, 66))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
67733	23934175	Additionally, recent genotyping studies showed SNP variants mapping to 8q24.21, near the cMYC gene locus, associated with increased risk for development of IDH1/2 mutant gliomas, which further suggests their interaction in gliomagenesis.	('cMYC', 'Gene', (89, 93))	('IDH1/2', 'Gene', (156, 162))	('associated', 'Reg', (106, 116))	('glioma', 'Disease', (170, 176))	('cMYC', 'Gene', '4609', (89, 93))	('gliomas', 'Disease', (170, 177))	('mutant', 'Var', (163, 169))	('variants', 'Var', (51, 59))	('glioma', 'Disease', 'MESH:D005910', (223, 229))	('gliomas', 'Disease', 'MESH:D005910', (170, 177))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('glioma', 'Phenotype', 'HP:0009733', (223, 229))	('glioma', 'Disease', 'MESH:D005910', (170, 176))	('glioma', 'Phenotype', 'HP:0009733', (170, 176))	('IDH1/2', 'Gene', '3417;3418', (156, 162))	('glioma', 'Disease', (223, 229))	('SNP', 'Gene', (47, 50))
67735	23934175	Interestingly, cMYC co-expression predicted decreased time to malignant transformation among IDH1 (R132H) mutants, suggesting the prognostic significance of cMYC may depend on IDH1 mutation status.	('cMYC', 'Gene', '4609', (15, 19))	('IDH1', 'Gene', (93, 97))	('R132H', 'Mutation', 'rs121913500', (99, 104))	('cMYC', 'Gene', '4609', (157, 161))	('IDH1', 'Gene', '3417', (93, 97))	('IDH1', 'Gene', '3417', (176, 180))	('time to malignant transformation', 'CPA', (54, 86))	('cMYC', 'Gene', (15, 19))	('cMYC', 'Gene', (157, 161))	('mutants', 'Var', (106, 113))	('decreased', 'NegReg', (44, 53))	('IDH1', 'Gene', (176, 180))
67738	23934175	Although it is unclear how IDH1 mutations affect cMYC protein nuclear levels, strong evidence supports IDH1 mutations as early events in infiltrating gliomas and links IDH1 to profound metabolic and epigenetic effects that putatively may affect cMYC expression downstream (Figure 4B).	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('IDH1', 'Gene', (168, 172))	('IDH1', 'Gene', (103, 107))	('cMYC', 'Gene', (49, 53))	('mutations', 'Var', (32, 41))	('IDH1', 'Gene', '3417', (168, 172))	('IDH1', 'Gene', '3417', (103, 107))	('cMYC', 'Gene', (245, 249))	('cMYC', 'Gene', '4609', (49, 53))	('gliomas', 'Disease', (150, 157))	('IDH1', 'Gene', (27, 31))	('epigenetic effects', 'Var', (199, 217))	('mutations', 'Var', (108, 117))	('affect', 'Reg', (238, 244))	('gliomas', 'Disease', 'MESH:D005910', (150, 157))	('IDH1', 'Gene', '3417', (27, 31))	('expression', 'MPA', (250, 260))	('cMYC', 'Gene', '4609', (245, 249))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
67740	23934175	Interestingly, prior studies demonstrated growth inhibition by inhibiting glutaminase in the context of IDH1 mutations.	('IDH1', 'Gene', '3417', (104, 108))	('glutaminase', 'Protein', (74, 85))	('growth inhibition', 'MPA', (42, 59))	('inhibiting', 'NegReg', (63, 73))	('mutations', 'Var', (109, 118))	('IDH1', 'Gene', (104, 108))
67741	23934175	Among IDH1 (R132H) mutants with better prognosis, both age and cMYC protein co-expression predicted decrease survival among malignant gliomas, consistent with prior associations with increased proliferation and WHO grade.	('IDH1', 'Gene', '3417', (6, 10))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('cMYC', 'Gene', (63, 67))	('malignant gliomas', 'Disease', (124, 141))	('survival', 'MPA', (109, 117))	('cMYC', 'Gene', '4609', (63, 67))	('malignant gliomas', 'Disease', 'MESH:D005910', (124, 141))	('decrease', 'NegReg', (100, 108))	('gliomas', 'Phenotype', 'HP:0009733', (134, 141))	('mutants', 'Var', (19, 26))	('R132H', 'Mutation', 'rs121913500', (12, 17))	('IDH1', 'Gene', (6, 10))
67742	23934175	One caveat is that all of these associations were limited by the rarity of cMYC-negative IDH1 (R132H) mutants, and therefore will require validation in larger cohorts.	('mutants', 'Var', (102, 109))	('cMYC', 'Gene', '4609', (75, 79))	('IDH1', 'Gene', (89, 93))	('cMYC', 'Gene', (75, 79))	('R132H', 'Mutation', 'rs121913500', (95, 100))	('IDH1', 'Gene', '3417', (89, 93))
67743	23934175	Interestingly, cMYC amplification showed a non significant trend for improved survival among IDH1 (R132) mutated TCGA glioblastomas, although we found no bona fide cMYC amplifications in the limited cases tested by FISH in our cohort.	('cMYC', 'Gene', (164, 168))	('IDH1', 'Gene', (93, 97))	('TCGA', 'Disease', (113, 117))	('cMYC', 'Gene', '4609', (15, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('improved', 'PosReg', (69, 77))	('glioblastomas', 'Disease', (118, 131))	('IDH1', 'Gene', '3417', (93, 97))	('cMYC', 'Gene', (15, 19))	('cMYC', 'Gene', '4609', (164, 168))	('mutated', 'Var', (105, 112))	('amplification', 'Var', (20, 33))	('glioblastomas', 'Phenotype', 'HP:0012174', (118, 131))	('glioblastomas', 'Disease', 'MESH:D005909', (118, 131))
67745	23934175	In contrast to TCGA results but in support of our findings, a prior aCGH study of oligodendrogliomas, characterized by a high frequency of IDH1/2 mutations, 8q gain was a feature in a subset (17%) and associated with worse outcome.	('IDH1/2', 'Gene', (139, 145))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (82, 100))	('mutations', 'Var', (146, 155))	('gliomas', 'Phenotype', 'HP:0009733', (93, 100))	('gain', 'PosReg', (160, 164))	('IDH1/2', 'Gene', '3417;3418', (139, 145))	('oligodendrogliomas', 'Disease', (82, 100))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))
67747	23934175	A recent study identified CIC and FUBP1 as putative tumor suppressor genes frequently mutated in oligodendrogliomas.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('mutated', 'Var', (86, 93))	('oligodendrogliomas', 'Disease', (97, 115))	('CIC', 'Gene', '23152', (26, 29))	('tumor', 'Disease', (52, 57))	('FUBP1', 'Gene', (34, 39))	('CIC', 'Gene', (26, 29))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (97, 115))	('FUBP1', 'Gene', '8880', (34, 39))
67750	23934175	The impact of cMYC on survival among IDH1 (R132H) mutants should, thus, account for protein, mRNA and gene dosage variations separately.	('cMYC', 'Gene', (14, 18))	('IDH1', 'Gene', (37, 41))	('cMYC', 'Gene', '4609', (14, 18))	('IDH1', 'Gene', '3417', (37, 41))	('R132H', 'Var', (43, 48))	('R132H', 'Mutation', 'rs121913500', (43, 48))
67751	23934175	In conclusion, our study showed frequent co-expression of IDH1 (R132H) and cMYC nuclear protein by immunohistochemistry in our malignant glioma cohort and with mRNA expression and copy number alterations in the TCGA glioblastoma cohort.	('malignant glioma cohort', 'Disease', (127, 150))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('co-expression', 'Interaction', (41, 54))	('IDH1', 'Gene', '3417', (58, 62))	('R132H', 'Mutation', 'rs121913500', (64, 69))	('malignant glioma cohort', 'Disease', 'MESH:D005910', (127, 150))	('cMYC', 'Gene', '4609', (75, 79))	('glioblastoma', 'Disease', (216, 228))	('copy number alterations', 'Var', (180, 203))	('glioblastoma', 'Disease', 'MESH:D005909', (216, 228))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('cMYC', 'Gene', (75, 79))	('R132H', 'Var', (64, 69))	('IDH1', 'Gene', (58, 62))
67753	23934175	The independent prognostic significance of cMYC is still unclear since it is difficult to dissociate from IDH1 mutations, a more robust, prognostic factor in gliomas.	('cMYC', 'Gene', '4609', (43, 47))	('mutations', 'Var', (111, 120))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('IDH1', 'Gene', (106, 110))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('gliomas', 'Disease', (158, 165))	('cMYC', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (106, 110))
67755	23934175	However, our data support a role for cMYC protein as an adverse prognostic factor among malignant gliomas expressing mutant IDH1.	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('mutant', 'Var', (117, 123))	('IDH1', 'Gene', '3417', (124, 128))	('gliomas', 'Phenotype', 'HP:0009733', (98, 105))	('cMYC', 'Gene', (37, 41))	('IDH1', 'Gene', (124, 128))	('malignant gliomas', 'Disease', (88, 105))	('malignant gliomas', 'Disease', 'MESH:D005910', (88, 105))	('cMYC', 'Gene', '4609', (37, 41))
67756	23934175	Future evaluation of the prognostic and predictive value of cMYC expression at the DNA, mRNA or protein levels should allow for stratification by IDH1 mutation status and WHO grade and via prospective ascertainment of response to therapy and survival.	('IDH1', 'Gene', (146, 150))	('cMYC', 'Gene', '4609', (60, 64))	('IDH1', 'Gene', '3417', (146, 150))	('mutation', 'Var', (151, 159))	('cMYC', 'Gene', (60, 64))
67775	32608376	Three phase II clinical trials (#NCT00025675, #NCT00238797, #NCT00016991) highlighted the efficacy of gefinitib, pointing out a progression-free survival at 6 months (PFS-6) of 13%.	('#NCT00025675', 'Var', (32, 44))	('gefinitib', 'Chemical', '-', (102, 111))	('#NCT00016991', 'Var', (60, 72))
67805	32608376	Several studies reported the presence of BRAF V600E mutation, especially in infant gliomas.	('gliomas', 'Disease', 'MESH:D005910', (83, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('gliomas', 'Disease', (83, 90))	('V600E', 'Mutation', 'rs113488022', (46, 51))	('V600E', 'Var', (46, 51))	('BRAF', 'Gene', '673', (41, 45))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('BRAF', 'Gene', (41, 45))
67807	32608376	The dysregulation of p53 signaling pathways is found in more than 80% of high-grade gliomas.	('dysregulation', 'Var', (4, 17))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('p53', 'Gene', (21, 24))	('p53', 'Gene', '7157', (21, 24))
67813	32608376	Zotiraclib, a multi-CDK inhibitor, has been explored in clinical trials for newly diagnosed or recurrent gliomas (#NCT02942264, #NCT03224104).	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('CDK', 'Gene', (20, 23))	('Zotiraclib', 'Chemical', '-', (0, 10))	('CDK', 'Gene', '1019;12567;1021;12571', (20, 23))	('#NCT02942264', 'Var', (114, 126))
67814	32608376	Isocitrate dehydrogenase-1 (IDH1) mutation is one of the most frequent abnormalities found in high-grade gliomas, and according to the World Health Organization, is a new classification of brain tumors also having predictive value of treatment response.	('brain tumors', 'Disease', (189, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('IDH1', 'Gene', '3417', (28, 32))	('mutation', 'Var', (34, 42))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('Isocitrate dehydrogenase-1', 'Gene', '3417', (0, 26))	('Isocitrate dehydrogenase-1', 'Gene', (0, 26))	('brain tumors', 'Disease', 'MESH:D001932', (189, 201))	('brain tumors', 'Phenotype', 'HP:0030692', (189, 201))	('brain tumor', 'Phenotype', 'HP:0030692', (189, 200))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('IDH1', 'Gene', (28, 32))
67826	32608376	Cabozantinib is a promising agent against VEGFR and MET signaling, evaluated in two phase II studies involving newly diagnosed (#NCT00960492) and recurrent GBM (#NCT00704288).	('#NCT00704288', 'Var', (161, 173))	('VEGFR', 'Gene', '3791', (42, 47))	('MET', 'Gene', '79811', (52, 55))	('Cabozantinib', 'Chemical', 'MESH:C558660', (0, 12))	('VEGFR', 'Gene', (42, 47))	('MET', 'Gene', (52, 55))	('#NCT00960492', 'Var', (128, 140))	('GBM', 'Phenotype', 'HP:0012174', (156, 159))
67891	31323961	Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines.	('5-AcTMF', 'Chemical', '-', (25, 32))	('inducing', 'Reg', (87, 95))	('viability', 'CPA', (48, 57))	('clonogenicity', 'CPA', (62, 75))	('apoptosis', 'CPA', (96, 105))	('human', 'Species', '9606', (118, 123))	('5-AcTMF', 'Var', (25, 32))	('suppressed', 'NegReg', (33, 43))
67892	31323961	Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6.	('STAT3', 'Gene', '6774', (101, 106))	('STAT3', 'Gene', '6774', (110, 115))	('Tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('5-AcTMF lowered', 'Phenotype', 'HP:0025455', (43, 58))	('STAT3', 'Gene', (101, 106))	('STAT3', 'Gene', (110, 115))	('5-AcTMF', 'Chemical', '-', (43, 50))	('dampened', 'NegReg', (167, 175))	('5-AcTMF', 'Var', (43, 50))	('lowered', 'NegReg', (51, 58))	('Interleukin-6', 'Gene', '3569', (209, 222))	('STAT3', 'Gene', '6774', (140, 145))	('STAT3', 'Gene', '6774', (178, 183))	('STAT3', 'Gene', (140, 145))	('Interleukin-6', 'Gene', (209, 222))	('STAT3', 'Gene', (178, 183))
67893	31323961	Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth.	('ectopic expression', 'Var', (9, 27))	('5-AcTMF', 'Chemical', '-', (61, 68))	('impeded', 'NegReg', (53, 60))	('STAT3', 'Gene', '6774', (190, 195))	('5-AcTMF', 'Chemical', '-', (234, 241))	('STAT3', 'Gene', '6774', (47, 52))	('STAT3', 'Gene', (190, 195))	('STAT3', 'Gene', (47, 52))	('suppression', 'NegReg', (77, 88))	('dominant-active', 'Var', (31, 46))
67894	31323961	Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner.	('JAK2', 'Gene', '3717', (71, 75))	('STAT3', 'Gene', '6774', (135, 140))	('downregulated', 'NegReg', (85, 98))	('STAT3', 'Gene', (49, 54))	('BCL-2', 'Gene', '596', (113, 118))	('BCL-2', 'Gene', (113, 118))	('BCL-xL', 'Gene', (123, 129))	('BCL-xL', 'Gene', '598', (123, 129))	('JAK2', 'Gene', (71, 75))	('STAT3', 'Gene', (135, 140))	('5-AcTMF', 'Chemical', '-', (14, 21))	('activation', 'MPA', (35, 45))	('impaired', 'NegReg', (22, 30))	('5-AcTMF', 'Var', (14, 21))	('STAT3', 'Gene', '6774', (49, 54))
67896	31323961	Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis.	('JAK2', 'Gene', (131, 135))	('5-AcTMF', 'Chemical', '-', (72, 79))	('BCL-2', 'Gene', '596', (142, 147))	('BCL-xL', 'Gene', '598', (148, 154))	('STAT3', 'Gene', '6774', (136, 141))	('BCL-xL', 'Gene', (148, 154))	('BCL-2', 'Gene', (142, 147))	('thwarting', 'NegReg', (117, 126))	('JAK2', 'Gene', '3717', (131, 135))	('5-AcTMF', 'Var', (72, 79))	('anticancer effect', 'CPA', (51, 68))	('STAT3', 'Gene', (136, 141))
67905	31323961	Notably, preclinical evidence has substantiated the therapeutic potential of STAT3 inhibition, either by RNAi knockdown or pharmacological inhibitors, for GBM treatment, thereby highlighting STAT3 as a promising target for developing novel GBM therapeutics.	('knockdown', 'Var', (110, 119))	('inhibition', 'NegReg', (83, 93))	('GBM', 'Disease', (155, 158))	('STAT3', 'Gene', '6774', (191, 196))	('STAT3', 'Gene', '6774', (77, 82))	('STAT3', 'Gene', (191, 196))	('STAT3', 'Gene', (77, 82))	('RNAi', 'Gene', (105, 109))
67909	31323961	It is worth noting that 5-AcTMF has been demonstrated to exert in vitro or in vivo anticancer activity against a wide range of human cancers, including breast, colon, lung, and multiple myeloma.	('human', 'Species', '9606', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('5-AcTMF', 'Chemical', '-', (24, 31))	('cancers', 'Disease', (133, 140))	('multiple myeloma', 'Phenotype', 'HP:0006775', (177, 193))	('breast', 'Disease', (152, 158))	('multiple myeloma', 'Disease', 'MESH:D009101', (177, 193))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('5-AcTMF', 'Var', (24, 31))	('multiple myeloma', 'Disease', (177, 193))	('lung', 'Disease', (167, 171))	('anticancer activity', 'CPA', (83, 102))	('colon', 'Disease', (160, 165))
67913	31323961	Mechanistic investigation further identified that 5-AcTMF markedly impaired the STAT3-BCL-2/BCL-xL prosurvival signaling axis, which was responsible for the proapoptotic action of 5-AcTMF on GBM cells.	('STAT3', 'Gene', '6774', (80, 85))	('5-AcTMF', 'Var', (50, 57))	('BCL-2', 'Gene', '596', (86, 91))	('STAT3', 'Gene', (80, 85))	('impaired', 'NegReg', (67, 75))	('5-AcTMF', 'Chemical', '-', (180, 187))	('BCL-2', 'Gene', (86, 91))	('5-AcTMF', 'Chemical', '-', (50, 57))	('BCL-xL', 'Gene', (92, 98))	('BCL-xL', 'Gene', '598', (92, 98))
67914	31323961	For the first time, our findings reveal 5-AcTMF-elicited suppression of GBM cell growth and viability, as well as the inhibitory action of 5-AcTMF on STAT3 signaling, and further implicate the potential of including 5-AcTMF in the therapeutic regimens for GBM.	('5-AcTMF', 'Chemical', '-', (216, 223))	('5-AcTMF', 'Chemical', '-', (40, 47))	('suppression', 'NegReg', (57, 68))	('STAT3', 'Gene', '6774', (150, 155))	('5-AcTMF', 'Chemical', '-', (139, 146))	('5-AcTMF-elicited', 'Var', (40, 56))	('STAT3', 'Gene', (150, 155))
67916	31323961	We observed that 5-AcAMF treatment clearly led to a decline in the viability of all three cell lines compared to drug-untreated controls (p < 0.001), where T98G cells seemed to be most sensitive (Figure 1A).	('5-AcAMF', 'Chemical', '-', (17, 24))	('5-AcAMF', 'Var', (17, 24))	('decline', 'NegReg', (52, 59))	('viability', 'CPA', (67, 76))
67918	31323961	It is noteworthy that the clonogenicty of GBM8401 and U-87 MG cells was already reduced by more than 50% when treated with 50 muM of 5-AcTMF (p < 0.001), and the clonogenicity of T98G was lowered to 46.5 +- 3.51% of drug-free control by 5-AcTMF at 100 muM (p < 0.001) (Figure 1B).	('muM', 'Gene', '56925', (126, 129))	('GBM8401', 'Var', (42, 49))	('5-AcTMF', 'Chemical', '-', (133, 140))	('lowered', 'NegReg', (188, 195))	('5-AcTMF', 'Chemical', '-', (237, 244))	('muM', 'Gene', (126, 129))	('reduced', 'NegReg', (80, 87))	('clonogenicty', 'CPA', (26, 38))	('muM', 'Gene', '56925', (252, 255))	('clonogenicity', 'CPA', (162, 175))	('T98G', 'Var', (179, 183))	('muM', 'Gene', (252, 255))
67926	31323961	We found that in all GBM cell lines tested, 5-AcTMF markedly reduced the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a surrogate marker of STAT3 activation (Figure 2A; Supplementary Figures S1B and S2).	('STAT3', 'Gene', (111, 116))	('5-AcTMF', 'Var', (44, 51))	('STAT3', 'Gene', '6774', (150, 155))	('STAT3', 'Gene', '6774', (120, 125))	('Tyrosine', 'Chemical', 'MESH:D014443', (83, 91))	('STAT3', 'Gene', (150, 155))	('STAT3', 'Gene', (120, 125))	('5-AcTMF', 'Chemical', '-', (44, 51))	('reduced', 'NegReg', (61, 68))	('STAT3', 'Gene', '6774', (111, 116))
67927	31323961	This result illustrated that 5-AcTMF was able to impair constitutive STAT3 activation in GBM cells.	('STAT3', 'Gene', (69, 74))	('5-AcTMF', 'Var', (29, 36))	('impair', 'NegReg', (49, 55))	('5-AcTMF', 'Chemical', '-', (29, 36))	('STAT3', 'Gene', '6774', (69, 74))
67928	31323961	To further support the negative effect of 5-AcTMF on STAT3, we probed whether 5-AcTMF also impedes STAT3 activation induced by interleukin 6 (IL-6).	('impedes', 'NegReg', (91, 98))	('IL-6', 'Gene', '3569', (142, 146))	('STAT3', 'Gene', '6774', (53, 58))	('5-AcTMF', 'Chemical', '-', (42, 49))	('5-AcTMF', 'Var', (78, 85))	('STAT3', 'Gene', (53, 58))	('interleukin 6', 'Gene', (127, 140))	('STAT3', 'Gene', '6774', (99, 104))	('STAT3', 'Gene', (99, 104))	('interleukin 6', 'Gene', '3569', (127, 140))	('5-AcTMF', 'Chemical', '-', (78, 85))	('IL-6', 'Gene', (142, 146))
67929	31323961	Indeed, IL-6 stimulation promoted STAT3 activation, as evidenced by IL-6-induced upregulation of p-STAT3, as well as STAT3 downstream targets BCL-2 and BCL-xL; remarkably, 5-AcTMF almost nullified IL-6-induced upregulation of p-STAT3, BCL-2 and BCL-xL (Figure 2B).	('IL-6', 'Gene', (8, 12))	('5-AcTMF', 'Chemical', '-', (172, 179))	('IL-6', 'Gene', '3569', (197, 201))	('IL-6', 'Gene', '3569', (68, 72))	('BCL-xL', 'Gene', '598', (152, 158))	('STAT3', 'Gene', (117, 122))	('IL-6', 'Gene', (68, 72))	('IL-6', 'Gene', (197, 201))	('BCL-2', 'Gene', '596', (142, 147))	('STAT3', 'Gene', (228, 233))	('BCL-xL', 'Gene', (152, 158))	('BCL-2', 'Gene', (142, 147))	('STAT3', 'Gene', '6774', (117, 122))	('5-AcTMF', 'Var', (172, 179))	('BCL-xL', 'Gene', '598', (245, 251))	('STAT3', 'Gene', '6774', (228, 233))	('BCL-2', 'Gene', '596', (235, 240))	('STAT3', 'Gene', (99, 104))	('nullified', 'NegReg', (187, 196))	('upregulation', 'PosReg', (210, 222))	('BCL-2', 'Gene', (235, 240))	('BCL-xL', 'Gene', (245, 251))	('STAT3', 'Gene', (34, 39))	('STAT3', 'Gene', '6774', (99, 104))	('IL-6', 'Gene', '3569', (8, 12))	('STAT3', 'Gene', '6774', (34, 39))
67932	31323961	In light of this, we examined whether 5-AcTMF suppresses STAT3 activation via inhibiting the activities of JAK2, a canonical upstream kinase for STAT3 phosphorylation.	('STAT3', 'Gene', (145, 150))	('suppresses', 'NegReg', (46, 56))	('5-AcTMF', 'Chemical', '-', (38, 45))	('inhibiting', 'NegReg', (78, 88))	('STAT3', 'Gene', '6774', (57, 62))	('activities', 'MPA', (93, 103))	('JAK2', 'Gene', '3717', (107, 111))	('5-AcTMF', 'Var', (38, 45))	('STAT3', 'Gene', (57, 62))	('JAK2', 'Gene', (107, 111))	('STAT3', 'Gene', '6774', (145, 150))
67933	31323961	As shown in Figure 2C, 5-AcTMF markedly lowered the levels of Tyrosine 1007/1008-phosphorylated JAK2 (p-JAK2), suggesting that inhibition of JAK2 by 5-AcTMF is likely responsible for the 5-AcTMF-mediated suppression of STAT3 activation.	('JAK2', 'Gene', (141, 145))	('lowered', 'NegReg', (40, 47))	('5-AcTMF', 'Var', (23, 30))	('JAK2', 'Gene', '3717', (104, 108))	('JAK2', 'Gene', '3717', (96, 100))	('5-AcTMF', 'Chemical', '-', (187, 194))	('5-AcTMF', 'Chemical', '-', (149, 156))	('JAK2', 'Gene', '3717', (141, 145))	('JAK2', 'Gene', (104, 108))	('inhibition', 'NegReg', (127, 137))	('JAK2', 'Gene', (96, 100))	('STAT3', 'Gene', '6774', (219, 224))	('Tyrosine', 'Chemical', 'MESH:D014443', (62, 70))	('STAT3', 'Gene', (219, 224))	('5-AcTMF', 'Chemical', '-', (23, 30))
67935	31323961	To address this question, T98G cells stably expressing a constitutively active STAT3 mutant with an N-terminal hemagglutinin (HA) tag (HA-STAT3-CA) were generated to neutralize the suppression of STAT3 by 5-AcTMF.	('STAT3', 'Gene', (196, 201))	('STAT3', 'Gene', (138, 143))	('STAT3', 'Gene', '6774', (79, 84))	('5-AcTMF', 'Chemical', '-', (205, 212))	('STAT3', 'Gene', '6774', (138, 143))	('mutant', 'Var', (85, 91))	('STAT3', 'Gene', '6774', (196, 201))	('STAT3', 'Gene', (79, 84))
67937	31323961	Immunoblotting revealed that a clear elevation of PARP cleavage was observed in 5-AcTMF-treated vector control clones, as expected; however, 5-AcTMF barely elicited PARP cleavage when STAT3 was constitutively activated (Figure 3A).	('PARP', 'Gene', '1302', (165, 169))	('STAT3', 'Gene', '6774', (184, 189))	('PARP', 'Gene', (165, 169))	('STAT3', 'Gene', (184, 189))	('5-AcTMF', 'Chemical', '-', (141, 148))	('PARP', 'Gene', '1302', (50, 54))	('5-AcTMF', 'Chemical', '-', (80, 87))	('elicited', 'Reg', (156, 164))	('PARP', 'Gene', (50, 54))	('5-AcTMF', 'Var', (141, 148))
67943	31323961	We have shown in Figure 2B that 5-AcTMF curtailed the levels of IL-6-induced p-STAT3, as well as those of antiapoptotic BCL-2 and BCL-xL, both of which are known STAT3 downstream targets.	('5-AcTMF', 'Var', (32, 39))	('STAT3', 'Gene', (162, 167))	('BCL-2', 'Gene', (120, 125))	('IL-6', 'Gene', (64, 68))	('STAT3', 'Gene', '6774', (162, 167))	('curtailed', 'NegReg', (40, 49))	('IL-6', 'Gene', '3569', (64, 68))	('5-AcTMF', 'Chemical', '-', (32, 39))	('STAT3', 'Gene', '6774', (79, 84))	('levels', 'MPA', (54, 60))	('BCL-xL', 'Gene', '598', (130, 136))	('STAT3', 'Gene', (79, 84))	('BCL-xL', 'Gene', (130, 136))	('BCL-2', 'Gene', '596', (120, 125))
67944	31323961	Indeed, when 5-AcTMF ablated constitutive STAT3 activation, both BCL-2 and BCL-xL were clearly down-regulated as well, whereas persistent activation of STAT3 restored the levels of these two proteins (Figure 4A).	('5-AcTMF ablated', 'Var', (13, 28))	('STAT3', 'Gene', (42, 47))	('5-AcTMF', 'Chemical', '-', (13, 20))	('STAT3', 'Gene', '6774', (152, 157))	('down-regulated', 'NegReg', (95, 109))	('levels of', 'MPA', (171, 180))	('BCL-2', 'Gene', '596', (65, 70))	('ablated', 'Var', (21, 28))	('STAT3', 'Gene', (152, 157))	('BCL-2', 'Gene', (65, 70))	('STAT3', 'Gene', '6774', (42, 47))	('BCL-xL', 'Gene', '598', (75, 81))	('BCL-xL', 'Gene', (75, 81))
67948	31323961	To this end, T98G stable clones overexpressing BCL-2 were generated and then subjected to 5-AcTMF treatment for 24 h, followed by immunoblotting for the levels of PARP cleavage.	('BCL-2', 'Gene', (47, 52))	('5-AcTMF', 'Chemical', '-', (90, 97))	('T98G', 'Var', (13, 17))	('PARP', 'Gene', '1302', (163, 167))	('PARP', 'Gene', (163, 167))	('BCL-2', 'Gene', '596', (47, 52))
67949	31323961	In vector clones, PARP cleavage was clearly induced by 5-AcTMF, along with BCL-2 downregulation (Figure 5A) and a marked reduction in cell viability (Figure 5B, blue line).	('BCL-2', 'Gene', (75, 80))	('BCL-2', 'Gene', '596', (75, 80))	('induced', 'Reg', (44, 51))	('PARP', 'Gene', '1302', (18, 22))	('downregulation', 'NegReg', (81, 95))	('5-AcTMF', 'Chemical', '-', (55, 62))	('PARP', 'Gene', (18, 22))	('reduction', 'NegReg', (121, 130))	('5-AcTMF', 'Var', (55, 62))	('cell viability', 'CPA', (134, 148))
67950	31323961	In BCL-2-overexpressing clones, conversely, 5-AcTMF hardly provoked PARP cleavage (Figure 5A) and cytotoxicity (Figure 5B).	('PARP', 'Gene', (68, 72))	('BCL-2', 'Gene', '596', (3, 8))	('cytotoxicity', 'Disease', (98, 110))	('5-AcTMF', 'Var', (44, 51))	('PARP', 'Gene', '1302', (68, 72))	('BCL-2', 'Gene', (3, 8))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('5-AcTMF', 'Chemical', '-', (44, 51))
67951	31323961	Specifically, under 48 h-treatment with 50 muM of 5-AcTMF, the viability was enhanced by BCL-2 overexpression from 58.54 +- 1.83% to 85.01 +- 2.05% (p < 0.001).	('muM', 'Gene', (43, 46))	('enhanced', 'PosReg', (77, 85))	('5-AcTMF', 'Var', (50, 57))	('BCL-2', 'Gene', '596', (89, 94))	('BCL-2', 'Gene', (89, 94))	('viability', 'CPA', (63, 72))	('overexpression', 'PosReg', (95, 109))	('5-AcTMF', 'Chemical', '-', (50, 57))	('muM', 'Gene', '56925', (43, 46))
67953	31323961	Overall, these results confirmed BLC-2 downregulation as a pivotal mechanism whereby 5-AcTMF induces GBM cell apoptosis.	('5-AcTMF', 'Chemical', '-', (85, 92))	('GBM cell apoptosis', 'CPA', (101, 119))	('induces', 'PosReg', (93, 100))	('5-AcTMF', 'Var', (85, 92))	('BLC-2', 'Gene', (33, 38))	('downregulation', 'NegReg', (39, 53))
67956	31323961	Our results indicated that neither PARP cleavage (Figure 6A) nor cytotoxicity (Figure 6B) was noticeably induced by 5-AcTMF whenever 5-AcTMF failed to downregulate BCL-xL.	('5-AcTMF', 'Chemical', '-', (116, 123))	('5-AcTMF', 'Chemical', '-', (133, 140))	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('BCL-xL', 'Gene', (164, 170))	('BCL-xL', 'Gene', '598', (164, 170))	('PARP', 'Gene', '1302', (35, 39))	('5-AcTMF', 'Var', (116, 123))	('cytotoxicity', 'Disease', (65, 77))	('PARP', 'Gene', (35, 39))
67958	31323961	Notably, the apoptotic population elicited by 100 muM of 5-AcTMF was reduced by about 2.5 fold (from 52.23 +- 0.63% to 20.02 +- 1.82%; p < 0.001) when BCL-xL was overexpressed.	('BCL-xL', 'Gene', (151, 157))	('reduced', 'NegReg', (69, 76))	('BCL-xL', 'Gene', '598', (151, 157))	('5-AcTMF', 'Var', (57, 64))	('muM', 'Gene', '56925', (50, 53))	('apoptotic population', 'CPA', (13, 33))	('muM', 'Gene', (50, 53))	('5-AcTMF', 'Chemical', '-', (57, 64))
67961	31323961	Specifically, we demonstrated that 5-AcTMF evidently suppressed cell viability and clonogenicity as well as promoted apoptosis of multiple human GBM cell lines (Figure 1).	('clonogenicity', 'CPA', (83, 96))	('5-AcTMF', 'Chemical', '-', (35, 42))	('human', 'Species', '9606', (139, 144))	('5-AcTMF', 'Var', (35, 42))	('apoptosis', 'CPA', (117, 126))	('promoted', 'PosReg', (108, 116))	('suppressed', 'NegReg', (53, 63))	('cell viability', 'CPA', (64, 78))
67964	31323961	Collectively, we conclude that one of the pivotal mechanisms of action whereby 5-AcTMF exerts its anti-GBM effect is through targeted suppression of the antiapoptotic JAK2-STAT3-BCL-2/BCL-xL signaling axis.	('JAK2', 'Gene', '3717', (167, 171))	('BCL-2', 'Gene', '596', (178, 183))	('STAT3', 'Gene', (172, 177))	('5-AcTMF', 'Chemical', '-', (79, 86))	('JAK2', 'Gene', (167, 171))	('BCL-2', 'Gene', (178, 183))	('anti-GBM effect', 'Disease', (98, 113))	('BCL-xL', 'Gene', '598', (184, 190))	('BCL-xL', 'Gene', (184, 190))	('suppression', 'NegReg', (134, 145))	('5-AcTMF', 'Var', (79, 86))	('STAT3', 'Gene', '6774', (172, 177))
67965	31323961	To the best of our knowledge, the findings about 5-AcTMF-elicited suppression of GBM cell growth and survival, as well as the inhibition of STAT3 signaling, have not been previously reported.	('5-AcTMF', 'Chemical', '-', (49, 56))	('5-AcTMF-elicited', 'Var', (49, 65))	('STAT3', 'Gene', '6774', (140, 145))	('STAT3', 'Gene', (140, 145))	('suppression', 'NegReg', (66, 77))
67976	31323961	It is perplexing that in our study, 5-AcTMF lowered GBM cell viability at a relatively high dosage.	('lowered', 'NegReg', (44, 51))	('5-AcTMF lowered', 'Phenotype', 'HP:0025455', (36, 51))	('5-AcTMF', 'Var', (36, 43))	('GBM cell viability', 'CPA', (52, 70))	('5-AcTMF', 'Chemical', '-', (36, 43))
67978	31323961	Given that 5-AcTMF inhibits STAT3 signaling and has also been shown to induce autophagy, an examination of whether 5-AcTMF elicits the protective autophagy that, in turn, blunts its own cytotoxicity against GBM cells is currently underway.	('STAT3', 'Gene', (28, 33))	('5-AcTMF', 'Var', (115, 122))	('elicits', 'Reg', (123, 130))	('blunts', 'NegReg', (171, 177))	('5-AcTMF', 'Chemical', '-', (11, 18))	('cytotoxicity', 'Disease', 'MESH:D064420', (186, 198))	('STAT3', 'Gene', '6774', (28, 33))	('5-AcTMF', 'Chemical', '-', (115, 122))	('autophagy', 'CPA', (78, 87))	('induce', 'Reg', (71, 77))	('inhibits', 'NegReg', (19, 27))	('5-AcTMF', 'Var', (11, 18))	('cytotoxicity', 'Disease', (186, 198))
67979	31323961	Data presented here regarding the anti-GBM effect of 5-AcTMF primarily focused on proapoptotic action of 5-AcTMF on GBM cells due to impairing the antiapoptotic STAT3-BCL-2/BCL-xL signaling axis.	('BCL-2', 'Gene', (167, 172))	('5-AcTMF', 'Var', (105, 112))	('antiapoptotic', 'MPA', (147, 160))	('proapoptotic action', 'MPA', (82, 101))	('STAT3', 'Gene', '6774', (161, 166))	('impairing', 'NegReg', (133, 142))	('BCL-xL', 'Gene', '598', (173, 179))	('5-AcTMF', 'Chemical', '-', (53, 60))	('STAT3', 'Gene', (161, 166))	('BCL-xL', 'Gene', (173, 179))	('5-AcTMF', 'Chemical', '-', (105, 112))	('BCL-2', 'Gene', '596', (167, 172))
67982	31323961	In conclusion, we report here the newly identified anticancer effect of 5-AcTMF on GBM cells, which is mainly attributed to 5-AcTMF-mediated suppression of the JAK2-STAT3-BCL-2/BCL-xL antiapoptotic signaling axis (Figure 7).	('BCL-2', 'Gene', '596', (171, 176))	('JAK2', 'Gene', (160, 164))	('5-AcTMF-mediated', 'Var', (124, 140))	('BCL-2', 'Gene', (171, 176))	('suppression', 'NegReg', (141, 152))	('5-AcTMF', 'Chemical', '-', (72, 79))	('5-AcTMF', 'Chemical', '-', (124, 131))	('STAT3', 'Gene', '6774', (165, 170))	('BCL-xL', 'Gene', (177, 183))	('BCL-xL', 'Gene', '598', (177, 183))	('anticancer effect', 'CPA', (51, 68))	('JAK2', 'Gene', '3717', (160, 164))	('STAT3', 'Gene', (165, 170))
67983	31323961	Moreover, our findings implicate the potential of applying 5-AcTMF to GBM treatment, either as a monotherapy drug or as a radio-/chemotherapies-sensitizing agent due to its inhibitory effect on STAT3 signaling.	('STAT3', 'Gene', '6774', (194, 199))	('5-AcTMF', 'Chemical', '-', (59, 66))	('STAT3', 'Gene', (194, 199))	('GBM', 'Disease', (70, 73))	('5-AcTMF', 'Var', (59, 66))
68000	31323961	The open reading frame (ORF) of the dominant-active STAT3 mutant (STAT3 (A661C/N663C); STAT3-CA) and BCL-2 were PCR-amplified using the plasmids pMXs-STAT3-C (plasmid #13373) and 3336 pcDNA3 Bcl-2 (plasmid #8768) deposited in Addgene (Cambridge, MA, USA) as the template, respectively.	('STAT3', 'Gene', (87, 92))	('STAT3', 'Gene', (52, 57))	('STAT3', 'Gene', (66, 71))	('A661C', 'SUBSTITUTION', 'None', (73, 78))	('STAT3', 'Gene', '6774', (52, 57))	('N663C', 'Var', (79, 84))	('N663C', 'SUBSTITUTION', 'None', (79, 84))	('BCL-2', 'Gene', '596', (101, 106))	('Bcl-2', 'Gene', (191, 196))	('STAT3', 'Gene', '6774', (150, 155))	('Bcl-2', 'Gene', '596', (191, 196))	('A661C', 'Var', (73, 78))	('BCL-2', 'Gene', (101, 106))	('STAT3', 'Gene', (150, 155))	('STAT3', 'Gene', '6774', (87, 92))	('STAT3', 'Gene', '6774', (66, 71))
68003	31323961	The accession-numbers of STAT3, BCL-2 and BCL-xL mRNA are NM_139276, NM_000633, and NM_138578, respectively.	('BCL-2', 'Gene', '596', (32, 37))	('BCL-xL', 'Gene', (42, 48))	('STAT3', 'Gene', (25, 30))	('BCL-xL', 'Gene', '598', (42, 48))	('NM_000633', 'Var', (69, 78))	('STAT3', 'Gene', '6774', (25, 30))	('NM_139276', 'Var', (58, 67))	('NM_138578', 'Var', (84, 93))	('BCL-2', 'Gene', (32, 37))
68009	31323961	Primary antibodies against BCL-2 (#2872), BCL-xL (#2762), HA-tag (#3724), JAK 2 (#3230), STAT3 (#12640) and c-PARP (#9541) were purchased from Cell signaling Technology (Boston, MA, USA); alpha-tubulin (GTX102078), beta-actin (GTX109639) and GAPDH (GTX627408) were obtained from Genetex (Irvine, CA, USA); p-JAK2 (ab32101) and p-STAT3 (ab76315) were obtained from Abcam (Cambridge, GBR).	('alpha-tubulin', 'Gene', '10376', (188, 201))	('BCL-xL', 'Gene', (42, 48))	('BCL-2', 'Gene', '596', (27, 32))	('STAT3', 'Gene', '6774', (89, 94))	('BCL-2', 'Gene', (27, 32))	('GAPDH', 'Gene', (242, 247))	('JAK2', 'Gene', '3717', (308, 312))	('beta-actin', 'Gene', '728378', (215, 225))	('alpha-tubulin', 'Gene', (188, 201))	('PARP', 'Gene', '1302', (110, 114))	('JAK2', 'Gene', (308, 312))	('STAT3', 'Gene', (329, 334))	('JAK 2', 'Gene', '3717', (74, 79))	('BCL-xL', 'Gene', '598', (42, 48))	('JAK 2', 'Gene', (74, 79))	('beta-actin', 'Gene', (215, 225))	('GAPDH', 'Gene', '2597', (242, 247))	('PARP', 'Gene', (110, 114))	('STAT3', 'Gene', '6774', (329, 334))	('STAT3', 'Gene', (89, 94))	('ab32101', 'Var', (314, 321))
68012	31088402	We found over-expression of ARHI can also inhibit cancer cell proliferation, decrease tumorigenicity, and induce autophagic cell death in human glioma and inhibition of the late stage of autophagy can further enhance the antitumor effect of ARHI through inducing apoptosis in vitro or vivo.	('ARHI', 'Gene', '9077', (241, 245))	('cancer', 'Disease', (50, 56))	('tumor', 'Disease', (225, 230))	('ARHI', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('induce', 'Reg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('decrease', 'NegReg', (77, 85))	('inducing', 'Reg', (254, 262))	('ARHI', 'Gene', (241, 245))	('glioma', 'Disease', (144, 150))	('autophagic cell death', 'CPA', (113, 134))	('enhance', 'PosReg', (209, 216))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('over-expression', 'PosReg', (9, 24))	('ARHI', 'Gene', '9077', (28, 32))	('apoptosis', 'CPA', (263, 272))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('tumor', 'Disease', (86, 91))	('human', 'Species', '9606', (138, 143))	('inhibit', 'NegReg', (42, 49))	('inhibition', 'Var', (155, 165))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
68027	31088402	ARHI is downregulated in multiple malignant tumors, including ovarian cancer, breast cancer, lung cancer, prostate cancer, thyroid cancer, pancreatic cancer and glioma, and over-expression of ARHI at physiological levels can retard proliferation, reduce motility and enhance cancer cell dormancy.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('cancer', 'Disease', (98, 104))	('thyroid cancer', 'Disease', (123, 137))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('breast cancer', 'Disease', (78, 91))	('ARHI', 'Gene', '9077', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('ARHI', 'Gene', (192, 196))	('motility', 'CPA', (254, 262))	('prostate cancer', 'Disease', (106, 121))	('cancer', 'Disease', (150, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('lung cancer', 'Disease', (93, 104))	('malignant tumors', 'Disease', 'MESH:D018198', (34, 50))	('glioma', 'Disease', (161, 167))	('cancer', 'Disease', (70, 76))	('downregulated', 'NegReg', (8, 21))	('enhance', 'PosReg', (267, 274))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('thyroid cancer', 'Disease', 'MESH:D013964', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('ARHI', 'Gene', (0, 4))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('cancer', 'Disease', (85, 91))	('malignant tumors', 'Disease', (34, 50))	('pancreatic cancer', 'Disease', (139, 156))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('thyroid cancer', 'Phenotype', 'HP:0002890', (123, 137))	('retard', 'NegReg', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', (115, 121))	('over-expression', 'Var', (173, 188))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('reduce', 'NegReg', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('ARHI', 'Gene', '9077', (192, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('ovarian cancer', 'Disease', (62, 76))
68030	31088402	Inhibition of autophagic function with chloroquine (CQ) can induce cancer death through necroptosis.	('induce', 'PosReg', (60, 66))	('CQ', 'Chemical', 'MESH:D002738', (52, 54))	('autophagic function', 'CPA', (14, 33))	('cancer death', 'Disease', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer death', 'Disease', 'MESH:D003643', (67, 79))	('Inhibition', 'Var', (0, 10))	('necroptosis', 'CPA', (88, 99))	('chloroquine', 'Chemical', 'MESH:D002738', (39, 50))
68041	31088402	LN229 (CRL-2611), T98G (CRL-1690), and U87 (HTB-14) were distributed by ATCC.	('T98G', 'Var', (18, 22))	('LN229', 'CellLine', 'CVCL:0393', (0, 5))	('CRL', 'Gene', (7, 10))	('CRL', 'Gene', (24, 27))	('T98G', 'CellLine', 'CVCL:0556', (18, 22))	('U87', 'Gene', (39, 42))	('CRL', 'Gene', '133396', (7, 10))	('U87', 'Gene', '641648', (39, 42))	('CRL', 'Gene', '133396', (24, 27))
68055	31088402	Antibody SQSTM1 (#23214), LC3B(#3868), Ras (#8955), Cleaved Caspase3 (#9662), mTOR (#2972), AKT (#9272) and Beta actin (#3700) were purchased from Cell Signaling Technology, ARHI antibody (ab107051) was purchased from abcam.	('ARHI', 'Gene', '9077', (174, 178))	('#8955', 'Var', (44, 49))	('#9272', 'Var', (97, 102))	('SQSTM1', 'Gene', '8878', (9, 15))	('ARHI', 'Gene', (174, 178))	('AKT', 'Gene', '207', (92, 95))	('LC3B', 'Gene', '81631', (26, 30))	('mTOR', 'Gene', (78, 82))	('#9662', 'Var', (70, 75))	('mTOR', 'Gene', '2475', (78, 82))	('#23214', 'Var', (17, 23))	('AKT', 'Gene', (92, 95))	('#2972', 'Var', (84, 89))	('LC3B', 'Gene', (26, 30))	('SQSTM1', 'Gene', (9, 15))
68056	31088402	A density of 5000 cells were planted into 96-well plates for each well and mixed 10 mul MTT at 72 h. After 24 h of transfection with the ARHI and control plasmid, cells (500 cells/well) were seeded into a six-well plates and cultured for two weeks.	('transfection', 'Var', (115, 127))	('ARHI', 'Gene', (137, 141))	('MTT', 'Chemical', 'MESH:C070243', (88, 91))	('ARHI', 'Gene', '9077', (137, 141))
68081	31088402	The results showed that glioma tissues had lower ARHI expression, and higher grades of glioma corresponded to lower ARHI protein expression (T1-T3 WHO IV, T4-T6 WHO III, T7-T9 WHO II, N1-N3 normal brain tissues).	('T7-T9 WHO', 'CellLine', 'CVCL:0063', (170, 179))	('ARHI', 'Gene', '9077', (49, 53))	('glioma', 'Disease', (87, 93))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('ARHI', 'Gene', (116, 120))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('T1-T3', 'Var', (141, 146))	('T4-T6 WHO', 'Var', (155, 164))	('lower', 'NegReg', (110, 115))	('ARHI', 'Gene', (49, 53))	('T7-T9', 'Var', (170, 175))	('ARHI', 'Gene', '9077', (116, 120))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('glioma', 'Disease', (24, 30))	('lower', 'NegReg', (43, 48))
68153	31088402	The appearance of tumors usually begins with the mutation of genes.	('genes', 'Gene', (61, 66))	('mutation', 'Var', (49, 57))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
68159	31088402	Furthermore, over-expressing ARHI can induce autophagy-mediated cell death in glioma, which further supports the hypothesis that ARHI represents a tumor suppressor gene in glioma.	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('ARHI', 'Gene', (129, 133))	('autophagy-mediated cell death', 'CPA', (45, 74))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('ARHI', 'Gene', '9077', (129, 133))	('ARHI', 'Gene', '9077', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('over-expressing', 'Var', (13, 28))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('glioma', 'Disease', (78, 84))	('glioma', 'Disease', (172, 178))	('ARHI', 'Gene', (29, 33))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
68167	31088402	Autophagosome formation has been implicated in the process of apoptosis, and inhibition of the early stagy of autophagy reduced the activation of caspase-3, while the effect of the late stage of autophagy inhibition was opposite.	('caspase-3', 'Gene', (146, 155))	('inhibition', 'Var', (77, 87))	('caspase-3', 'Gene', '836', (146, 155))	('Autophagosome formation', 'CPA', (0, 23))	('activation', 'MPA', (132, 142))	('reduced', 'NegReg', (120, 127))
68188	30583528	The latter methylates DNA purine residues, preferentially O-6 guanine (O6-MeG, 6%) in guanine-rich regions, but also N-7 guanine (N7-MeG, 70%) and N-3 adenine (N3-MeA, 9%).	('O-6 guanine', 'Chemical', '-', (58, 69))	('N-3 adenine', 'Chemical', '-', (147, 158))	('guanine', 'Chemical', 'MESH:D006147', (86, 93))	('guanine', 'Chemical', 'MESH:D006147', (62, 69))	('MeG', 'Gene', '5775', (74, 77))	('MeG', 'Gene', '5775', (133, 136))	('MeG', 'Gene', (74, 77))	('MeG', 'Gene', (133, 136))	('purine', 'Chemical', 'MESH:C030985', (26, 32))	('N3-MeA', 'Chemical', '-', (160, 166))	('preferentially', 'PosReg', (43, 57))	('guanine', 'Chemical', 'MESH:D006147', (121, 128))	('O-6', 'Var', (58, 61))	('N-7', 'Var', (117, 120))	('N-7 guanine', 'Chemical', '-', (117, 128))
68189	30583528	Alkylation of the O6 site on guanine promotes the insertion of a thymine instead of a cytosine during DNA replication, which can result in cell death.	('insertion', 'MPA', (50, 59))	('Alkylation', 'Var', (0, 10))	('result in', 'Reg', (129, 138))	('thymine', 'Chemical', 'MESH:D013941', (65, 72))	('guanine', 'Chemical', 'MESH:D006147', (29, 36))	('cytosine', 'Chemical', 'MESH:D003596', (86, 94))	('cell death', 'CPA', (139, 149))
68194	30583528	Defects in apoptotic mechanisms foster tumorigenesis and contribute to the resistance to temozolomide, since its cytotoxic activity is exerted in part through the triggering of apoptosis.	('apoptotic', 'Protein', (11, 20))	('foster', 'PosReg', (32, 38))	('temozolomide', 'Chemical', 'MESH:D000077204', (89, 101))	('contribute', 'Reg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Defects', 'Var', (0, 7))	('resistance', 'MPA', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
68216	30583528	In contrast, the rats receiving mifepristone/temozolomide maintained their weight throughout the study (Figure 2a), and those having no tumor cell implantation (sham operation) gained weight.	('rats', 'Species', '10116', (17, 21))	('rat', 'Species', '10116', (169, 172))	('rat', 'Species', '10116', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('weight', 'MPA', (75, 81))	('temozolomide', 'Chemical', 'MESH:D000077204', (45, 57))	('mifepristone', 'Chemical', 'MESH:D015735', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('gained', 'PosReg', (177, 183))	('mifepristone/temozolomide', 'Var', (32, 57))	('tumor', 'Disease', (136, 141))
68222	30583528	Compared to the groups receiving the vehicle only, temozolomide alone or mifepristone alone, rats given mifepristone/temozolomide displayed a lower proportion of Ki-67 positive cells in tumors.	('mifepristone', 'Chemical', 'MESH:D015735', (73, 85))	('mifepristone', 'Chemical', 'MESH:D015735', (104, 116))	('mifepristone/temozolomide', 'Var', (104, 129))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('Ki-67 positive', 'Protein', (162, 176))	('lower', 'NegReg', (142, 147))	('temozolomide', 'Chemical', 'MESH:D000077204', (51, 63))	('temozolomide', 'Chemical', 'MESH:D000077204', (117, 129))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('rats', 'Species', '10116', (93, 97))
68225	30583528	In the mifepristone/temozolomide group, a close correlation can be observed between a lower level of Ki-67 and the significant reduction in tumor growth illustrated in the PET/CT images.	('temozolomide', 'Chemical', 'MESH:D000077204', (20, 32))	('mifepristone', 'Chemical', 'MESH:D015735', (7, 19))	('lower', 'NegReg', (86, 91))	('Ki-67', 'Var', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('reduction', 'NegReg', (127, 136))	('rat', 'Species', '10116', (159, 162))	('tumor', 'Disease', (140, 145))
68230	30583528	Western blot data and band intensity showed the protein expression of MGMT to be strikingly downregulated in the mifepristone/temozolomide group and slightly decreased in the mifepristone only group compared to the animals administered temozolomide only (Figure 5).	('decreased', 'NegReg', (158, 167))	('temozolomide', 'Chemical', 'MESH:D000077204', (236, 248))	('protein expression', 'MPA', (48, 66))	('MGMT', 'Gene', (70, 74))	('temozolomide', 'Chemical', 'MESH:D000077204', (126, 138))	('MGMT', 'Gene', '4255', (70, 74))	('mifepristone', 'Chemical', 'MESH:D015735', (175, 187))	('mifepristone', 'Chemical', 'MESH:D015735', (113, 125))	('mifepristone/temozolomide', 'Var', (113, 138))	('downregulated', 'NegReg', (92, 105))
68237	30583528	A significant difference in tumor growth was observed between the animals administered mifepristone/temozolomide and those given the vehicle only, temozolomide only or mifepristone only.	('tumor', 'Disease', (28, 33))	('temozolomide', 'Chemical', 'MESH:D000077204', (147, 159))	('mifepristone', 'Chemical', 'MESH:D015735', (87, 99))	('mifepristone', 'Chemical', 'MESH:D015735', (168, 180))	('temozolomide', 'Chemical', 'MESH:D000077204', (100, 112))	('mifepristone/temozolomide', 'Var', (87, 112))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
68240	30583528	Ki-67 was abundant in the tumor cells of the groups given temozolomide only, mifepristone only or the vehicle only, but was scarcely detected in tumor cells of the animals receiving mifepristone/temozolomide.	('Ki-67', 'Gene', (0, 5))	('mifepristone', 'Chemical', 'MESH:D015735', (182, 194))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('temozolomide', 'Chemical', 'MESH:D000077204', (195, 207))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('temozolomide', 'Chemical', 'MESH:D000077204', (58, 70))	('tumor', 'Disease', (145, 150))	('temozolomide', 'Var', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mifepristone', 'Chemical', 'MESH:D015735', (77, 89))
68258	30583528	Moreover, mifepristone inhibits cell growth by arresting cell cycle progression at the S phase, triggers apoptosis by activating caspase-3, and modulates the genes involved in apoptosis (including BCL2/BAX and FAS/FASLG) in Ishikawa cells.	('modulates', 'Reg', (144, 153))	('FASLG', 'Gene', '356', (214, 219))	('inhibits', 'NegReg', (23, 31))	('BCL2', 'Gene', (197, 201))	('mifepristone', 'Chemical', 'MESH:D015735', (10, 22))	('cell growth', 'CPA', (32, 43))	('triggers', 'Reg', (96, 104))	('activating', 'PosReg', (118, 128))	('arresting', 'NegReg', (47, 56))	('cell cycle progression', 'CPA', (57, 79))	('caspase-3', 'Gene', '836', (129, 138))	('mifepristone', 'Var', (10, 22))	('apoptosis', 'CPA', (105, 114))	('FASLG', 'Gene', (214, 219))	('BAX', 'Gene', (202, 205))	('caspase-3', 'Gene', (129, 138))	('genes', 'Gene', (158, 163))	('BAX', 'Gene', '581', (202, 205))	('BCL2', 'Gene', '596', (197, 201))
68263	30583528	On the other hand, the epigenetic silencing of MGMT was shown to enhance the response of GBM patients to chemotherapy based on alkylating agents, leading to longer mean survival.	('enhance', 'PosReg', (65, 72))	('longer', 'PosReg', (157, 163))	('response', 'MPA', (77, 85))	('MGMT', 'Gene', (47, 51))	('MGMT', 'Gene', '4255', (47, 51))	('GBM', 'Disease', (89, 92))	('patients', 'Species', '9606', (93, 101))	('epigenetic silencing', 'Var', (23, 43))
68265	30583528	Whereas most patients are resistant to temozolomide, epigenetic inactivation of MGMT, occurring in approximately 40% of patients, is associated with a better response..	('temozolomide', 'Chemical', 'MESH:D000077204', (39, 51))	('MGMT', 'Gene', '4255', (80, 84))	('patients', 'Species', '9606', (13, 21))	('MGMT', 'Gene', (80, 84))	('patients', 'Species', '9606', (120, 128))	('epigenetic inactivation', 'Var', (53, 76))
68267	30583528	It is still unknown whether mifepristone epigenetically inhibits MGMT.	('MGMT', 'Gene', (65, 69))	('mifepristone', 'Chemical', 'MESH:D015735', (28, 40))	('MGMT', 'Gene', '4255', (65, 69))	('inhibits', 'NegReg', (56, 64))	('epigenetically', 'Var', (41, 55))
68271	30583528	Since knockdown of SP1 strongly reduced MGMT protein expression, SP1 is one of the main factors regulating MGMT.	('MGMT', 'Gene', '4255', (107, 111))	('MGMT', 'Gene', (107, 111))	('reduced', 'NegReg', (32, 39))	('MGMT', 'Gene', '4255', (40, 44))	('MGMT', 'Gene', (40, 44))	('SP1', 'Gene', (19, 22))	('knockdown', 'Var', (6, 15))
68285	30583528	Drug resistance to temozolomide is associated with DNA damage repair, which impedes apoptosis.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('apoptosis', 'CPA', (84, 93))	('associated', 'Reg', (35, 45))	('Drug resistance', 'Var', (0, 15))	('impedes', 'NegReg', (76, 83))	('temozolomide', 'Chemical', 'MESH:D000077204', (19, 31))
68325	30583528	Proteins were then electrophoretically transferred from the gel onto PVDF membranes (Amersham, Buckinghamshire, UK), which were blocked with 5% non-fat dry milk at room temperature for 2 h. Membranes were incubated overnight at 4  C with antibodies against MGMT (sc-166528, 1:500), Bcl-2 (sc-7382, 1:1000), Bax (sc-20067, 1:1000), actin (sc-69879, 1:1000; Santa Cruz Biotechnology, Dallas, TX, USA) and cleaved caspase 3 (9661, 1:1000; Cell Signaling Technology, MAB230, R&D Systems, Minneapolis, MN, USA).	('Bax', 'Gene', (307, 310))	('Bcl-2', 'Gene', (282, 287))	('caspase 3', 'Gene', '836', (411, 420))	('Bcl-2', 'Gene', '596', (282, 287))	('Bax', 'Gene', '581', (307, 310))	('sc-69879', 'Var', (338, 346))	('sc-20067', 'Var', (312, 320))	('MN', 'CellLine', 'CVCL:U508', (497, 499))	('rat', 'Species', '10116', (174, 177))	('caspase 3', 'Gene', (411, 420))	('MGMT', 'Gene', (257, 261))	('MGMT', 'Gene', '4255', (257, 261))
68353	29764359	Glioblastoma is characterized by a large number and variety of genetic mutations that heavily disregulate major signaling pathways controlling cell survival, proliferation, and invasion: the allmarks of glioblastoma malignancy.	('Glioblastoma', 'Disease', (0, 12))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('disregulate', 'Reg', (94, 105))	('glioblastoma malignancy', 'Disease', (203, 226))	('mutations', 'Var', (71, 80))	('major signaling pathways', 'Pathway', (106, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (203, 215))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('glioblastoma malignancy', 'Disease', 'MESH:D005909', (203, 226))
68377	29764359	The fourth contribution reviews the currently available evidence for a functional role of KCa3.1 channels in in vivo glioblastoma tissue, with the object of establishing whether modulating KCa3.1 activity can be an adjuvant therapeutic approach to classic chemotherapy, to contrast tumor growth and prolong patient's survival.	('prolong', 'PosReg', (299, 306))	('KCa3.1', 'Gene', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('KCa3.1', 'Gene', (90, 96))	('contrast', 'PosReg', (273, 281))	('tumor', 'Disease', (282, 287))	('KCa3.1', 'Gene', '3783', (90, 96))	('KCa3.1', 'Gene', '3783', (189, 195))	('glioblastoma', 'Disease', (117, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))	('patient', 'Species', '9606', (307, 314))	('activity', 'MPA', (196, 204))	('modulating', 'Var', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
68551	25907361	Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10-11), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls).	('Glioma', 'Phenotype', 'HP:0009733', (33, 39))	('Glioma', 'Disease', (33, 39))	('glioma', 'Disease', 'MESH:D005910', (367, 373))	('glioma', 'Phenotype', 'HP:0009733', (367, 373))	('rs78378222', 'Mutation', 'rs78378222', (182, 192))	('rs78378222:A>C', 'Var', (182, 196))	('rs78378222', 'Mutation', 'rs78378222', (53, 63))	('TP53', 'Gene', '7157', (308, 312))	('glioma', 'Disease', (367, 373))	('rs78378222:A>C', 'DBSNP_MENTION', 'None', (182, 196))	('TP53', 'Gene', '7157', (67, 71))	('Glioma', 'Disease', 'MESH:D005910', (33, 39))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', (308, 312))	('Tumor', 'Phenotype', 'HP:0002664', (95, 100))	('rs78378222', 'Var', (53, 63))
68557	25907361	Genetic studies suggest an inherited component of risk for glioma, both in the general population and in rare familial syndromes, as observed in TP53 (MIM #191170) gene mutations in Li-Fraumeni syndrome as well as POT1 (MIM #606478) gene mutations described in glioma family.	('glioma', 'Disease', (261, 267))	('Li-Fraumeni syndrome', 'Disease', (182, 202))	('glioma', 'Disease', (59, 65))	('POT1', 'Gene', '25913', (214, 218))	('MIM #191170', 'Gene', (151, 162))	('mutations', 'Var', (169, 178))	('MIM #606478', 'Gene', (220, 231))	('POT1', 'Gene', (214, 218))	('glioma', 'Disease', 'MESH:D005910', (261, 267))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (182, 202))
68559	25907361	In addition, a moderately penetrant risk locus marked by the rare single-nucleotide polymorphism (SNP) rs78378222 in the 3'untranslated region (3'-UTR) of TP53 was recently reported.	('TP53', 'Gene', '7157', (155, 159))	('TP53', 'Gene', (155, 159))	('rs78378222', 'Mutation', 'rs78378222', (103, 113))	('rs78378222', 'Var', (103, 113))	('single-nucleotide', 'Var', (66, 83))
68560	25907361	To investigate the previous findings of the association of the rs78378222 with glioma risk, we performed an imputation analysis using our previously reported GWAS of 1,856 cases and 4,955 controls.	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('rs78378222', 'Mutation', 'rs78378222', (63, 73))	('rs78378222', 'Var', (63, 73))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('association', 'Interaction', (44, 55))
68561	25907361	After additional quality control, metrics were applied to the previously reported genotype data; specifically for the region of chromosome 17 bounded by 70717528071752 (hg19), we performed an imputation analysis based on a hybrid reference set including both the 1000 Genomes Project data release v3 and the Division of Cancer Epidemiology and Genetics (DCEG) Reference Set version 1.	('DCEG', 'Chemical', '-', (354, 358))	('70717528071752', 'Var', (153, 167))	('Cancer', 'Phenotype', 'HP:0002664', (320, 326))	('Cancer', 'Disease', (320, 326))	('Cancer', 'Disease', 'MESH:D009369', (320, 326))
68563	25907361	The SNP marker, rs78378222, was shown to be the strongest associated SNP within this region with a P value of 6.48 x 10-11 and per allele OR of 3.14 (95% confidence interval [CI]: 2.23-4.43); rs35850753 was ranked the second top SNP with a P value of 2.68 x 10-6 and per allele OR of 1.88 (95% CI: 1.45-2.45) (Table 1; and Fig.	('rs35850753', 'Var', (192, 202))	('rs35850753', 'Mutation', 'rs35850753', (192, 202))	('rs78378222', 'Mutation', 'rs78378222', (16, 26))	('rs78378222', 'Var', (16, 26))
68564	25907361	Moreover, TaqMan validation for rs78378222 performed with 236 samples (including 86 heterozygotes) showed high correlation between the imputed and TaqMan genotypes (r2 = 0.96), thus confirming the accuracy of imputation.	('rs78378222', 'Var', (32, 42))	('correlation', 'Interaction', (111, 122))	('rs78378222', 'Mutation', 'rs78378222', (32, 42))
68565	25907361	It is noteworthy that the imputation INFO score for rs78378222 and rs35850753 were 0.92 and 0.95, respectively, compared with 0.66 and 0.61 previously reported.	('rs78378222', 'Mutation', 'rs78378222', (52, 62))	('rs35850753', 'Var', (67, 77))	('rs35850753', 'Mutation', 'rs35850753', (67, 77))	('rs78378222', 'Var', (52, 62))
68569	25907361	We conducted an integrative analysis of the region including rs78378222 based on the rich set of Cancer Genome Atlas (TCGA) data to investigate the contribution of this germline variation in somatic settings.	('Cancer Genome Atlas', 'Disease', (97, 116))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (97, 116))	('rs78378222', 'Mutation', 'rs78378222', (61, 71))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs78378222', 'Var', (61, 71))
68570	25907361	In particular, we examined both GBM and LUAD data from TCGA for a comparison because the rare allele (C) of rs78378222 does not seem to be associated with risk for LUAD.	('rs78378222', 'Mutation', 'rs78378222', (108, 118))	('LUAD', 'Disease', (164, 168))	('associated', 'Reg', (139, 149))	('rs78378222', 'Var', (108, 118))
68575	25907361	Since the aberrant transcripts almost exclusively appear in GBM with AC genotype for rs78378222, it is likely that the aberrant transcripts would also carry the risk allele C, which was known to disrupt the proper termination of transcription as well as polyadenylation of TP53 mRNA.	('rs78378222', 'Var', (85, 95))	('rs78378222', 'Mutation', 'rs78378222', (85, 95))	('polyadenylation', 'MPA', (254, 269))	('termination of transcription', 'MPA', (214, 242))	('TP53', 'Gene', '7157', (273, 277))	('appear', 'Reg', (50, 56))	('TP53', 'Gene', (273, 277))
68578	25907361	The number of reads carrying the risk allele C at rs78378222 is predominant, approximately 9.5 times on average more than those with the A allele.	('rs78378222', 'Mutation', 'rs78378222', (50, 60))	('rs78378222', 'Var', (50, 60))	('more', 'PosReg', (112, 116))
68581	25907361	To verify this, we checked the raw reads and variant calls based on whole-exome sequencing data from both tumor and matched blood sample for several neighboring SNPs with each of their rare alleles sharing the same haplotype with the rare allele (C) of rs78378222 (pairwise d' = 1); and for three out of four GBM samples with heterozygous genotype in blood, there appears to be a deletion of the common (reference) allele in matched tumor (Supp.	('rs78378222', 'Var', (253, 263))	('rs78378222', 'Mutation', 'rs78378222', (253, 263))	('tumor', 'Disease', (433, 438))	('deletion', 'Var', (380, 388))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (433, 438))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (433, 438))
68582	25907361	Our bioinformatic analysis suggests a functional mechanism for rs78378222, a germline rare variant in TP53 (Supp.	('TP53', 'Gene', '7157', (102, 106))	('TP53', 'Gene', (102, 106))	('rs78378222', 'Mutation', 'rs78378222', (63, 73))	('rs78378222', 'Var', (63, 73))
68584	25907361	In this study, we present further independent confirmation that a rare susceptibility allele, marked by rs78378222 in TP53, confers glioma risk of approximately the same effect size.	('glioma', 'Disease', (132, 138))	('TP53', 'Gene', '7157', (118, 122))	('rs78378222', 'Var', (104, 114))	('TP53', 'Gene', (118, 122))	('rs78378222', 'Mutation', 'rs78378222', (104, 114))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))
68586	25907361	Nonsynonymous mutations in TP53 are one of the most frequent somatic events in glioma.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('Nonsynonymous mutations', 'Var', (0, 23))	('frequent', 'Reg', (52, 60))
68587	25907361	In addition to glioma, rs78378222 has also been shown to be associated with multiple other cancers including basal cell carcinoma, prostate cancer, colorectal adenoma, esophageal squamous cell carcinoma in Huaian Han Chinese, squamous cell carcinoma of head and neck, and pediatric neuroblastoma.	('pediatric neuroblastoma', 'Disease', 'MESH:D009447', (272, 295))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (226, 249))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('rs78378222', 'Var', (23, 33))	('colorectal adenoma', 'Disease', (148, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (109, 129))	('pediatric neuroblastoma', 'Disease', (272, 295))	('glioma', 'Phenotype', 'HP:0009733', (15, 21))	('squamous cell carcinoma', 'Disease', (226, 249))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('rs78378222', 'Mutation', 'rs78378222', (23, 33))	('esophageal squamous cell carcinoma', 'Disease', (168, 202))	('basal cell carcinoma', 'Disease', (109, 129))	('colorectal adenoma', 'Disease', 'MESH:D015179', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('associated', 'Reg', (60, 70))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (168, 202))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('neuroblastoma', 'Phenotype', 'HP:0003006', (282, 295))	('cancers', 'Disease', (91, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('glioma', 'Disease', (15, 21))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (109, 129))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('glioma', 'Disease', 'MESH:D005910', (15, 21))	('prostate cancer', 'Disease', (131, 146))
68589	25907361	As noted by, the allele frequency of rs78378222 is only approximately 1% in the European population, but it accounts for 6% of the familial risk of glioma.	('glioma', 'Disease', (148, 154))	('rs78378222', 'Mutation', 'rs78378222', (37, 47))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('rs78378222', 'Var', (37, 47))
68591	25907361	It is notable that the rare SNP, rs78378222 (A>C), could have a functional effect because it changes the fifth nucleotide of the TP53 polyadenylation signal (AATAAA>AATACA), resulting in an impaired 3'-end processing of TP53 mRNA, the downregulation of both p53 mRNA and protein level as well as reduction of cellular apoptosis with potential implication in prognosis.	('TP53', 'Gene', '7157', (220, 224))	('TP53', 'Gene', (220, 224))	('p53', 'Gene', (258, 261))	("3'-end processing", 'MPA', (199, 216))	('impaired', 'NegReg', (190, 198))	('downregulation', 'NegReg', (235, 249))	('p53', 'Gene', '7157', (258, 261))	('TP53', 'Gene', (129, 133))	('cellular apoptosis', 'CPA', (309, 327))	('TP53', 'Gene', '7157', (129, 133))	('rs78378222', 'Mutation', 'rs78378222', (33, 43))	('changes', 'Reg', (93, 100))	('reduction', 'NegReg', (296, 305))	('rs78378222', 'Var', (33, 43))
68592	25907361	We performed an integrative analysis using multidimensional TCGA data and provide preliminary evidence for the functional underpinning of rs78378222 as a glioma susceptibility allele.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('glioma', 'Disease', (154, 160))	('rs78378222', 'Mutation', 'rs78378222', (138, 148))	('rs78378222', 'Var', (138, 148))
68595	25907361	Moreover, the lack of somatic LOH in LUAD could possibly explain the observed effect of the rare variant on glioma risk but not LUAD risk.	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('variant', 'Var', (97, 104))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('glioma', 'Disease', (108, 114))
68600	26838672	We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice.	('TLX', 'Gene', '4179', (26, 29))	('inhibits', 'NegReg', (41, 49))	('TLX', 'Gene', (26, 29))	('human', 'Species', '9606', (50, 55))	('knockdown', 'Var', (13, 22))	('human GSC tumorigenicity', 'CPA', (50, 74))	('mice', 'Species', '10090', (78, 82))
68625	26838672	Dendrimers are one of the most promising non-viral vectors for delivering small RNAs by virtue of their well-defined structure and unique multivalent cooperativity alongside the high payload confined within a nanosized volume.	('small', 'Var', (74, 79))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('RNAs', 'Protein', (80, 84))
68629	26838672	In this study, we demonstrate that knockdown of TLX using dendrimer nanovector-delivered synthetic siRNAs or virally expressed short hairpin RNAs (shRNAs) dramatically reduces GSC growth and self-renewal.	('knockdown', 'Var', (35, 44))	('reduces', 'NegReg', (168, 175))	('TLX', 'Gene', (48, 51))	('GSC growth', 'CPA', (176, 186))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('TLX', 'Gene', '4179', (48, 51))
68630	26838672	By transplanting TLX shRNA-transduced GSCs into immunodeficient NOD SCID Gamma (NSG) mice, we show that knockdown of TLX leads to almost complete failure of GSCs to develop tumours in transplanted mouse brains.	('TLX', 'Gene', (17, 20))	('mice', 'Species', '10090', (85, 89))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('failure', 'NegReg', (146, 153))	('immunodeficient NOD SCID Gamma', 'Disease', (48, 78))	('TLX', 'Gene', (117, 120))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('TLX', 'Gene', '4179', (17, 20))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('N', 'Chemical', 'MESH:D009584', (80, 81))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('immunodeficient NOD SCID Gamma', 'Disease', 'MESH:D020191', (48, 78))	('mouse', 'Species', '10090', (197, 202))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('TLX', 'Gene', '4179', (117, 120))	('knockdown', 'Var', (104, 113))
68634	26838672	Among them, PBT003, PBT022, PBT726 and PBT1030 are classical, PBT017, PBT030 and PBT1008 are mesenchymal, whereas PBT024, PBT111 and PBT707 are proneural.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('P', 'Chemical', 'MESH:D010758', (81, 82))	('PBT726', 'Var', (28, 34))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('PBT030', 'Var', (70, 76))	('PBT022', 'Var', (20, 26))	('PBT1030', 'Var', (39, 46))	('P', 'Chemical', 'MESH:D010758', (122, 123))	('mesenchymal', 'CPA', (93, 104))	('P', 'Chemical', 'MESH:D010758', (20, 21))	('PBT1008', 'Var', (81, 88))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('P', 'Chemical', 'MESH:D010758', (62, 63))	('PBT017', 'Var', (62, 68))	('P', 'Chemical', 'MESH:D010758', (70, 71))	('P', 'Chemical', 'MESH:D010758', (114, 115))	('P', 'Chemical', 'MESH:D010758', (12, 13))	('PBT003', 'Var', (12, 18))
68638	26838672	To study the function of TLX in GSCs, two shRNAs were designed to knockdown TLX expression in GSCs with two scrambled RNAs as negative controls.	('N', 'Chemical', 'MESH:D009584', (119, 120))	('TLX', 'Gene', '4179', (25, 28))	('TLX', 'Gene', (76, 79))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('expression', 'MPA', (80, 90))	('knockdown', 'Var', (66, 75))	('TLX', 'Gene', '4179', (76, 79))	('TLX', 'Gene', (25, 28))
68642	26838672	We next determined the effect of knocking down TLX on the self-renewal ability of GSCs using clonal analysis and limiting dilution assay.	('self-renewal ability', 'CPA', (58, 78))	('knocking down', 'Var', (33, 46))	('TLX', 'Gene', '4179', (47, 50))	('TLX', 'Gene', (47, 50))
68645	26838672	The dramatic inhibitory effect of TLX shRNAs on GSC growth and self-renewal in vitro prompted us to test whether knockdown of TLX affects the ability of GSCs to form tumours in vivo.	('TLX', 'Gene', (34, 37))	('TLX', 'Gene', (126, 129))	('GSC growth', 'CPA', (48, 58))	('tumours', 'Disease', (166, 173))	('affects', 'Reg', (130, 137))	('test', 'Reg', (100, 104))	('inhibitory effect', 'NegReg', (13, 30))	('self-renewal', 'CPA', (63, 75))	('TLX', 'Gene', '4179', (34, 37))	('TLX', 'Gene', '4179', (126, 129))	('knockdown', 'Var', (113, 122))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumours', 'Disease', 'MESH:D009369', (166, 173))
68656	26838672	Together, these results indicate that knockdown of TLX suppresses tumour growth and increases the lifespan of GSC-grafted mice.	('mice', 'Species', '10090', (122, 126))	('TLX', 'Gene', (51, 54))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour growth', 'Disease', (66, 79))	('lifespan', 'CPA', (98, 106))	('increases', 'PosReg', (84, 93))	('TLX', 'Gene', '4179', (51, 54))	('tumour growth', 'Disease', 'MESH:D006130', (66, 79))	('knockdown', 'Var', (38, 47))	('suppresses', 'NegReg', (55, 65))
68657	26838672	Next we tested if knocking down TLX in vivo could suppress the progression of human GSC-initiated tumours in a xenograft model.	('GSC-initiated tumours', 'Disease', 'MESH:D009369', (84, 105))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('knocking down', 'Var', (18, 31))	('suppress', 'NegReg', (50, 58))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('TLX', 'Gene', (32, 35))	('progression', 'CPA', (63, 74))	('human', 'Species', '9606', (78, 83))	('TLX', 'Gene', '4179', (32, 35))	('GSC-initiated tumours', 'Disease', (84, 105))
68676	26838672	In addition to knocking down TLX using a TLX shRNA-expressing viral vector, we explored delivering TLX siRNA oligonucleotides using a non-viral nanovector.	('TLX', 'Gene', '4179', (29, 32))	('TLX', 'Gene', (41, 44))	('oligonucleotides', 'Chemical', 'MESH:D009841', (109, 125))	('TLX', 'Gene', '4179', (99, 102))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('TLX', 'Gene', '4179', (41, 44))	('knocking', 'Var', (15, 23))	('TLX', 'Gene', (29, 32))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('TLX', 'Gene', (99, 102))
68691	26838672	RT-PCR confirmed efficient TLX knockdown by dendrimer-delivered TLX siRNA.	('TLX', 'Gene', (27, 30))	('P', 'Chemical', 'MESH:D010758', (3, 4))	('TLX', 'Gene', '4179', (64, 67))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('TLX', 'Gene', '4179', (27, 30))	('TLX', 'Gene', (64, 67))	('knockdown', 'Var', (31, 40))
68698	26838672	The in vivo TLX knockdown was confirmed by RT-PCR (Fig.	('P', 'Chemical', 'MESH:D010758', (46, 47))	('TLX', 'Gene', '4179', (12, 15))	('TLX', 'Gene', (12, 15))	('knockdown', 'Var', (16, 25))
68712	26838672	Of note, TET3, TDG and MBD2 are all involved in DNA methylation modification, suggesting epigenetic regulation of DNA methylation may be an important downstream event of knocking down TLX in GSCs.	('TLX', 'Gene', '4179', (184, 187))	('TDG', 'Gene', '21665', (15, 18))	('N', 'Chemical', 'MESH:D009584', (115, 116))	('knocking', 'Var', (170, 178))	('MBD2', 'Gene', (23, 27))	('TLX', 'Gene', (184, 187))	('epigenetic regulation', 'Var', (89, 110))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('involved', 'Reg', (36, 44))	('MBD2', 'Gene', '17191', (23, 27))	('TDG', 'Gene', (15, 18))
68714	26838672	To test this hypothesis, two shRNAs were designed to knockdown TET3 in GSCs.	('knockdown', 'Var', (53, 62))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('TET3', 'Gene', (63, 67))
68716	26838672	PBT003 cells expressing TET3 shRNAs showed increased cell growth compared with control RNA-treated cells (Fig.	('N', 'Chemical', 'MESH:D009584', (32, 33))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('cell growth', 'CPA', (53, 64))	('TET3 shRNAs', 'Var', (24, 35))	('increased', 'PosReg', (43, 52))
68717	26838672	Consistent with increased cell growth, PBT003 cells with TET3 knockdown also showed increased sphere formation rate compared with control cells (Fig.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('cell growth', 'CPA', (26, 37))	('TET3', 'Gene', (57, 61))	('increased', 'PosReg', (16, 25))	('sphere formation rate', 'CPA', (94, 115))	('increased', 'PosReg', (84, 93))	('knockdown', 'Var', (62, 71))
68718	26838672	The increased cell growth and sphere formation rate after knockdown of TET3 were also observed in PBT707 cells (Fig.	('sphere formation rate', 'CPA', (30, 51))	('P', 'Chemical', 'MESH:D010758', (98, 99))	('knockdown', 'Var', (58, 67))	('TET3', 'Gene', (71, 75))	('cell growth', 'CPA', (14, 25))	('increased', 'PosReg', (4, 13))
68722	26838672	Overexpressing either TET3-1 or TET3-2 reduced the growth of both PBT003 and PBT707 cells (Fig.	('P', 'Chemical', 'MESH:D010758', (77, 78))	('P', 'Chemical', 'MESH:D010758', (66, 67))	('TET3-2', 'Var', (32, 38))	('reduced', 'NegReg', (39, 46))	('growth', 'MPA', (51, 57))
68723	26838672	Consistent with decreased cell growth, PBT003 and PBT707 cells overexpressing TET3-1 or TET3-2 also showed decreased sphere formation rate compared with control cells (Fig.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('sphere formation rate', 'CPA', (117, 138))	('cell growth', 'CPA', (26, 37))	('TET3-1', 'Var', (78, 84))	('TET3-2', 'Var', (88, 94))	('decreased', 'NegReg', (107, 116))	('decreased', 'NegReg', (16, 25))	('P', 'Chemical', 'MESH:D010758', (50, 51))
68726	26838672	Tumour formation and expansion by the TET3 shRNA-treated GSCs were compared with that by control RNA-treated GSCs maintained under identical conditions.	('Tumour formation', 'CPA', (0, 16))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('TET3 shRNA-treated', 'Var', (38, 56))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('expansion', 'CPA', (21, 30))
68727	26838672	Stereological measurement of tumour volumes confirmed the development of significantly larger tumours in brains transplanted with GSCs treated with TET3 shRNA, compared with that in brains transplanted with control GSCs (Fig.	('tumour', 'Disease', (94, 100))	('tumours', 'Disease', (94, 101))	('N', 'Chemical', 'MESH:D009584', (156, 157))	('larger', 'PosReg', (87, 93))	('tumour', 'Disease', (29, 35))	('TET3 shRNA', 'Var', (148, 158))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
68728	26838672	Mice transplanted with TET3 shRNA-transduced PBT003 cells had significantly shorter survival compared with mice transplanted with control RNA-transduced cells (Fig.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('PBT003', 'Gene', (45, 51))	('TET3 shRNA-transduced', 'Var', (23, 44))	('mice', 'Species', '10090', (107, 111))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('P', 'Chemical', 'MESH:D010758', (45, 46))	('Mice', 'Species', '10090', (0, 4))	('shorter', 'NegReg', (76, 83))	('survival', 'CPA', (84, 92))
68729	26838672	Together, these results indicate that knockdown of TET3 increases tumour progression and decreases the lifespan of GSC-grafted mice, in a manner opposite to knockdown of TLX.	('lifespan', 'CPA', (103, 111))	('TLX', 'Gene', '4179', (170, 173))	('mice', 'Species', '10090', (127, 131))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('increases tumour', 'Disease', (56, 72))	('TLX', 'Gene', (170, 173))	('TET3', 'Gene', (51, 55))	('increases tumour', 'Disease', 'MESH:D009369', (56, 72))	('knockdown', 'Var', (38, 47))	('decreases', 'NegReg', (89, 98))
68735	26838672	As expected, the expression of TET3 was upregulated after dox-induced knockdown of TLX (Fig.	('knockdown', 'Var', (70, 79))	('TLX', 'Gene', (83, 86))	('expression', 'MPA', (17, 27))	('dox', 'Chemical', 'MESH:D004318', (58, 61))	('TLX', 'Gene', '4179', (83, 86))	('TET3', 'Gene', (31, 35))	('upregulated', 'PosReg', (40, 51))
68736	26838672	Dox-induced TET3 knockdown reversed the expression of TET3 to control levels in cells expressing both inducible TLX shRNA and inducible TET3 shRNA (Fig.	('Dox', 'Chemical', 'MESH:D004318', (0, 3))	('inducible', 'Var', (126, 135))	('TLX', 'Gene', '4179', (112, 115))	('N', 'Chemical', 'MESH:D009584', (144, 145))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('TLX', 'Gene', (112, 115))
68737	26838672	Next we tested whether inducible TET3 knockdown could rescue the inhibitory effect of inducible TLX knockdown on GSC growth and self-renewal.	('GSC growth', 'CPA', (113, 123))	('TLX', 'Gene', (96, 99))	('knockdown', 'Var', (100, 109))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('TLX', 'Gene', '4179', (96, 99))
68739	26838672	The decreased cell growth resulted from induced TLX knockdown was rescued substantially by induced TET3 knockdown in both PBT003 and PBT707 cells (Fig.	('decreased', 'NegReg', (4, 13))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('P', 'Chemical', 'MESH:D010758', (122, 123))	('TLX', 'Gene', (48, 51))	('TET3', 'Gene', (99, 103))	('TLX', 'Gene', '4179', (48, 51))	('cell growth', 'CPA', (14, 25))	('knockdown', 'Var', (52, 61))	('knockdown', 'Var', (104, 113))
68740	26838672	The reduced self-renewal of PBT003 and PBT707 cells resulted from dox-induced TLX knockdown was also rescued by dox-induced TET3 knockdown (Fig.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('reduced', 'NegReg', (4, 11))	('TLX', 'Gene', '4179', (78, 81))	('knockdown', 'Var', (82, 91))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('dox', 'Chemical', 'MESH:D004318', (112, 115))	('self-renewal', 'CPA', (12, 24))	('TLX', 'Gene', (78, 81))	('dox', 'Chemical', 'MESH:D004318', (66, 69))
68750	26838672	Specifically, genes related to tumour-suppressive function, including BTG2, TUSC1, BAK1, LATS2, FZD6 and PPP2R1B, were upregulated in TLX knockdown cells, but downregulated in TET3 knockdown cells (Fig.	('TLX', 'Gene', (134, 137))	('BTG2', 'Gene', (70, 74))	('knockdown', 'Var', (138, 147))	('BAK1', 'Gene', '12018', (83, 87))	('upregulated', 'PosReg', (119, 130))	('TUSC1', 'Gene', (76, 81))	('LATS2', 'Gene', (89, 94))	('FZD6', 'Gene', (96, 100))	('TUSC1', 'Gene', '69136', (76, 81))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('FZD6', 'Gene', '14368', (96, 100))	('TLX', 'Gene', '4179', (134, 137))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('downregulated', 'NegReg', (159, 172))	('LATS2', 'Gene', '50523', (89, 94))	('BAK1', 'Gene', (83, 87))	('tumour', 'Disease', (31, 37))	('PPP2R1B', 'Gene', (105, 112))
68753	26838672	Dot blot analysis using a 5hmC-specific antibody revealed increased 5hmC level upon TLX knockdown, but decreased 5hmC level upon TET3 knockdown in PBT003 cells (Fig.	('TLX', 'Gene', '4179', (84, 87))	('increased', 'PosReg', (58, 67))	('5hmC', 'Chemical', 'MESH:C011865', (68, 72))	('5hmC', 'Chemical', 'MESH:C011865', (113, 117))	('P', 'Chemical', 'MESH:D010758', (147, 148))	('decreased', 'NegReg', (103, 112))	('knockdown', 'Var', (88, 97))	('5hmC', 'Chemical', 'MESH:C011865', (26, 30))	('5hmC level', 'MPA', (113, 123))	('TLX', 'Gene', (84, 87))	('5hmC level', 'MPA', (68, 78))
68755	26838672	8g), which were also upregulated upon TLX knockdown in PBT003-grafted brain tumours in NSG mice (Supplementary Fig.	('mice', 'Species', '10090', (91, 95))	('brain tumours', 'Disease', 'MESH:D001932', (70, 83))	('brain tumours', 'Phenotype', 'HP:0030692', (70, 83))	('brain tumours', 'Disease', (70, 83))	('TLX', 'Gene', (38, 41))	('upregulated', 'PosReg', (21, 32))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('P', 'Chemical', 'MESH:D010758', (55, 56))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('TLX', 'Gene', '4179', (38, 41))	('brain tumour', 'Phenotype', 'HP:0030692', (70, 82))	('knockdown', 'Var', (42, 51))
68759	26838672	In contrast, knockdown of TET3 reduced 5hmC level at the promoter region of BTG2 and PPP2R1B (Fig.	('BTG2', 'Gene', (76, 80))	('reduced', 'NegReg', (31, 38))	('5hmC level', 'MPA', (39, 49))	('5hmC', 'Chemical', 'MESH:C011865', (39, 43))	('PPP2R1B', 'Var', (85, 92))	('knockdown', 'Var', (13, 22))
68768	26838672	The finding that in vivo knockdown of TLX expression inhibits brain tumour development suggests that TLX is a promising target for anti-GBM therapy.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('brain tumour', 'Disease', 'MESH:D001932', (62, 74))	('TLX', 'Gene', (38, 41))	('brain tumour', 'Disease', (62, 74))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('TLX', 'Gene', (101, 104))	('brain tumour', 'Phenotype', 'HP:0030692', (62, 74))	('TLX', 'Gene', '4179', (38, 41))	('inhibits', 'NegReg', (53, 61))	('TLX', 'Gene', '4179', (101, 104))	('knockdown', 'Var', (25, 34))
68772	26838672	In this study, we showed direct evidence that targeting TLX in GSCs derived from human GBM patients efficiently inhibited the growth, self-renewal and tumorigenicity of GSCs in vitro and in vivo.	('targeting', 'Var', (46, 55))	('patients', 'Species', '9606', (91, 99))	('inhibited', 'NegReg', (112, 121))	('TLX', 'Gene', (56, 59))	('human', 'Species', '9606', (81, 86))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('TLX', 'Gene', '4179', (56, 59))	('growth', 'CPA', (126, 132))	('tumorigenicity of GSCs', 'CPA', (151, 173))
68777	26838672	Our study, by knocking down TLX in vivo, provided proof-of-concept that targeting TLX is effective to suppress the progression of human GSC-derived tumours.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('TLX', 'Gene', (28, 31))	('knocking', 'Var', (14, 22))	('TLX', 'Gene', '4179', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('TLX', 'Gene', '4179', (28, 31))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('suppress', 'NegReg', (102, 110))	('TLX', 'Gene', (82, 85))	('human', 'Species', '9606', (130, 135))
68778	26838672	Our study, by knocking down TLX expression in GSCs, demonstrates that TLX is necessary for GSC self-renewal and tumorigenesis.	('TLX', 'Gene', (28, 31))	('knocking', 'Var', (14, 22))	('tumorigenesis', 'CPA', (112, 125))	('TLX', 'Gene', (70, 73))	('TLX', 'Gene', '4179', (28, 31))	('TLX', 'Gene', '4179', (70, 73))
68782	26838672	Only when combined with loss of p53 or, to a less extent, ageing, overexpression of TLX led to glioma progression over time.	('loss', 'Var', (24, 28))	('TLX', 'Gene', '4179', (84, 87))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('led to', 'Reg', (88, 94))	('glioma', 'Disease', (95, 101))	('p53', 'Gene', (32, 35))	('TLX', 'Gene', (84, 87))	('p53', 'Gene', '22060', (32, 35))	('overexpression', 'PosReg', (66, 80))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
68786	26838672	Our microarray confirmed that p21 is upregulated upon TLX knockdown as previously reported by us and others.	('TLX', 'Gene', '4179', (54, 57))	('upregulated', 'PosReg', (37, 48))	('TLX', 'Gene', (54, 57))	('p21', 'Gene', (30, 33))	('knockdown', 'Var', (58, 67))	('p21', 'Gene', '12575', (30, 33))
68789	26838672	In our study, human GSCs after TLX knockdown were investigated, whereas previous study examined the expression of genes altered by TLX knockout using RNAs isolated from tumour tissues of a mouse tumour model.	('TLX', 'Gene', '4179', (131, 134))	('mouse', 'Species', '10090', (189, 194))	('knockout', 'Var', (135, 143))	('tumour', 'Disease', (169, 175))	('TLX', 'Gene', (31, 34))	('human', 'Species', '9606', (14, 19))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Disease', (195, 201))	('TLX', 'Gene', (131, 134))	('amine', 'Chemical', 'MESH:D000588', (89, 94))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('TLX', 'Gene', '4179', (31, 34))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
68793	26838672	Although growing evidence showing that epigenetic regulation plays an important role in cancer development, our knowledge on the role of TET family members, especially TET3, in tumour development is rather limited.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (177, 183))	('TET', 'Chemical', 'MESH:C010349', (137, 140))	('TET', 'Chemical', 'MESH:C010349', (168, 171))	('epigenetic', 'Var', (39, 49))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
68814	26838672	A potential clinical significance of this finding is derived from the ability of knocking down TLX in GSCs via lentivirus-delivered shRNA or nanoparticle-delivered siRNA to compromise the self-renewal and tumour formation potential of GSCs in vivo.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('compromise', 'NegReg', (173, 183))	('TLX', 'Gene', '4179', (95, 98))	('tumour', 'Disease', (205, 211))	('self-renewal', 'CPA', (188, 200))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('TLX', 'Gene', (95, 98))	('knocking down', 'Var', (81, 94))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('N', 'Chemical', 'MESH:D009584', (135, 136))
68815	26838672	Our studies demonstrated that TLX knockdown inhibited tumour initiation and progression from human GSCs in a xenografted tumour model and increased the survival of grafted animals substantially.	('increased', 'PosReg', (138, 147))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('TLX', 'Gene', '4179', (30, 33))	('TLX', 'Gene', (30, 33))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Disease', (54, 60))	('inhibited', 'NegReg', (44, 53))	('human', 'Species', '9606', (93, 98))	('knockdown', 'Var', (34, 43))	('tumour initiation', 'Disease', 'MESH:D009369', (54, 71))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('progression', 'CPA', (76, 87))	('tumour', 'Disease', (121, 127))	('tumour initiation', 'Disease', (54, 71))	('survival', 'CPA', (152, 160))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
68817	26838672	The small RNA approach to knock down TLX in GSCs has the potential to help improve the outcome and survival of GBM patients.	('patients', 'Species', '9606', (115, 123))	('TLX', 'Gene', (37, 40))	('TLX', 'Gene', '4179', (37, 40))	('GBM', 'Disease', (111, 114))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('knock down', 'Var', (26, 36))	('improve', 'PosReg', (75, 82))	('GBM', 'Phenotype', 'HP:0012174', (111, 114))
68859	26838672	For knocking down of TLX, PBT003 cells were treated with the G5 dendrimer-TLX siRNA complex or G5-control siRNA complex with or without RGDK coating, TLX expression was analysed by RT-PCR after 2 days of dendrimer-TLX siRNA treatment.	('knocking', 'Var', (4, 12))	('TLX', 'Gene', (214, 217))	('TLX', 'Gene', (21, 24))	('P', 'Chemical', 'MESH:D010758', (26, 27))	('TLX', 'Gene', '4179', (74, 77))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('TLX', 'Gene', '4179', (214, 217))	('TLX', 'Gene', '4179', (150, 153))	('TLX', 'Gene', '4179', (21, 24))	('TLX', 'Gene', (74, 77))	('TLX', 'Gene', (150, 153))	('P', 'Chemical', 'MESH:D010758', (184, 185))	('N', 'Chemical', 'MESH:D009584', (221, 222))
68883	26838672	Three days after viral transduction, total RNA was extracted from tumour tissues and RT-PCR was performed using human gene-specific primers to determine in vivo TLX knockdown and expression of downstream target genes TET3, BTG2 and PPP2R1B.	('P', 'Chemical', 'MESH:D010758', (234, 235))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('P', 'Chemical', 'MESH:D010758', (233, 234))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('TLX', 'Gene', '4179', (161, 164))	('TET3', 'Gene', (217, 221))	('BTG2', 'Gene', (223, 227))	('knockdown', 'Var', (165, 174))	('PPP2R1B', 'Gene', (232, 239))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('P', 'Chemical', 'MESH:D010758', (232, 233))	('human', 'Species', '9606', (112, 117))	('P', 'Chemical', 'MESH:D010758', (88, 89))	('TLX', 'Gene', (161, 164))
68894	24434573	It remains unclear, however, how MDSC depletion can affect glioma immunotherapy.	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('depletion', 'Var', (38, 47))	('affect', 'Reg', (52, 58))
68898	24434573	Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P =0.026).	('IL-12', 'Gene', (38, 43))	('IL-12', 'Gene', '64546', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('immunotherapy', 'Var', (44, 57))	('tumor', 'Disease', (161, 166))
68899	24434573	Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P =0.007).	('Mice', 'Species', '10090', (0, 4))	('MDSCs', 'MPA', (62, 67))	('Ad.5/3.cRGD-mIL12p70', 'Var', (15, 35))	('less', 'NegReg', (57, 61))
68903	24434573	Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.	('mDCs', 'Var', (101, 105))	('IL-12', 'Gene', (49, 54))	('IL-12', 'Gene', '64546', (49, 54))	('antigen presentation', 'MPA', (134, 154))
68910	24434573	The role of regulatory T cells (CD4 +CD25 +FoxP3 +) in GBM has been studied extensively in glioma and their depletion is well known to improve survival across a variety of murine glioma models.	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('CD25', 'Gene', (37, 41))	('survival', 'CPA', (143, 151))	('FoxP3', 'Gene', '20371', (43, 48))	('CD25', 'Gene', '16184', (37, 41))	('glioma', 'Disease', (91, 97))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('CD4', 'Gene', (32, 35))	('FoxP3', 'Gene', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('murine', 'Species', '10090', (172, 178))	('CD4', 'Gene', '12504', (32, 35))	('depletion', 'Var', (108, 117))	('glioma', 'Disease', (179, 185))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('improve', 'PosReg', (135, 142))
68912	24434573	Recently, it has been shown that MDSC depletion prolongs mouse survival, while blocking chemotactic CCL2 signaling in GL261 reduces recruitment of MDSCs and tissue-associated macrophages.	('blocking', 'NegReg', (79, 87))	('recruitment', 'MPA', (132, 143))	('CCL2', 'Gene', '20296', (100, 104))	('CCL2', 'Gene', (100, 104))	('reduces', 'NegReg', (124, 131))	('depletion', 'Var', (38, 47))	('mouse survival', 'CPA', (57, 71))	('mouse', 'Species', '10090', (57, 62))	('prolongs', 'PosReg', (48, 56))
68950	24434573	Cell suspensions of mouse brains containing GL261 gliomas injected with Ad.mIL12 or Ad.GFP were prepared as described above.	('Ad.GFP', 'Var', (84, 90))	('gliomas', 'Disease', (50, 57))	('gliomas', 'Disease', 'MESH:D005910', (50, 57))	('gliomas', 'Phenotype', 'HP:0009733', (50, 57))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))	('Ad.mIL12', 'Var', (72, 80))	('mouse', 'Species', '10090', (20, 25))
68959	24434573	After 7 days, animals were injected intracranially, in the same location, with PBS, Ad.GFP or Ad.mIL12.	('PBS', 'Chemical', '-', (79, 82))	('Ad.mIL12', 'Var', (94, 102))	('Ad.GFP', 'Var', (84, 90))
68972	24434573	To test the in vivo efficacy of IL-12-mediated immunotherapy, we established intracranial GL261 gliomas, and a week later, injected intratumorally PBS, Ad.GFP vector control or Ad.mIL12.	('tumor', 'Disease', (137, 142))	('rat', 'Species', '10116', (135, 138))	('Ad.mIL12', 'Var', (177, 185))	('Ad.GFP', 'Var', (152, 158))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('IL-12', 'Gene', (32, 37))	('PBS', 'Chemical', '-', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('IL-12', 'Gene', '64546', (32, 37))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('gliomas', 'Disease', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))
68973	24434573	Mice that received intracranial PBS or Ad.GFP had a median survival of 31 and 33 days, respectively; with all animals expiring within 40 days of glioma establishment.	('glioma establishment', 'Disease', (145, 165))	('glioma establishment', 'Disease', 'MESH:D005910', (145, 165))	('Ad.GFP', 'Var', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('Mice', 'Species', '10090', (0, 4))	('intracranial PBS', 'Disease', 'MESH:D011535', (19, 35))	('intracranial PBS', 'Disease', (19, 35))
68980	24434573	Interestingly, mRNA levels for arginase-1 (Figure 2d; *P =0.0315) and inducible nitric oxide synthase (Figure 2e; *P =0.006), enzymes associated with promoting immunosuppressive function, were decreased by 50% after administration of IL-12 gene therapy.	('IL-12', 'Gene', '64546', (234, 239))	('IL-12', 'Gene', (234, 239))	('gene therapy', 'Var', (240, 252))	('inducible nitric oxide synthase', 'Gene', (70, 101))	('mRNA levels', 'MPA', (15, 26))	('rat', 'Species', '10116', (224, 227))	('arginase-1', 'Gene', (31, 41))	('arginase-1', 'Gene', '11846', (31, 41))	('decreased', 'NegReg', (193, 202))	('inducible nitric oxide synthase', 'Gene', '18126', (70, 101))
68982	24434573	Given the previous observations demonstrating a difference in MDSC phenotype after IL-12 gene therapy, we sought to determine whether these alterations were significant enough to affect the in vivo induced immune response.	('affect', 'Reg', (179, 185))	('MDSC phenotype', 'MPA', (62, 76))	('IL-12', 'Gene', (83, 88))	('IL-12', 'Gene', '64546', (83, 88))	('gene therapy', 'Var', (89, 101))	('rat', 'Species', '10116', (39, 42))	('rat', 'Species', '10116', (144, 147))
68990	24434573	Following Ad.mIL12 immunotherapy, the level of MDSCs was decreased by 50% (*P =0.007), whereas the number of mDCs doubled (Figures 4a and bi; *P =0.0069), resulting in fourfold more mDCs than MDSCs in the glioma microenvironment.	('more', 'PosReg', (177, 181))	('mDCs', 'MPA', (182, 186))	('glioma', 'Disease', (205, 211))	('Ad.mIL12', 'Var', (10, 18))	('MDSCs', 'MPA', (47, 52))	('glioma', 'Disease', 'MESH:D005910', (205, 211))	('decreased', 'NegReg', (57, 66))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))
68991	24434573	In contrast, pDC frequency decreased after IL-12 gene therapy (Figure 4ci; *P =0.045).	('decreased', 'NegReg', (27, 36))	('gene therapy', 'Var', (49, 61))	('IL-12', 'Gene', '64546', (43, 48))	('pDC frequency', 'MPA', (13, 26))	('IL-12', 'Gene', (43, 48))
69000	24434573	It is well known that IL-12 immunotherapy prolongs survival in this model by inducing cytotoxic immune responses.	('immunotherapy', 'Var', (28, 41))	('cytotoxic immune responses', 'CPA', (86, 112))	('survival', 'CPA', (51, 59))	('IL-12', 'Gene', '64546', (22, 27))	('inducing', 'PosReg', (77, 85))	('IL-12', 'Gene', (22, 27))	('prolongs', 'PosReg', (42, 50))
69014	24434573	In our study, considering the very low efficacy of our construct to produce mIL12p70 in stem cells, we decided to infect glioma cells directly through intratumoral injection for in vivo studies.	('infect glioma', 'Disease', 'MESH:D005910', (114, 127))	('infect glioma', 'Disease', (114, 127))	('mIL12p70', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('rat', 'Species', '10116', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('tumor', 'Disease', (156, 161))
69016	24434573	Supernatants from GL261 glioma cells infected with Ad.mIL12 or Ad.GFP vector control were used as conditioned media to incubate mouse splenocytes.	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('glioma', 'Disease', (24, 30))	('mouse', 'Species', '10090', (128, 133))	('Ad.mIL12', 'Var', (51, 59))
69023	24434573	Intracranial injection of Ad.mIL12 reduced MDSCs' presence in glioma by half and altered their phenotype: increased MHCII/CD80 expression and reduced arginase-1 and inducible nitric oxide synthase transcription.	('MHCII', 'Gene', '111364', (116, 121))	('CD80', 'Gene', (122, 126))	('glioma', 'Disease', 'MESH:D005910', (62, 68))	('reduced', 'NegReg', (35, 42))	('expression', 'MPA', (127, 137))	('reduced', 'NegReg', (142, 149))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('Ad.mIL12', 'Var', (26, 34))	('MHCII', 'Gene', (116, 121))	('CD80', 'Gene', '12519', (122, 126))	('arginase-1 and inducible nitric oxide synthase', 'Gene', '11846;18126', (150, 196))	('increased', 'PosReg', (106, 115))	('altered', 'Reg', (81, 88))	('glioma', 'Disease', (62, 68))
69032	24434573	Both groups receiving intracranial Ad.mIL12, with or without MDSC depletion, had more than 60% long-term survivors (Figure 3a) and showed similar recruitment of cytotoxic CD8 T cells (Figure 3bi).	('CD8', 'Gene', (171, 174))	('Ad.mIL12', 'Var', (35, 43))	('CD8', 'Gene', '925', (171, 174))
69044	24434573	At the same time, the effects of Ad.mIL12 on MHCII upregulation were noticed across all the three groups analyzed.	('MHCII', 'Gene', (45, 50))	('Ad.mIL12', 'Var', (33, 41))	('upregulation', 'PosReg', (51, 63))	('MHCII', 'Gene', '111364', (45, 50))
69049	24434573	We show that Ad.mIL12 immunotherapy reduces the presence of MDSCs and alters their phenotype in an orthotopic mouse glioma model.	('MDSCs', 'Protein', (60, 65))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('glioma', 'Disease', (116, 122))	('Ad.mIL12', 'Var', (13, 21))	('mouse', 'Species', '10090', (110, 115))	('reduces', 'NegReg', (36, 43))	('alters', 'Reg', (70, 76))	('presence', 'MPA', (48, 56))	('phenotype', 'MPA', (83, 92))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
69052	24434573	At the same time, we reveal that IL-12 immunotherapy increases recruitment of mDCs that may have a major role in glioma antigen presentation.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('mDCs', 'Protein', (78, 82))	('IL-12', 'Gene', (33, 38))	('glioma', 'Disease', (113, 119))	('immunotherapy', 'Var', (39, 52))	('IL-12', 'Gene', '64546', (33, 38))	('increases', 'PosReg', (53, 62))	('recruitment', 'MPA', (63, 74))
69093	24416092	It has been shown that the knockdown of GLI2 mRNA has significantly decreased the migratory ability of human glioblastoma cells.	('knockdown', 'Var', (27, 36))	('decreased', 'NegReg', (68, 77))	('glioblastoma', 'Disease', (109, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('human', 'Species', '9606', (103, 108))	('GLI2', 'Gene', (40, 44))	('GLI2', 'Gene', '2736', (40, 44))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))
69103	24416092	Therefore, joint modeling of all subtypes using our DPS method can help us to interpret similarities and differences of the conditional gene relationships given micro-RNAs among different cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('DPS', 'Chemical', '-', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('micro-RNAs', 'Var', (161, 171))	('cancer', 'Disease', (188, 194))
69117	33376561	Loss or inactivation of TRPV2 promoted glioblastoma cell proliferation and increased resistance to CD95-induced apoptotic cell death.	('resistance', 'CPA', (85, 95))	('glioblastoma', 'Disease', (39, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('CD95', 'Gene', (99, 103))	('promoted', 'PosReg', (30, 38))	('Loss', 'NegReg', (0, 4))	('rat', 'Species', '10116', (64, 67))	('inactivation', 'Var', (8, 20))	('TRPV2', 'Gene', (24, 29))	('increased', 'PosReg', (75, 84))	('CD95', 'Gene', '355', (99, 103))
69126	33376561	Depending on the type of cancer, different alterations in the TRPV2 gene (i.e., loss, gain, and splicing) were found to exhibit oncogenic capacity linked to a tumor's growth and metastasis.	('splicing', 'Var', (96, 104))	('loss', 'Disease', 'MESH:D014786', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('rat', 'Species', '10116', (47, 50))	('gain', 'PosReg', (86, 90))	('tumor', 'Disease', (159, 164))	('loss', 'Disease', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('oncogenic capacity', 'CPA', (128, 146))	('cancer', 'Disease', (25, 31))	('TRPV2', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
69135	33376561	The 3D structure of TRPV2 reveals "hanging gondola architecture" with a calmodulin-binding site present in the C-terminal of TRPV2 (654-683) and six ankyrin repeats present in the N-terminal tail and may play a role in the interaction between subunits of TRPV2 (see Figure 1(b)).	('interaction', 'Interaction', (223, 234))	('play', 'Reg', (204, 208))	('role', 'Reg', (211, 215))	('TRPV2', 'Gene', (20, 25))	('N', 'Chemical', 'MESH:D009584', (180, 181))	('654-683', 'Var', (132, 139))	('TRPV2', 'Gene', (125, 130))
69142	33376561	Loss, gain, or mutation of the TRPV2 gene have been reported in hematological tumors, including mantle cell lymphoma, multiple myeloma, Burkitt lymphoma, acute myeloid leukemia, and myelodysplastic syndrome.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('multiple myeloma', 'Disease', 'MESH:D009101', (118, 134))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('Burkitt lymphoma', 'Disease', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (136, 152))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', (182, 206))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (96, 116))	('mantle cell lymphoma', 'Disease', (96, 116))	('multiple myeloma', 'Disease', (118, 134))	('Loss', 'NegReg', (0, 4))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('hematological tumors', 'Disease', (64, 84))	('TRPV2', 'Gene', (31, 36))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (136, 152))	('acute myeloid leukemia', 'Disease', (154, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (182, 206))	('mutation', 'Var', (15, 23))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))	('gain', 'PosReg', (6, 10))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (182, 206))	('multiple myeloma', 'Phenotype', 'HP:0006775', (118, 134))	('cell lymphoma', 'Phenotype', 'HP:0012191', (103, 116))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('hematological tumors', 'Disease', 'MESH:D019337', (64, 84))
69146	33376561	SKF96365 and tranilast, known to target TRPV2 Ca2+ activity, altered the expression profiles of this channel's isoforms and exhibited anticancer properties in LBs.	('cancer', 'Disease', (138, 144))	('SKF96365', 'Var', (0, 8))	('tranilast', 'Chemical', 'MESH:C012293', (13, 22))	('expression profiles', 'MPA', (73, 92))	('SKF96365', 'Chemical', 'MESH:C063159', (0, 8))	('isoforms', 'MPA', (111, 119))	('TRPV2', 'Gene', (40, 45))	('Ca2+', 'Chemical', 'MESH:D000069285', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('altered', 'Reg', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
69147	33376561	Furthermore, this study showed that targeting TRPV2 could affect the signaling pathways associated with chemotaxis/infiltration processes, prompting the assessment of TRPV2 as a potential pharmacodynamic biomarker especially in the setting where leukemia might be associated with a high risk of organ (lung) infiltration by LBs.	('leukemia', 'Disease', (246, 254))	('TRPV2', 'Gene', (46, 51))	('rat', 'Species', '10116', (314, 317))	('targeting', 'Var', (36, 45))	('signaling pathways', 'Pathway', (69, 87))	('leukemia', 'Phenotype', 'HP:0001909', (246, 254))	('leukemia', 'Disease', 'MESH:D007938', (246, 254))	('affect', 'Reg', (58, 64))	('rat', 'Species', '10116', (121, 124))
69153	33376561	Interestingly, this cascade of events was suppressed when TRPV2 Ca2+ influx activity was blocked by SKF96365.	('TRPV2', 'Protein', (58, 63))	('SKF96365', 'Var', (100, 108))	('blocked', 'NegReg', (89, 96))	('Ca2+ influx activity', 'MPA', (64, 84))	('SKF96365', 'Chemical', 'MESH:C063159', (100, 108))	('Ca2+', 'Chemical', 'MESH:D000069285', (64, 68))
69159	33376561	TRPV2 silencing increased proliferation and resistance to apoptosis in the high-grade U87MG glioma cell line, which displays a predominant mesenchymal stem cell (MSC) phenotype, whereas overexpression of TRPV2 enhanced differentiation of glioblastoma stem-like cells (GSCs) and reduced tumor size and viability.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('rat', 'Species', '10116', (33, 36))	('TRPV2', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('silencing', 'Var', (6, 15))	('overexpression', 'PosReg', (186, 200))	('proliferation', 'CPA', (26, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (238, 250))	('TRPV2', 'Gene', (204, 209))	('reduced', 'NegReg', (278, 285))	('tumor', 'Disease', (286, 291))	('glioblastoma', 'Disease', (238, 250))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('U87MG', 'CellLine', 'CVCL:0022', (86, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('enhanced', 'PosReg', (210, 218))	('glioma', 'Disease', (92, 98))	('increased', 'PosReg', (16, 25))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('resistance', 'CPA', (44, 54))	('differentiation', 'CPA', (219, 234))
69166	33376561	For example, the TRPV2 agonist CBD was shown to induce GSC differentiation by inhibiting their clonogenic capacity.	('GSC differentiation', 'CPA', (55, 74))	('clonogenic capacity', 'CPA', (95, 114))	('inhibiting', 'NegReg', (78, 88))	('induce', 'PosReg', (48, 54))	('CBD', 'Var', (31, 34))	('TRPV2', 'Gene', (17, 22))	('CBD', 'Chemical', 'MESH:D002185', (31, 34))
69169	33376561	CBD was also found to increase GSC chemosensitivity to other conventional anticancer drugs such as carmustine (BCNU).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('carmustine', 'Chemical', 'MESH:D002330', (99, 109))	('BC', 'Phenotype', 'HP:0009725', (111, 113))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('CBD', 'Var', (0, 3))	('GSC chemosensitivity', 'MPA', (31, 51))	('increase', 'PosReg', (22, 30))	('BCNU', 'Chemical', 'MESH:D002330', (111, 115))	('CBD', 'Chemical', 'MESH:D002185', (0, 3))
69173	33376561	In this regard, CBD was found to upregulate the expression of the transcription factor acute myeloid leukemia-1 (AML-1A) isoform, which is involved in GSC differentiation.	('upregulate', 'PosReg', (33, 43))	('CBD', 'Var', (16, 19))	('acute myeloid leukemia-1', 'Disease', (87, 111))	('acute myeloid leukemia-1', 'Disease', 'MESH:D015470', (87, 111))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('expression', 'MPA', (48, 58))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (87, 109))	('CBD', 'Chemical', 'MESH:D002185', (16, 19))	('AML', 'Disease', (113, 116))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))
69183	33376561	TRPV2 silencing abrogated LL-37-induced migration of all cell lines tested.	('LL-37', 'Gene', '820', (26, 31))	('silencing', 'Var', (6, 15))	('rat', 'Species', '10116', (43, 46))	('TRPV2', 'Gene', (0, 5))	('abrogated', 'NegReg', (16, 25))	('LL-37', 'Gene', (26, 31))
69190	33376561	Therefore, the therapeutic approach taken for modulating TRPV2 expression should be carefully evaluated to obtain a beneficial outcome for breast cancer patients.	('patients', 'Species', '9606', (153, 161))	('TRPV2', 'Gene', (57, 62))	('modulating', 'Var', (46, 56))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))
69191	33376561	Patients with esophageal squamous cell carcinoma (ESCC) harboring high expression levels of TRPV2 had a worse five-year overall survival rate after surgery when compared to patients with low TRPV2 expression.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (14, 48))	('patients', 'Species', '9606', (173, 181))	('TRPV2', 'Gene', (92, 97))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('worse', 'NegReg', (104, 109))	('esophageal squamous cell carcinoma', 'Disease', (14, 48))	('high expression levels', 'Var', (66, 88))	('Patients', 'Species', '9606', (0, 8))	('rat', 'Species', '10116', (137, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))
69193	33376561	In particular, knockdown of TRPV2 decreased cell proliferation, cell cycle progression, and migration (invasion).	('rat', 'Species', '10116', (56, 59))	('cell proliferation', 'CPA', (44, 62))	('knockdown', 'Var', (15, 24))	('decreased', 'NegReg', (34, 43))	('rat', 'Species', '10116', (95, 98))	('cell cycle progression', 'CPA', (64, 86))	('TRPV2', 'Gene', (28, 33))
69194	33376561	Moreover, microarray analysis demonstrated that TRPV2 silencing caused downregulation of WNT/beta-catenin signaling-related genes and basal cell carcinoma signaling-related genes.	('downregulation', 'NegReg', (71, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('beta-catenin', 'Gene', (93, 105))	('silencing', 'Var', (54, 63))	('rat', 'Species', '10116', (37, 40))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('beta-catenin', 'Gene', '1499', (93, 105))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (134, 154))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (134, 154))	('TRPV2', 'Gene', (48, 53))	('basal cell carcinoma', 'Disease', (134, 154))
69204	33376561	In the human hepatocellular carcinoma cell lines HepG2 and Huh-7, TRPV2 was found to mediate H2O2-induced oxidative stress and cell death by potentiating the inhibition of the prosurvival signaling proteins (Akt, Nrf2) and enhancing prodeath signaling proteins (p38, JNK1).	('Akt', 'Gene', '207', (208, 211))	('potentiating', 'PosReg', (141, 153))	('H2O2', 'Chemical', 'MESH:D006861', (93, 97))	('enhancing', 'PosReg', (223, 232))	('JNK1', 'Gene', '5599', (267, 271))	('p38', 'Gene', '1432', (262, 265))	('inhibition', 'NegReg', (158, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (13, 37))	('HepG2', 'CellLine', 'CVCL:0027', (49, 54))	('JNK1', 'Gene', (267, 271))	('oxidative stress', 'MPA', (106, 122))	('hepatocellular carcinoma', 'Disease', (13, 37))	('prodeath', 'MPA', (233, 241))	('Nrf2', 'Gene', '4780', (213, 217))	('human', 'Species', '9606', (7, 12))	('Huh-7', 'Gene', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Huh-7', 'Gene', '284424', (59, 64))	('H2O2-induced', 'Var', (93, 105))	('p38', 'Gene', (262, 265))	('oxidative stress', 'Phenotype', 'HP:0025464', (106, 122))	('Akt', 'Gene', (208, 211))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (13, 37))	('Nrf2', 'Gene', (213, 217))	('TRPV2', 'Gene', (66, 71))
69206	33376561	Interestingly, in the liver cancer cell line HepG2, shRNA-based TRPV2 knockdown promoted the expression of stem cell markers (i.e., CD133, CD44, and ALDH1), spheroid, and colony formation.	('liver cancer', 'Disease', 'MESH:D006528', (22, 34))	('promoted', 'PosReg', (80, 88))	('knockdown', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('liver cancer', 'Disease', (22, 34))	('CD44', 'Gene', (139, 143))	('ALDH1', 'Gene', (149, 154))	('CD133', 'Gene', (132, 137))	('CD133', 'Gene', '8842', (132, 137))	('ALDH1', 'Gene', '216', (149, 154))	('TRPV2', 'Gene', (64, 69))	('colony formation', 'CPA', (171, 187))	('expression', 'MPA', (93, 103))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('liver cancer', 'Phenotype', 'HP:0002896', (22, 34))	('CD44', 'Gene', '960', (139, 143))	('HepG2', 'CellLine', 'CVCL:0027', (45, 50))	('spheroid', 'CPA', (157, 165))
69208	33376561	Similarly, the TRPV2 antagonist tranilast induced expression of liver cancer stem-like cell (LCSLC) markers and led to spheroid and colony formation, whereas the TRPV2 agonist probenecid produced an opposite effect on liver cancer cell lines.	('colony formation', 'CPA', (132, 148))	('liver cancer', 'Disease', (64, 76))	('liver cancer', 'Disease', (218, 230))	('tranilast', 'Chemical', 'MESH:C012293', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('induced', 'PosReg', (42, 49))	('TRPV2', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('probenecid', 'Chemical', 'MESH:D011339', (176, 186))	('led to', 'Reg', (112, 118))	('antagonist', 'Var', (21, 31))	('liver cancer', 'Phenotype', 'HP:0002896', (218, 230))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (64, 76))	('expression', 'MPA', (50, 60))	('liver cancer', 'Disease', 'MESH:D006528', (218, 230))
69216	33376561	CBD triggered Ca2+ influx and apoptosis in the cell line T24, which represents a model of a poorly differentiated and high-grade human bladder carcinoma.	('Ca2+ influx', 'MPA', (14, 25))	('Ca2+', 'Chemical', 'MESH:D000069285', (14, 18))	('apoptosis', 'CPA', (30, 39))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (135, 152))	('CBD', 'Var', (0, 3))	('bladder carcinoma', 'Disease', (135, 152))	('bladder carcinoma', 'Disease', 'MESH:D001749', (135, 152))	('human', 'Species', '9606', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('CBD', 'Chemical', 'MESH:D002185', (0, 3))
69220	33376561	The abundance of the s-TRPV2 variant in normal and low-grade bladder cancer tissues suggests that it may function as a regulator of f-TRPV2 isoform.	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('variant', 'Var', (29, 36))	('bladder cancer', 'Disease', (61, 75))	('s-TRPV2', 'Gene', (21, 28))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))
69228	33376561	TRPV2 silencing with siRNA technology decreased PCa cell migration without affecting cell proliferation.	('rat', 'Species', '10116', (97, 100))	('decreased', 'NegReg', (38, 47))	('PCa', 'Disease', (48, 51))	('rat', 'Species', '10116', (60, 63))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('TRPV2', 'Gene', (0, 5))	('PCa', 'Phenotype', 'HP:0012125', (48, 51))	('silencing', 'Var', (6, 15))
69229	33376561	Similarly, TRPV2 silencing reduced metastasis of PC3-derived tumors established in nude mouse xenografts.	('reduced', 'NegReg', (27, 34))	('tumors', 'Disease', (61, 67))	('metastasis', 'CPA', (35, 45))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('PC3', 'CellLine', 'CVCL:0035', (49, 52))	('mouse', 'Species', '10090', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TRPV2', 'Gene', (11, 16))	('silencing', 'Var', (17, 26))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
69235	33376561	The deletion of the PDZ-binding domain of the calcitonin receptor abrogates the bone metastasis in an orthotopic PCa model.	('calcitonin receptor', 'Gene', (46, 65))	('bone metastasis in an', 'CPA', (80, 101))	('PCa', 'Phenotype', 'HP:0012125', (113, 116))	('deletion', 'Var', (4, 12))	('calcitonin receptor', 'Gene', '799', (46, 65))	('abrogates', 'NegReg', (66, 75))
69251	32977522	PolyR confers the cell membrane permeability and tumor selectivity of BSH.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PolyR', 'Var', (0, 5))	('tumor', 'Disease', (49, 54))	('cell membrane permeability', 'CPA', (18, 44))	('PolyR', 'Chemical', '-', (0, 5))	('BSH', 'Chemical', 'MESH:C014651', (70, 73))
69256	32977522	As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells.	('induced', 'Reg', (131, 138))	('glioma', 'Disease', (67, 73))	('BSH-polyR', 'Chemical', '-', (108, 117))	('BNCT-dependent', 'MPA', (139, 153))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('BSH-polyR', 'Var', (108, 117))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('BSH-polyR', 'Chemical', '-', (38, 47))
69277	32977522	Generally, cell-penetrating peptides (CPPs), such as polyR and human immunodeficiency virus (HIV)-derived trans-activator of transcription protein (TAT) peptides consist of serial amino acid sequences of lysine (K) or arginine (R), whose charge is positive.	('immunodeficiency', 'Phenotype', 'HP:0002721', (69, 85))	('R', 'Chemical', 'MESH:D001120', (57, 58))	('TAT', 'Gene', '6898', (148, 151))	('R', 'Chemical', 'MESH:D001120', (228, 229))	('arginine', 'Chemical', 'MESH:D001120', (218, 226))	('lysine', 'Chemical', 'MESH:D008239', (204, 210))	('HIV', 'Species', '12721', (93, 96))	('human immunodeficiency virus', 'Species', '12721', (63, 91))	('TAT', 'Gene', (148, 151))	('rat', 'Species', '10116', (21, 24))	('arginine', 'Var', (218, 226))	('polyR', 'Chemical', '-', (53, 58))
69280	32977522	showed that arginine 12-mer peptide (R12), but not 8-mer bound to C-X-C chemokine receptor type 4 (CXCR4), further stimulated the macropinocytosis of the R12-conjugated molecule.	('R', 'Chemical', 'MESH:D001120', (37, 38))	('macropinocytosis of the R12-conjugated molecule', 'MPA', (130, 177))	('arginine 12-mer peptide', 'Var', (12, 35))	('CXCR4', 'Gene', '7852', (99, 104))	('C-X-C chemokine receptor type 4', 'Gene', (66, 97))	('R', 'Chemical', 'MESH:D001120', (102, 103))	('C-X-C chemokine receptor type 4', 'Gene', '7852', (66, 97))	('R', 'Chemical', 'MESH:D001120', (154, 155))	('CXCR4', 'Gene', (99, 104))	('arginine', 'Chemical', 'MESH:D001120', (12, 20))	('stimulated', 'PosReg', (115, 125))
69295	32977522	The sequences of the shRNA targeting human cluster of differentiation 44 (CD44)#1: 5'-GGACCAATTACCATAACTATTCTCGAGAATAGTTATGGTAATTGGTCC-3', human CD44#2: 5'-CCTCCCAGTATGACACATATTCTCGAGAATATGTGTCATACTGGGAGG-3', and negative control: 5'-CCTAAGGTTAAGTCGCCCTCGCTCGAGCGAGGGCGACTTAACCTTAGG-3' (Addgene, #1864).	('TAT', 'Gene', (119, 122))	('TAT', 'Gene', (164, 167))	('CD44#', 'Var', (145, 150))	('R', 'Chemical', 'MESH:D001120', (23, 24))	('TAT', 'Gene', (185, 188))	('TAT', 'Gene', '6898', (173, 176))	('TAT', 'Gene', '6898', (119, 122))	('TAT', 'Gene', '6898', (164, 167))	('TAT', 'Gene', (103, 106))	('TAT', 'Gene', (173, 176))	('human', 'Species', '9606', (139, 144))	('human', 'Species', '9606', (37, 42))	('TAT', 'Gene', '6898', (185, 188))	('TAT', 'Gene', '6898', (103, 106))
69318	32977522	Primary antibodies against CD44 (#5640), eIF4E (#2067), eIF4A (#2013, 2490), eIF4G (#2469), poly(A)-binding protein 1 (PABP1) (#4992), eIF6 (#3833), and eRF3 (#14980) were obtained from Cell Signaling Technology Inc. (Danvers, MA, USA).	('#2469', 'Var', (84, 89))	('eIF4E', 'Gene', (41, 46))	('eIF4E', 'Gene', '1977', (41, 46))	('#14980', 'Var', (159, 165))	('#2067', 'Var', (48, 53))	('#4992', 'Var', (127, 132))	('eIF4A', 'Gene', '1973', (56, 61))	('eIF4A', 'Gene', (56, 61))	('eIF6', 'Gene', '3692', (135, 139))	('R', 'Chemical', 'MESH:D001120', (154, 155))	('eIF4G', 'Gene', '1981', (77, 82))	('PABP1', 'Gene', (119, 124))	('CD44', 'Gene', (27, 31))	('#5640', 'Var', (33, 38))	('eIF6', 'Gene', (135, 139))	('PABP1', 'Gene', '26986', (119, 124))	('eIF4G', 'Gene', (77, 82))
69319	32977522	Primary antibodies against beta-actin (#A5316), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (#MAB374), and yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) (#sc-101199) were purchased from Sigma-Aldrich Co. LLC (St. Louis, MO, USA), MilliporeSigma (Burlington, MA, USA), and Santa Cruz Biotechnology (Santa Cruz, CA, USA), respectively.	('YAP', 'Gene', (136, 139))	('Sigma-Aldrich Co', 'Disease', (231, 247))	('#A5316', 'Var', (39, 45))	('YAP', 'Gene', '10413', (136, 139))	('Sigma-Aldrich Co', 'Disease', 'MESH:D014923', (231, 247))	('yes-associated protein', 'Gene', (112, 134))	('yes-associated protein', 'Gene', '10413', (112, 134))
69340	32977522	We treated glioma cells (U87MG and U251MG), breast cancer cells (MCF7 and MDA-MB-231), and pancreatic cancer cells (CFPAC1 and PANC1) with BSH-11R at 10 microM for 24 h. We noticed that the efficiency of BSH-11R penetration was different among cell lines; U87MG, U251MG, MDA-MB-231, and PANC1 demonstrated BSH-11R uptake, but MCF7 and CFPAC1 did not (Figure 1C).	('CFPAC1', 'CellLine', 'CVCL:1119', (335, 341))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PANC1', 'CellLine', 'CVCL:0480', (127, 132))	('rat', 'Species', '10116', (217, 220))	('BSH-11R', 'Chemical', '-', (204, 211))	('glioma', 'Disease', (11, 17))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('U87MG', 'CellLine', 'CVCL:0022', (256, 261))	('U251MG', 'CellLine', 'CVCL:0021', (35, 41))	('BSH-11R', 'Chemical', '-', (306, 313))	('U87MG', 'CellLine', 'CVCL:0022', (25, 30))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (74, 84))	('BSH-11R', 'Chemical', '-', (139, 146))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))	('U251MG', 'CellLine', 'CVCL:0021', (263, 269))	('rat', 'Species', '10116', (300, 303))	('MCF7', 'CellLine', 'CVCL:0031', (65, 69))	('CFPAC1', 'CellLine', 'CVCL:1119', (116, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (271, 281))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('BSH-11R uptake', 'MPA', (306, 320))	('U87MG', 'Var', (256, 261))	('MCF7', 'CellLine', 'CVCL:0031', (326, 330))	('pancreatic cancer', 'Disease', (91, 108))	('PANC1', 'CellLine', 'CVCL:0480', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Disease', (44, 57))	('U251MG', 'Var', (263, 269))
69359	32977522	BSH-3R appeared less efficient for the intracellular delivery of BSH than BSH-11R, but both in BSH-3R-treated and BSH-11R-treated cells, CD44 knockdown significantly attenuated the cellular uptake of BSH (Figure 2B).	('BSH', 'Chemical', 'MESH:C014651', (200, 203))	('BSH-11R', 'Chemical', '-', (74, 81))	('BSH', 'Chemical', 'MESH:C014651', (95, 98))	('cellular uptake', 'CPA', (181, 196))	('BSH', 'Chemical', 'MESH:C014651', (74, 77))	('BSH', 'Chemical', 'MESH:C014651', (114, 117))	('BSH-3R', 'Chemical', '-', (95, 101))	('CD44', 'Gene', (137, 141))	('attenuated', 'NegReg', (166, 176))	('BSH-3R', 'Chemical', '-', (0, 6))	('BSH', 'Chemical', 'MESH:C014651', (0, 3))	('BSH-11R', 'Chemical', '-', (114, 121))	('BSH', 'Chemical', 'MESH:C014651', (65, 68))	('knockdown', 'Var', (142, 151))
69371	32977522	Then, the U87MG cells were fixed and applied to a Duolink assay with anti-BSH and anti-CD44 antibodies.	('anti-CD44', 'Gene', (82, 91))	('anti-BSH', 'Protein', (69, 77))	('BSH', 'Chemical', 'MESH:C014651', (74, 77))	('anti-CD44', 'Var', (82, 91))	('U87MG', 'CellLine', 'CVCL:0022', (10, 15))
69372	32977522	As shown in Figure 3C, the cells treated with BSH-11R showed much stronger signals than those treated with BSH.	('BSH', 'Chemical', 'MESH:C014651', (46, 49))	('BSH', 'Chemical', 'MESH:C014651', (107, 110))	('BSH-11R', 'Var', (46, 53))	('stronger', 'PosReg', (66, 74))	('BSH-11R', 'Chemical', '-', (46, 53))
69376	32977522	The NMuMG cells were transformed upon HRas overexpression and p53 knockdown, and they acquired cancer stem cell-related properties such as the capacity for self-renewal and anchorage-independent growth (Figure 4B).	('NMuMG', 'CellLine', 'CVCL:0075', (4, 9))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('knockdown', 'Var', (66, 75))	('HRas', 'Gene', '15461', (38, 42))	('p53', 'Gene', '22060', (62, 65))	('HRas', 'Gene', (38, 42))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('p53', 'Gene', (62, 65))	('anchorage-independent growth', 'CPA', (173, 201))
69385	32977522	These results demonstrated that BSH-11R selectively and specifically targeted CD44High cancer cells, which was usually overexpressed in cancer stem cells of various types of cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('BSH-11R', 'Gene', (32, 39))	('CD44High', 'Var', (78, 86))	('cancer', 'Disease', (136, 142))	('rat', 'Species', '10116', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('BSH-11R', 'Chemical', '-', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
69395	32977522	We predicted that BSH-11R, but not BSH, would efficiently kill the MGG18 cells after neutron irradiation, while the MGG4 cell viability was not affected due to the lack of CD44 expression.	('BSH-11R', 'Var', (18, 25))	('MGG18', 'Gene', (67, 72))	('BSH-11R', 'Chemical', '-', (18, 25))	('BSH', 'Chemical', 'MESH:C014651', (18, 21))	('BSH', 'Chemical', 'MESH:C014651', (35, 38))
69398	32977522	As we expected, the pretreatment of BSH-11R and neutron irradiation significantly induced cell death only in MGG18 (CD44High), not in MGG4 (CD44Low) (Figure 5E).	('MGG18 (CD44High', 'Var', (109, 124))	('induced', 'Reg', (82, 89))	('BSH-11R', 'Gene', (36, 43))	('cell death', 'CPA', (90, 100))	('BSH-11R', 'Chemical', '-', (36, 43))
69426	32977522	Interestingly, in the TCGA (The Cancer Genome Atlas) GBM dataset, we realized that the patients with a CD44High signature tended to show higher expressions of the genes that encoded the proteins of the intracellular targets of BSH-polyR (eIF4E, eIF4A, eRF3, and eIF4G) (Figure 8C).	('Cancer', 'Disease', (32, 38))	('BSH-polyR', 'Chemical', '-', (227, 236))	('expressions', 'MPA', (144, 155))	('CD44High', 'Var', (103, 111))	('eIF4E', 'Gene', '1977', (238, 243))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('R', 'Chemical', 'MESH:D001120', (253, 254))	('GBM', 'Phenotype', 'HP:0012174', (53, 56))	('higher', 'PosReg', (137, 143))	('eIF4E', 'Gene', (238, 243))	('eIF4G', 'Gene', (262, 267))	('eIF4G', 'Gene', '1981', (262, 267))	('R', 'Chemical', 'MESH:D001120', (235, 236))	('eIF4A', 'Gene', (245, 250))	('eIF4A', 'Gene', '1973', (245, 250))	('patients', 'Species', '9606', (87, 95))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
69428	32977522	Although in vivo studies using appropriate tumor models are warranted in the future, these data suggest a potential of BSH-polyR as a boron delivery agent for BNCT.	('BSH-polyR', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('boron', 'Chemical', 'MESH:D001895', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('BSH-polyR', 'Chemical', '-', (119, 128))
69431	32977522	Consistent with this, BSH-polyR was readily penetrated into CD44-expressing cells, whose properties were similar to those of cancer stem-like cells (Figure 4).	('BSH-polyR', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BSH-polyR', 'Chemical', '-', (22, 31))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (49, 52))
69438	32977522	Indeed, in the BNCT experiment in this study, we observed efficient cell death in MGG18 cells treated with BSH-polyR.	('BSH-polyR', 'Var', (107, 116))	('cell death', 'CPA', (68, 78))	('BSH-polyR', 'Chemical', '-', (107, 116))
69439	32977522	This suggests that BSH-polyR-based BNCT can induce cell death in a different way from that usually is associated with X-ray irradiation.	('BSH-polyR', 'Chemical', '-', (19, 28))	('BSH-polyR-based', 'Var', (19, 34))	('cell death', 'CPA', (51, 61))	('induce', 'Reg', (44, 50))
69459	33057419	Overexpressing ZNF787 during neurogenesis resulted in explicit repression of neuronal differentiation.	('neuronal differentiation', 'CPA', (77, 101))	('ZNF787', 'Gene', (15, 21))	('ZNF787', 'Gene', '126208', (15, 21))	('Overexpressing', 'Var', (0, 14))	('repression', 'NegReg', (63, 73))
69475	33057419	Since ZNF787 is more highly expressed in miR-124 knock-out compared to wildtype iPSC, we overexpressed ZNF787 in the wildtype cells to experimentally validate our result.	('ZNF787', 'Gene', '126208', (103, 109))	('knock-out', 'Var', (49, 58))	('ZNF787', 'Gene', '126208', (6, 12))	('ZNF787', 'Gene', (103, 109))	('miR-124', 'Gene', (41, 48))	('more highly', 'PosReg', (16, 27))	('ZNF787', 'Gene', (6, 12))
69507	33057419	Because TF deregulation is central to disease progression in many disease states, and particularly in cancers, we focused on a comparison of the TF co-expression networks between the three different kinds of tumors.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('deregulation', 'Var', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('tumors', 'Disease', (208, 214))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('cancers', 'Disease', (102, 109))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
69579	31787462	Data analysis identified a family of compounds featuring a 2-amino-1,3-benzoxazole moiety (eCF309 to eCF334) for their antiproliferative properties in the nM range.	('2-amino-1,3-benzoxazole', 'Chemical', 'MESH:D001583', (59, 82))	('eCF309', 'Var', (91, 97))	('antiproliferative properties', 'MPA', (119, 147))
69597	31787462	To confirm the results, U87 and T98 cell viability assays were repeated for the most potent hits (eCF309, eCF311, eCF312, eCF324, eCF325, eCF333 and eCF334, all of which feature a 2-amino-1,3-benzoxazole moiety at the C3 position) using a 7-point half-log dose-response study (1 to 1,000 nM).	('T98', 'CellLine', 'CVCL:B368', (32, 35))	('eCF312', 'Var', (114, 120))	('U87', 'Gene', '641648', (24, 27))	('eCF333', 'Var', (138, 144))	('2-amino-1,3-benzoxazole', 'Chemical', 'MESH:D001583', (180, 203))	('eCF334', 'Var', (149, 155))	('eCF309', 'Var', (98, 104))	('U87', 'Gene', (24, 27))	('eCF324', 'Var', (122, 128))	('eCF325', 'Var', (130, 136))	('eCF311', 'Var', (106, 112))
69598	31787462	2b and c, eCF324 was the most potent compound in both cell lines, displaying EC50 values of 13 and 10 nM in U87 and T98 cells, respectively; values that were superior to those of the positive controls INK128 and SN-38.	('eCF324', 'Var', (10, 16))	('EC50', 'MPA', (77, 81))	('U87', 'Gene', '641648', (108, 111))	('T98', 'CellLine', 'CVCL:B368', (116, 119))	('U87', 'Gene', (108, 111))
69602	31787462	Data, all the hits display high inhibitory activity for mTOR kinase, being eCF309 the most selective (IC50 (mTOR) = 15 nM; IC50 (PI3Kalpha) = 981 nM) and eCF324 the most potent (IC50 (mTOR) = 1.8 nM; IC50 (PI3Kalpha) = 3.5 nM).	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (184, 188))	('mTOR', 'Gene', '2475', (108, 112))	('mTOR', 'Gene', '2475', (56, 60))	('PI3Kalpha', 'Gene', '5290', (206, 215))	('mTOR', 'Gene', (184, 188))	('PI3Kalpha', 'Gene', (206, 215))	('inhibitory activity', 'MPA', (32, 51))	('PI3Kalpha', 'Gene', '5290', (129, 138))	('eCF309', 'Var', (75, 81))	('eCF324', 'Var', (154, 160))	('PI3Kalpha', 'Gene', (129, 138))
69607	31787462	3, although both eCF309 and eCF324 display superior activity than the pan-PI3K inhibitor GDC0941, this selective inhibitor exhibits sub-microM activity against T98 (equivalent to that of eCF309) and low microM activity in U87 cells.	('T98', 'CellLine', 'CVCL:B368', (160, 163))	('activity', 'MPA', (52, 60))	('U87', 'Gene', (222, 225))	('U87', 'Gene', '641648', (222, 225))	('GDC0941', 'Chemical', 'MESH:C532162', (89, 96))	('eCF309', 'Var', (17, 23))
69608	31787462	Next, to test whether dual PI3K/mTOR inhibition could provide a therapeutic advantage to target glioma cells, cell viability studies were performed in U87 and T98 cells by combining eCF309 with the pan-PI3K inhibitor GDC0941 at a series of concentrations.	('GDC0941', 'Chemical', 'MESH:C532162', (217, 224))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('T98', 'CellLine', 'CVCL:B368', (159, 162))	('combining', 'Interaction', (172, 181))	('U87', 'Gene', (151, 154))	('U87', 'Gene', '641648', (151, 154))	('glioma', 'Disease', (96, 102))	('eCF309', 'Var', (182, 188))
69610	31787462	Since both compounds are known to be selective inhibitors of mTOR and PI3K, respectively, this study indicates that concurrent inhibition of mTOR and PI3Ks potentiate an antiproliferative effect in these two glioma cell lines.	('mTOR', 'Gene', '2475', (141, 145))	('glioma', 'Disease', (208, 214))	('mTOR', 'Gene', (141, 145))	('antiproliferative effect', 'CPA', (170, 194))	('PI3Ks', 'Var', (150, 155))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('inhibition', 'NegReg', (127, 137))	('mTOR', 'Gene', (61, 65))	('potentiate', 'PosReg', (156, 166))	('mTOR', 'Gene', '2475', (61, 65))	('glioma', 'Disease', 'MESH:D005910', (208, 214))
69613	31787462	This may indicate that the inherent inhibitory properties of eCF324 on mTOR and PI3K are not optimally balanced to reach maximal synergistic anticancer activity and additional PI3K inhibition can promote further the antiproliferative effect mediated by this agent.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('promote', 'PosReg', (196, 203))	('mTOR', 'Gene', '2475', (71, 75))	('eCF324', 'Var', (61, 67))	('inhibition', 'NegReg', (181, 191))	('PI3K', 'Var', (176, 180))	('mTOR', 'Gene', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('antiproliferative effect', 'CPA', (216, 240))
69615	31787462	In agreement with previous results, compound eCF324 exhibited the greatest potency with a GI50 valued of 7.2 nM, similar to INK128 but higher than the Topoisomerase-I inhibitor SN-38 and the pan-PI3K inhibitor GDC0941.	('higher', 'PosReg', (135, 141))	('potency', 'MPA', (75, 82))	('GDC0941', 'Chemical', 'MESH:C532162', (210, 217))	('eCF324', 'Var', (45, 51))
69618	31787462	To test the compounds under conditions that better represent the tumour microenvironment, G317 cells were cultured in 3D and pre-formed spheroids treated with eCF309, eCF324 and the positive controls at a range of concentrations (0.01-10 microM) for 8 days.	('eCF309', 'Var', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('eCF324', 'Var', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))
69630	31787462	G317 were cultured in DMEM/HAMS-F12 (Sigma) supplemented with 1.5 g L-1 D-(+)-Glucose (Sigma), MEM non-essential aminoacids (Gibco), 0.015% (w/v) Penicillin-Streptomycin (Gibco), 0.012% (w/v) BSA (Gibco), 0.1 mM beta-mercaptoethanol (Gibco), B27 (Gibco) and N2 supplements (Gibco).	('N2', 'Chemical', 'MESH:D009584', (258, 260))	('B27', 'Gene', (242, 245))	('0.015', 'Var', (133, 138))	('B27', 'Gene', '56246', (242, 245))	('Penicillin-Streptomycin', 'Chemical', 'MESH:D013307', (146, 169))	('beta-mercaptoethanol', 'Chemical', 'MESH:D008623', (212, 232))	('D-(+)-Glucose', 'Chemical', 'MESH:D005947', (72, 85))
69636	31787462	The hits belonged to a group of compounds known to target mTOR and/or PI3Ks, including the selective mTOR inhibitor eCF309 and the dual PI3K/mTOR inhibitor eCF324.	('mTOR', 'Gene', '2475', (141, 145))	('mTOR', 'Gene', (58, 62))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', (141, 145))	('mTOR', 'Gene', '2475', (101, 105))	('eCF309', 'Var', (116, 122))	('mTOR', 'Gene', '2475', (58, 62))
69638	31787462	Synergy studies with the commercially-available selective pan-PI3K inhibitor GDC0941 provided evidence of the synergistic effect of concurrently inhibiting mTOR and PI3Ks in glioma cell growth.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('mTOR', 'Gene', (156, 160))	('mTOR', 'Gene', '2475', (156, 160))	('PI3Ks', 'Var', (165, 170))	('glioma', 'Disease', (174, 180))	('GDC0941', 'Gene', (77, 84))	('GDC0941', 'Chemical', 'MESH:C532162', (77, 84))	('inhibiting', 'NegReg', (145, 155))
69643	29282221	A notable example is EGFR kinase inhibitors, which display poor clinical efficacy despite overexpression and/or mutation of EGFR in >50% of GBM.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (124, 128))	('mutation', 'Var', (112, 120))	('EGFR', 'Gene', (124, 128))	('clinical', 'Species', '191496', (64, 72))	('overexpression', 'PosReg', (90, 104))
69650	29282221	Similar to many peripheral cancers, the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is overexpressed and/or mutated in more than 50% of GBM tumors.	('RTK', 'Gene', '5979', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('epidermal growth factor receptor', 'Gene', '1956', (40, 72))	('receptor tyrosine kinase', 'Gene', (83, 107))	('RTK', 'Gene', (109, 112))	('receptor tyrosine kinase', 'Gene', '5979', (83, 107))	('mutated', 'Var', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('GBM tumors', 'Disease', (167, 177))	('overexpressed', 'PosReg', (118, 131))	('GBM tumors', 'Disease', 'MESH:D005910', (167, 177))	('peripheral cancers', 'Disease', 'MESH:D010523', (16, 34))	('EGFR', 'Gene', '1956', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('peripheral cancers', 'Disease', (16, 34))	('epidermal growth factor receptor', 'Gene', (40, 72))	('EGFR', 'Gene', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
69652	29282221	Targeted inhibition of EGFR has been largely successful in treatment of non-CNS malignancies with EGFR amplification and/or mutation, including breast cancer and non-small cell lung carcinoma.	('EGFR', 'Gene', (98, 102))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (162, 191))	('breast cancer', 'Disease', (144, 157))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (162, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('EGFR', 'Gene', '1956', (23, 27))	('malignancies', 'Disease', 'MESH:D009369', (80, 92))	('mutation', 'Var', (124, 132))	('non-small cell lung carcinoma', 'Disease', (162, 191))	('EGFR', 'Gene', '1956', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('EGFR', 'Gene', (23, 27))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (166, 191))	('amplification', 'Var', (103, 116))	('malignancies', 'Disease', (80, 92))
69709	29282221	This hypothesis was further supported by the observation that CD44 and p-EGFR were often co-expressed by GBM cells (Fig.	('CD44', 'Var', (62, 66))	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (73, 77))
69759	29282221	Although not statistically significant, a similar trend was observed for HK423 and GBM39 gliomaspheres (Fig.	('HK423', 'CellLine', 'CVCL:L805', (73, 78))	('HK423', 'Var', (73, 78))	('GBM39', 'Gene', (83, 88))
69779	29282221	Lack of CD44 mitigated both cytotoxic and cytostatic resistance to erlotinib (Fig.	('mitigated', 'NegReg', (13, 22))	('CD44', 'Gene', (8, 12))	('erlotinib', 'Chemical', 'MESH:D000069347', (67, 76))	('Lack', 'Var', (0, 4))	('cytostatic resistance to erlotinib', 'MPA', (42, 76))
69819	29282221	Although some HA is detected in subcutaneously implanted GBM tumors, it is thought that tumors contain high amounts of low molecular weight of HA, which contribute to tumor growth and angiogenesis.	('HA', 'Chemical', 'MESH:D006820', (143, 145))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GBM tumors', 'Disease', (57, 67))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('angiogenesis', 'CPA', (184, 196))	('HA', 'Chemical', 'MESH:D006820', (14, 16))	('GBM tumors', 'Disease', 'MESH:D005910', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (167, 172))	('contribute', 'Reg', (153, 163))	('tumors', 'Disease', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('low', 'Var', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (61, 66))
69830	29282221	As knockdown of CD44 restored the cytostatic and cytotoxic effects of erlotinib, we are confident that HA-CD44 interactions contributed to acquisition of erlotinib resistance (Fig.	('HA', 'Chemical', 'MESH:D006820', (103, 105))	('CD44', 'Gene', (16, 20))	('interactions', 'Interaction', (111, 123))	('erlotinib', 'Chemical', 'MESH:D000069347', (154, 163))	('knockdown', 'Var', (3, 12))	('erlotinib resistance', 'MPA', (154, 174))	('erlotinib', 'Chemical', 'MESH:D000069347', (70, 79))
69849	28675230	The one-pot synthesis is based on the addition of two types of parent nanospheres in terms of their surface chemical functionality (e.g., decorated with PEG-NH2 or PEG-COOH).	('PEG-COOH', 'Var', (164, 172))	('PEG', 'Chemical', '-', (153, 156))	('PEG-NH2', 'Var', (153, 160))	('PEG', 'Chemical', '-', (164, 167))	('COOH', 'Chemical', 'MESH:D002255', (168, 172))	('PEG-NH2', 'Chemical', '-', (153, 160))
69853	28675230	Overexpression of fibronectin is strongly associated with the perivascular regions of glioblastoma multiforme and plays a critical role in migrating and invasive glioma cells.	('invasive glioma', 'Disease', (153, 168))	('invasive glioma', 'Disease', 'MESH:D005910', (153, 168))	('glioma cells', 'Disease', (162, 174))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (86, 109))	('associated', 'Reg', (42, 52))	('fibronectin', 'Gene', (18, 29))	('perivascular regions', 'Phenotype', 'HP:0012520', (62, 82))	('migrating', 'CPA', (139, 148))	('Overexpression', 'Var', (0, 14))	('glioma cells', 'Disease', 'MESH:D005910', (162, 174))	('glioblastoma multiforme', 'Disease', (86, 109))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('fibronectin', 'Gene', '14268', (18, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
69854	28675230	In mice with invasive glioma tumors, 3.7% of the injected CREKA-targeted nanochains was found in gliomas within 1 h. Notably, the intratumoral deposition of the nanochain was ~2.6-fold higher than its spherical variant.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('gliomas', 'Disease', 'MESH:D005910', (97, 104))	('invasive glioma tumors', 'Disease', (13, 35))	('invasive glioma tumors', 'Disease', 'MESH:D005910', (13, 35))	('gliomas', 'Disease', (97, 104))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (135, 140))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('higher', 'PosReg', (185, 191))	('nanochain', 'Var', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
70144	28303930	5A, the TUSC3 mRNA harboured a potential miR-UL112-3p binding site (3227-3236 region of TUSC3 mRNA, ATCTCACTGT).	('TUSC3', 'Gene', '7991', (8, 13))	('3227-3236 region', 'Var', (68, 84))	('TUSC3', 'Gene', '7991', (88, 93))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('TUSC3', 'Gene', (88, 93))	('TUSC3', 'Gene', (8, 13))
70145	28303930	To validate whether miR-UL112-3p can directly bind to and regulate the levels of TUSC3 mRNA through the predicted binding sites, we cloned the wild-type and mutant sequence that contain the potential binding site using the luciferase reporter gene system (Fig.	('mutant', 'Var', (157, 163))	('TUSC3', 'Gene', '7991', (81, 86))	('levels', 'MPA', (71, 77))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('regulate', 'Reg', (58, 66))	('TUSC3', 'Gene', (81, 86))
70147	28303930	By contrast, the activity of the luciferase reporter gene linked to the mutant sequence did not change in the presence of the miR-UL112-3p mimics/inhibitor (Fig.	('luciferase', 'Enzyme', (33, 43))	('mutant', 'Var', (72, 78))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (126, 129))	('activity', 'MPA', (17, 25))
70154	28303930	The results indicated that the knockdown of TUSC3 caused by the overexpression of miR-UL112-3p could enhance the activity of the AKT pathway (Fig.	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('AKT', 'Gene', '207', (129, 132))	('TUSC3', 'Gene', '7991', (44, 49))	('overexpression', 'PosReg', (64, 78))	('activity', 'MPA', (113, 121))	('enhance', 'PosReg', (101, 108))	('TUSC3', 'Gene', (44, 49))	('AKT', 'Gene', (129, 132))	('knockdown', 'Var', (31, 40))
70161	28303930	Our result suggested that primary GBM cell transfected with CA-AKT exhibited a significant increase cell growth, invasion, migration, S phase percentage and a decrease cell apoptosis.	('cell growth', 'CPA', (100, 111))	('AKT', 'Gene', (63, 66))	('invasion', 'CPA', (113, 121))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('increase', 'PosReg', (91, 99))	('decrease', 'NegReg', (159, 167))	('cell apoptosis', 'CPA', (168, 182))	('AKT', 'Gene', '207', (63, 66))	('transfected', 'Var', (43, 54))	('migration', 'CPA', (123, 132))	('S phase percentage', 'CPA', (134, 152))
70169	28303930	The latest study indicates that cytomegalovirus-encoded CMV-70-3p increases GBM cancer stem cells stemness and acts as a potential regulator of CMV-mediated glioma progression, implying that HCMV-encoded miRNAs are involved in regulating carcinoma pathophysiological processes.	('carcinoma', 'Disease', 'MESH:D002277', (238, 247))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('increases', 'PosReg', (66, 75))	('stemness', 'Disease', (98, 106))	('stemness', 'Disease', 'MESH:D020295', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('GBM', 'Disease', (76, 79))	('HCMV', 'Species', '10359', (191, 195))	('carcinoma', 'Disease', (238, 247))	('glioma', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('GBM', 'Phenotype', 'HP:0012174', (76, 79))	('miR', 'Gene', '220972', (204, 207))	('CMV-70-3p', 'Var', (56, 65))	('cancer', 'Disease', (80, 86))	('miR', 'Gene', (204, 207))
70220	28303930	For the orthotopic implantation, the indicated GBM cells (1 x 104) transduced with luciferase were stereotactically injected into the right cerebral cortex at a depth of 3.5 mm of nude mice.	('luciferase', 'Gene', (83, 93))	('transduced', 'Var', (67, 77))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('nude mice', 'Species', '10090', (180, 189))
70253	27341166	Kinase signaling is frequently dysregulated in GBM, including subsets of tumors with amplification or activating mutations in the Epidermal Growth Factor Receptor (EGFR), increases in Platelet Derived Growth Factor Receptor (PDGFR) signaling, increased Phosphatidyl-Inositol-3 Kinase (PI3K) and tumor supporting angiogenic signaling through Vascular Endothelial Growth Factor Receptor (VEGFR) as well as other kinase driven pathways.	('EGFR', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (113, 122))	('dysregulated', 'Reg', (31, 43))	('amplification', 'Var', (85, 98))	('increased', 'PosReg', (243, 252))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (130, 162))	('tumors', 'Disease', (73, 79))	('EGFR', 'Gene', '1956', (387, 391))	('signaling', 'MPA', (232, 241))	('Platelet Derived Growth Factor Receptor', 'Gene', (184, 223))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('VEGFR', 'Gene', '3791', (386, 391))	('Phosphatidyl-Inositol-3', 'MPA', (253, 276))	('Vascular Endothelial Growth Factor Receptor', 'Gene', '3791', (341, 384))	('EGFR', 'Gene', '1956', (164, 168))	('tumor', 'Disease', (295, 300))	('Platelet Derived Growth Factor Receptor', 'Gene', '5159', (184, 223))	('VEGFR', 'Gene', (386, 391))	('Kinase signaling', 'MPA', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Disease', (73, 78))	('Vascular Endothelial Growth Factor Receptor', 'Gene', (341, 384))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PDGFR', 'Gene', (225, 230))	('EGFR', 'Gene', (387, 391))	('PDGFR', 'Gene', '5159', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('Epidermal Growth Factor Receptor', 'Gene', (130, 162))	('increases', 'PosReg', (171, 180))
70321	27341166	Remove supernatant and add 40 muL of lysis buffer containing PPI and PI to each tube and lyse for 30 minutes at 4  C. Pipette samples vigorously to break tumor beads.	('muL', 'Gene', (30, 33))	('PPI', 'Var', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('muL', 'Gene', '4591', (30, 33))	('tumor', 'Disease', (154, 159))
70340	27341166	Select image folder containing barcoded and time-stamped whole array images for PTK or STK data, select article number matched array layout file (86312 for PTK and 87102 for STK), and load previously generated array annotation File.	('86312', 'Var', (146, 151))	('PTK', 'Gene', '2264', (156, 159))	('PTK', 'Gene', '2264', (80, 83))	('PTK', 'Gene', (80, 83))	('PTK', 'Gene', (156, 159))
70361	27341166	Additionally, small modifications to the maintenance of the microtumors helped to speed up the process of changing medium and dosing the cells.	('microtumors', 'Disease', 'None', (60, 71))	('microtumors', 'Disease', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('modifications', 'Var', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
70362	27341166	Several of these modifications included, but were not limited to, using a multichannel electronic pipette to remove and replace medium from the 96-well plates and pre-mixing fresh drug dosing solutions and arranging the 2X solutions in a corresponding 2mL 96-well plate.	('modifications', 'Var', (17, 30))	('mul', 'Gene', (74, 77))	('mul', 'Gene', '4591', (74, 77))
70465	26296086	Table 2 shows the sensitivity and specificity using IAUC90 and ADC10 to differentiate tumor recurrence from post-treatment effect in post-treatment glioblastoma patients with uninterpretable DSC images.	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('ADC10', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ADC10', 'Gene', '113451', (63, 68))	('IAUC90', 'Var', (52, 58))	('tumor', 'Disease', (86, 91))	('men', 'Species', '9606', (118, 121))	('patients', 'Species', '9606', (161, 169))	('glioblastoma', 'Disease', (148, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (148, 160))	('men', 'Species', '9606', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
70470	26296086	Inter-reader agreement for the measurement of IAUC90 (ICC, 0.95) was higher than for the measurement of ADC10 (ICC, 0.87).	('men', 'Species', '9606', (96, 99))	('men', 'Species', '9606', (38, 41))	('men', 'Species', '9606', (18, 21))	('ADC10', 'Gene', (104, 109))	('ADC10', 'Gene', '113451', (104, 109))	('IAUC90', 'Var', (46, 52))
70515	24418474	The Cancer Genome Atlas Research Network for GBM showed the role of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of GBM.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (107, 116))	('PIK3R1', 'Gene', (181, 187))	('NF1', 'Gene', (75, 78))	('TP53', 'Gene', (83, 87))	('ERBB2', 'Gene', '2064', (68, 73))	('PIK3R1', 'Gene', '5295', (181, 187))	('NF1', 'Gene', '4763', (75, 78))	('ERBB2', 'Gene', (68, 73))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
70518	24418474	Preclinical data suggest that over-expression of EGFR confers radiation resistance on malignant glioma and that blocking EGFR restores radiosensitivity.	('blocking', 'Var', (112, 120))	('malignant glioma', 'Disease', (86, 102))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', '1956', (121, 125))	('EGFR', 'Gene', (49, 53))	('EGFR', 'Gene', (121, 125))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('restores', 'PosReg', (126, 134))	('radiosensitivity', 'MPA', (135, 151))	('radiation', 'CPA', (62, 71))	('over-expression', 'PosReg', (30, 45))	('malignant glioma', 'Disease', 'MESH:D005910', (86, 102))
70525	24418474	The molecular chaperone HSP90 is known to stabilize Akt and oncogenic forms of mutant EGFR, both of which contribute to the growth of a variety of cancers including gliomas.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Akt', 'Gene', (52, 55))	('EGFR', 'Gene', '1956', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('HSP90', 'Gene', (24, 29))	('mutant', 'Var', (79, 85))	('HSP90', 'Gene', '3320', (24, 29))	('EGFR', 'Gene', (86, 90))	('contribute', 'Reg', (106, 116))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('gliomas', 'Disease', (165, 172))	('growth', 'MPA', (124, 130))	('Akt', 'Gene', '207', (52, 55))	('gliomas', 'Disease', 'MESH:D005910', (165, 172))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))
70526	24418474	We previously reported that HDAC inhibitors potentiate radiation-induced cell killing in a panel of human cancer cells with activated EGFR signaling through diverse mechanisms.	('HDAC', 'Gene', (28, 32))	('potentiate', 'PosReg', (44, 54))	('HDAC', 'Gene', '9734', (28, 32))	('radiation-induced cell killing', 'CPA', (55, 85))	('EGFR', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (100, 105))	('cancer', 'Disease', (106, 112))	('EGFR', 'Gene', '1956', (134, 138))	('inhibitors', 'Var', (33, 43))
70529	24418474	Additionally, the signaling cascades downstream of aberrant EGFR activation contribute to invasive phenotype in GBM and a mesenchymal feature of GBM is considered to be a major therapeutic obstacle for GBM treatment.	('EGFR', 'Gene', (60, 64))	('aberrant', 'Var', (51, 59))	('signaling cascades', 'MPA', (18, 36))	('EGFR', 'Gene', '1956', (60, 64))	('GBM', 'Disease', (112, 115))	('contribute', 'Reg', (76, 86))	('activation', 'PosReg', (65, 75))
70544	24418474	As indicated, prior to irradiation cells were treated with TMZ (25 muM) with or without the inhibitors PI103 (0.4 muM), rapamycin (100 nM), 17-DMAG (25 nM), and LBH589 (20 nM) followed by incubation at 37 C for 10 to 14 days.	('LBH589', 'Chemical', 'MESH:D000077767', (161, 167))	('100', 'Var', (131, 134))	('PI103', 'Chemical', 'MESH:C522973', (103, 108))	('muM', 'Gene', '56925', (114, 117))	('muM', 'Gene', '56925', (67, 70))	('rapamycin', 'Chemical', 'MESH:D020123', (120, 129))	('17-DMAG', 'Chemical', '-', (140, 147))	('muM', 'Gene', (114, 117))	('muM', 'Gene', (67, 70))	('TMZ', 'Chemical', 'MESH:D000077204', (59, 62))
70572	24418474	As shown in Figure 2B, PI103, a dual inhibitor of class I PI3K and mTOR, markedly reduced p-Akt and p-p70S6K protein levels, and effectively potentiated the radiosensitizing effect of TMZ in both cell lines (p < 0.05 for U251 and T98G cells).	('T98G', 'CellLine', 'CVCL:0556', (230, 234))	('TMZ', 'Chemical', 'MESH:D000077204', (184, 187))	('Akt', 'Gene', '207', (92, 95))	('p70S6K', 'Gene', '6198', (102, 108))	('p70S6K', 'Gene', (102, 108))	('U251', 'CellLine', 'CVCL:0021', (221, 225))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('PI103', 'Chemical', 'MESH:C522973', (23, 28))	('Akt', 'Gene', (92, 95))	('PI103', 'Var', (23, 28))	('reduced', 'NegReg', (82, 89))	('potentiated', 'PosReg', (141, 152))	('radiosensitizing effect', 'CPA', (157, 180))
70574	24418474	PTEN-mutant U251 cells showed higher radiosensitizing effect of PI103 than that of T98G which has PTEN-wild type (SER0.5 1.41 vs. 1.26).	('PI103', 'Var', (64, 69))	('higher', 'PosReg', (30, 36))	('T98G', 'CellLine', 'CVCL:0556', (83, 87))	('U251', 'CellLine', 'CVCL:0021', (12, 16))	('PTEN', 'Gene', (98, 102))	('radiosensitizing', 'CPA', (37, 53))	('PTEN', 'Gene', '5728', (98, 102))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('PI103', 'Chemical', 'MESH:C522973', (64, 69))	('SER0', 'Chemical', '-', (114, 118))
70579	24418474	LBH589 effectively potentiated the radiosensitizing effect of TMZ (p < 0.05 for U251 cells).	('radiosensitizing effect', 'CPA', (35, 58))	('LBH589', 'Chemical', 'MESH:D000077767', (0, 6))	('potentiated', 'PosReg', (19, 30))	('U251', 'CellLine', 'CVCL:0021', (80, 84))	('LBH589', 'Var', (0, 6))	('TMZ', 'Chemical', 'MESH:D000077204', (62, 65))
70582	24418474	Pretreatment of U251 cells with the dual inhibitor PI103, the HSP90 inhibitor 17-DMAG, or the HDAC inhibitor LBH589 combined with TMZ caused marked prolongation of radiation-induced gammaH2AX foci formation 6 h after irradiation with 6 Gy (Figure 3A), indicating delayed DNA damage repair.	('radiation-induced gammaH2AX foci formation', 'CPA', (164, 206))	('PI103', 'Var', (51, 56))	('17-DMAG', 'Chemical', '-', (78, 85))	('HDAC', 'Gene', (94, 98))	('PI103', 'Chemical', 'MESH:C522973', (51, 56))	('HSP90', 'Gene', (62, 67))	('HDAC', 'Gene', '9734', (94, 98))	('HSP90', 'Gene', '3320', (62, 67))	('U251', 'CellLine', 'CVCL:0021', (16, 20))	('LBH589', 'Chemical', 'MESH:D000077767', (109, 115))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('prolongation', 'PosReg', (148, 160))
70583	24418474	Pretreatment of U251 with PI103, 17-DMAG, or LBH589 combined with TMZ attenuated expression of p-DNA-PK (Figure 3B).	('p-DNA-PK', 'Protein', (95, 103))	('attenuated', 'NegReg', (70, 80))	('LBH589', 'Chemical', 'MESH:D000077767', (45, 51))	('17-DMAG', 'Chemical', '-', (33, 40))	('PI103', 'Var', (26, 31))	('U251', 'CellLine', 'CVCL:0021', (16, 20))	('PI103', 'Chemical', 'MESH:C522973', (26, 31))	('TMZ', 'Chemical', 'MESH:D000077204', (66, 69))	('expression', 'MPA', (81, 91))
70588	24418474	Pretreatment with TMZ combined with rapamycin or PI103 increased punctate fluorescence or lysosomal localization of LysoTracker in U251 cells at 24 h (Figure 4C).	('TMZ', 'Chemical', 'MESH:D000077204', (18, 21))	('lysosomal localization of LysoTracker', 'MPA', (90, 127))	('PI103', 'Var', (49, 54))	('increased', 'PosReg', (55, 64))	('rapamycin', 'Chemical', 'MESH:D020123', (36, 45))	('PI103', 'Chemical', 'MESH:C522973', (49, 54))	('U251', 'CellLine', 'CVCL:0021', (131, 135))	('punctate fluorescence', 'MPA', (65, 86))
70590	24418474	Treatment with rapamycin or PI103 in the presence or absence of TMZ increased LC3-II (16 kDa) expression in U251 cells at 24 h after each combined treatment (Figure 4D).	('PI103', 'Var', (28, 33))	('PI103', 'Chemical', 'MESH:C522973', (28, 33))	('increased LC3', 'Phenotype', 'HP:0003141', (68, 81))	('rapamycin', 'Chemical', 'MESH:D020123', (15, 24))	('U251', 'CellLine', 'CVCL:0021', (108, 112))	('expression', 'MPA', (94, 104))	('TMZ', 'Chemical', 'MESH:D000077204', (64, 67))	('LC3', 'Gene', '84557', (78, 81))	('increased', 'PosReg', (68, 77))	('LC3', 'Gene', (78, 81))
70594	24418474	However, the combination treatment of TMZ with PI103 or 17-DMAG or LBH589 markedly inhibited the ability of migration and invasion of U251 glioma cells (Figure 5A, B, P < 0.05).	('U251', 'CellLine', 'CVCL:0021', (134, 138))	('TMZ', 'Chemical', 'MESH:D000077204', (38, 41))	('glioma', 'Disease', (139, 145))	('invasion', 'CPA', (122, 130))	('inhibited', 'NegReg', (83, 92))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('LBH589', 'Chemical', 'MESH:D000077767', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('17-DMAG', 'Var', (56, 63))	('PI103', 'Var', (47, 52))	('17-DMAG', 'Chemical', '-', (56, 63))	('PI103', 'Chemical', 'MESH:C522973', (47, 52))	('LBH589', 'Gene', (67, 73))
70598	24418474	PI103 or 17-DMAG or LBH589 combined with radiation and/or TMZ significantly impaired VM formation of U251 glioma cells compared with TMZ alone treatment (Figure 5C).	('impaired', 'NegReg', (76, 84))	('17-DMAG', 'Chemical', '-', (9, 16))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('LBH589', 'Gene', (20, 26))	('U251', 'CellLine', 'CVCL:0021', (101, 105))	('glioma', 'Disease', (106, 112))	('TMZ', 'Chemical', 'MESH:D000077204', (133, 136))	('VM formation', 'CPA', (85, 97))	('PI103', 'Var', (0, 5))	('TMZ', 'Chemical', 'MESH:D000077204', (58, 61))	('PI103', 'Chemical', 'MESH:C522973', (0, 5))	('LBH589', 'Chemical', 'MESH:D000077767', (20, 26))
70599	24418474	Consistent with the reduction of invasion, migration and VM formation, the combination treatment of TMZ with PI103 or 17-DMAG or LBH589 showed a decrease in expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP) 2 and EphA2.	('reduction', 'NegReg', (20, 29))	('PI103', 'Var', (109, 114))	('EphA2', 'Gene', (251, 256))	('EphA2', 'Gene', '1969', (251, 256))	('vascular endothelial growth factor', 'Gene', '7422', (171, 205))	('matrix metalloproteinase (MMP) 2', 'Gene', '4313', (214, 246))	('VEGF', 'Gene', '7422', (207, 211))	('TMZ', 'Chemical', 'MESH:D000077204', (100, 103))	('vascular endothelial growth factor', 'Gene', (171, 205))	('LBH589', 'Chemical', 'MESH:D000077767', (129, 135))	('PI103', 'Chemical', 'MESH:C522973', (109, 114))	('VEGF', 'Gene', (207, 211))	('LBH589', 'Gene', (129, 135))	('invasion', 'CPA', (33, 41))	('migration', 'CPA', (43, 52))	('decrease', 'NegReg', (145, 153))	('expression', 'MPA', (157, 167))	('VM formation', 'CPA', (57, 69))	('17-DMAG', 'Var', (118, 125))	('17-DMAG', 'Chemical', '-', (118, 125))
70600	24418474	In contrast, the treatment of TMZ with PI103 or 17-DMAG or LBH589 led up-regulation of epithelial marker E-cadherin (Figure 5D).	('epithelial marker', 'MPA', (87, 104))	('up-regulation', 'PosReg', (70, 83))	('E-cadherin', 'Gene', (105, 115))	('LBH589', 'Chemical', 'MESH:D000077767', (59, 65))	('E-cadherin', 'Gene', '999', (105, 115))	('TMZ', 'Chemical', 'MESH:D000077204', (30, 33))	('LBH589', 'Gene', (59, 65))	('PI103', 'Var', (39, 44))	('PI103', 'Chemical', 'MESH:C522973', (39, 44))	('17-DMAG', 'Chemical', '-', (48, 55))
70602	24418474	In contrast, the level of EphA2 was considerably lower when the cells were treated by TMZ with PI103 or 17-DMAG or LBH589.	('EphA2', 'Gene', '1969', (26, 31))	('LBH589', 'Chemical', 'MESH:D000077767', (115, 121))	('EphA2', 'Gene', (26, 31))	('lower', 'NegReg', (49, 54))	('17-DMAG', 'Chemical', '-', (104, 111))	('PI103', 'Var', (95, 100))	('TMZ', 'Chemical', 'MESH:D000077204', (86, 89))	('PI103', 'Chemical', 'MESH:C522973', (95, 100))
70604	24418474	Two decades of molecular studies have identified important genetic events such as dysregulation of growth factor signaling via amplification or mutation of receptor tyrosine kinase genes; activation of PI3K pathway; and inactivation of p53 and Rb tumor suppressor pathways.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('inactivation', 'NegReg', (220, 232))	('dysregulation', 'Var', (82, 95))	('growth', 'MPA', (99, 105))	('tumor', 'Disease', (247, 252))	('p53', 'Gene', (236, 239))	('mutation', 'Var', (144, 152))	('p53', 'Gene', '7157', (236, 239))	('activation', 'PosReg', (188, 198))	('PI3K pathway', 'Pathway', (202, 214))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('amplification', 'Var', (127, 140))
70615	24418474	In malignant gliomas, activity of this signaling network is frequently increased because of receptor tyrosine kinase over-activity, loss of PTEN tumor suppressor, and/or mutated oncogenic PI3K subunits.	('over-activity', 'PosReg', (117, 130))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('malignant gliomas', 'Disease', (3, 20))	('loss', 'NegReg', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('malignant gliomas', 'Disease', 'MESH:D005910', (3, 20))	('mutated', 'Var', (170, 177))	('receptor', 'Protein', (92, 100))	('increased', 'PosReg', (71, 80))	('activity', 'MPA', (22, 30))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))	('PTEN tumor', 'Disease', 'MESH:D006223', (140, 150))	('PTEN tumor', 'Disease', (140, 150))
70616	24418474	We observed a PTEN-mutant gloma cells showed higher radiosensitizing effect of PI103 than that of PTEN-wild type glioma cells.	('PI103', 'Chemical', 'MESH:C522973', (79, 84))	('PTEN', 'Gene', (14, 18))	('PI103', 'Var', (79, 84))	('PTEN', 'Gene', '5728', (14, 18))	('radiosensitizing effect', 'CPA', (52, 75))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('PTEN', 'Gene', '5728', (98, 102))	('type glioma', 'Disease', (108, 119))	('type glioma', 'Disease', 'MESH:D005910', (108, 119))	('PTEN', 'Gene', (98, 102))	('higher', 'PosReg', (45, 51))
70618	24418474	Attempts to inhibit the PI3K pathway with pan-PI3K inhibitors such as LY294002 have not progressed to clinical use due to concerns over organ toxicity and a lack of selectivity.	('PI3K pathway', 'Pathway', (24, 36))	('LY294002', 'Var', (70, 78))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('toxicity', 'Disease', (142, 150))	('LY294002', 'Chemical', 'MESH:C085911', (70, 78))
70624	24418474	In contrast, PI103 which is a dual inhibitor of class I PI3K and m-TOR prolonged gammH2AX foci formation with downregulation of p-DNA-PK, increased autophagy and increased cytotoxicity of radiation and temozolomide.	('PI103', 'Chemical', 'MESH:C522973', (13, 18))	('increased', 'PosReg', (138, 147))	('cytotoxicity', 'Disease', 'MESH:D064420', (172, 184))	('autophagy', 'CPA', (148, 157))	('increased', 'PosReg', (162, 171))	('temozolomide', 'Chemical', 'MESH:D000077204', (202, 214))	('TOR', 'Gene', (67, 70))	('TOR', 'Gene', '6097', (67, 70))	('PI103 which', 'Var', (13, 24))	('p-DNA-PK', 'Protein', (128, 136))	('cytotoxicity', 'Disease', (172, 184))	('downregulation', 'NegReg', (110, 124))
70625	24418474	Based on our results, we propose dual targeting PI3K/m-TOR with PI103 as a viable therapeutic strategy which should be explored to bypass the therapeutic resistance of GBM.	('PI103', 'Var', (64, 69))	('TOR', 'Gene', '6097', (55, 58))	('TOR', 'Gene', (55, 58))	('PI103', 'Chemical', 'MESH:C522973', (64, 69))
70627	24418474	HSP90, a molecular chaperon, is essential for the stability and function of many oncogenic client proteins that are frequently dysregulated in GBM, such as mutant EGFR, Akt, and p53.	('p53', 'Gene', '7157', (178, 181))	('Akt', 'Gene', (169, 172))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'Gene', (163, 167))	('mutant', 'Var', (156, 162))	('p53', 'Gene', (178, 181))	('Akt', 'Gene', '207', (169, 172))
70629	24418474	Both preclinical and clinical observations, however, have shown that HSP90 inhibitors can be given in vivo at doses and schedules that exert antitumor activity without causing host toxicity.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('inhibitors', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('HSP90', 'Gene', (69, 74))	('HSP90', 'Gene', '3320', (69, 74))	('host toxicity', 'Disease', (176, 189))	('host toxicity', 'Disease', 'MESH:D006086', (176, 189))
70630	24418474	In addition to counteracting pro-survival signaling, HSP90 inhibitors block cell motility and invasion by suppressing multiple pro-invasive and pro-angiogenic cellular processes, such as MMP-2, VEGF and EphA2 activity.	('invasion', 'CPA', (94, 102))	('HSP90', 'Gene', '3320', (53, 58))	('EphA2', 'Gene', '1969', (203, 208))	('block', 'NegReg', (70, 75))	('pro-invasive', 'CPA', (127, 139))	('suppressing', 'NegReg', (106, 117))	('MMP-2', 'Gene', '4313', (187, 192))	('VEGF', 'Gene', (194, 198))	('cell motility', 'CPA', (76, 89))	('inhibitors', 'Var', (59, 69))	('MMP-2', 'Gene', (187, 192))	('HSP90', 'Gene', (53, 58))	('VEGF', 'Gene', '7422', (194, 198))	('EphA2', 'Gene', (203, 208))
70632	24418474	Inhibition of multiple signaling circuitries through the abrogation of HSP90 may be an effective treatment strategy for highly recalcitrant tumors such as GBM.	('HSP90', 'Gene', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('GBM', 'Disease', (155, 158))	('tumors', 'Disease', (140, 146))	('HSP90', 'Gene', '3320', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('abrogation', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
70633	24418474	HDAC inhibitors (HDIs) target epigenetic modifications that interfere with transcriptional regulation and can induce growth arrest and cell death.	('HDAC', 'Gene', (0, 4))	('epigenetic modifications', 'Var', (30, 54))	('HDAC', 'Gene', '9734', (0, 4))	('growth arrest', 'Phenotype', 'HP:0001510', (117, 130))	('transcriptional regulation', 'MPA', (75, 101))	('interfere', 'NegReg', (60, 69))	('induce', 'Reg', (110, 116))	('cell death', 'CPA', (135, 145))	('growth arrest', 'Disease', 'MESH:D006323', (117, 130))	('growth arrest', 'Disease', (117, 130))
70634	24418474	We previously reported that HDIs potentiate radiation-induced cell killing in a panel of human cancer cells through diverse mechanism: LBH589 preferentially radiosensitized human glioma cells that exhibited activated EGFR signaling due to the EGFRVIII mutation.	('human', 'Species', '9606', (89, 94))	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (217, 221))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('mutation', 'Var', (252, 260))	('activated', 'PosReg', (207, 216))	('cancer', 'Disease', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('LBH589', 'Chemical', 'MESH:D000077767', (135, 141))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('human', 'Species', '9606', (173, 178))	('EGFR', 'Gene', '1956', (243, 247))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('EGFR', 'Gene', (243, 247))	('LBH589', 'Gene', (135, 141))	('glioma', 'Disease', (179, 185))
70635	24418474	Treatment with LBH589 led to acetylation of HSP90, which induced down-regulation of the client oncoproteins EGFR and decreased levels of p-Akt.	('LBH589', 'Var', (15, 21))	('acetylation', 'MPA', (29, 40))	('Akt', 'Gene', '207', (139, 142))	('HSP90', 'Gene', (44, 49))	('HSP90', 'Gene', '3320', (44, 49))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('decreased', 'NegReg', (117, 126))	('Akt', 'Gene', (139, 142))	('LBH589', 'Chemical', 'MESH:D000077767', (15, 21))	('down-regulation', 'NegReg', (65, 80))
70637	24418474	reported that MS-275 inhibited tumor cell proliferation, angiogenesis, metastasis and reversing EMT in vivo breast cancer xenograft model by causing "cadherin switch" and decreased expression of VEGF, HIF-1, MMP-2 and MMP-9.	('VEGF', 'Gene', '7422', (195, 199))	('HIF-1', 'Gene', '3091', (201, 206))	('metastasis', 'CPA', (71, 81))	('cadherin', 'Gene', (150, 158))	('HIF-1', 'Gene', (201, 206))	('inhibited', 'NegReg', (21, 30))	('VEGF', 'Gene', (195, 199))	('cadherin', 'Gene', '999', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('angiogenesis', 'CPA', (57, 69))	('MMP-9', 'Gene', '4318', (218, 223))	('MS-275', 'Chemical', 'MESH:C118739', (14, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('MMP-9', 'Gene', (218, 223))	('expression', 'MPA', (181, 191))	('MMP-2', 'Gene', '4313', (208, 213))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('EMT in vivo', 'CPA', (96, 107))	('breast cancer', 'Disease', (108, 121))	('decreased', 'NegReg', (171, 180))	('tumor', 'Disease', (31, 36))	('MS-275', 'Var', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MMP-2', 'Gene', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
70638	24418474	In our results, LBH589 significantly blocked migration, invasion, and vasculogenic mimicry formation through the down-regulation of VEGF, MMP-2, EphA2 and up-regulation of E-cadherin in U251 glioma cells.	('VEGF', 'Gene', (132, 136))	('U251', 'CellLine', 'CVCL:0021', (186, 190))	('MMP-2', 'Gene', '4313', (138, 143))	('vasculogenic mimicry formation', 'CPA', (70, 100))	('E-cadherin', 'Gene', '999', (172, 182))	('E-cadherin', 'Gene', (172, 182))	('blocked', 'NegReg', (37, 44))	('EphA2', 'Gene', (145, 150))	('migration', 'CPA', (45, 54))	('glioma', 'Disease', (191, 197))	('MMP-2', 'Gene', (138, 143))	('EphA2', 'Gene', '1969', (145, 150))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('LBH589', 'Chemical', 'MESH:D000077767', (16, 22))	('invasion', 'CPA', (56, 64))	('LBH589', 'Var', (16, 22))	('up-regulation', 'PosReg', (155, 168))	('down-regulation', 'NegReg', (113, 128))	('VEGF', 'Gene', '7422', (132, 136))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))
70640	24418474	Taken together, our data suggest that targeting PI3K and mTOR pathway, ligand-independent modulation using an inhibitor of HSP90, or epigenetic modulation through inhibition of HDAC could be potential strategies to improve the therapeutic outcome of GBM.	('HSP90', 'Gene', (123, 128))	('HSP90', 'Gene', '3320', (123, 128))	('HDAC', 'Gene', (177, 181))	('epigenetic modulation', 'Var', (133, 154))	('GBM', 'Disease', (250, 253))	('mTOR', 'Gene', (57, 61))	('HDAC', 'Gene', '9734', (177, 181))	('mTOR', 'Gene', '2475', (57, 61))	('PI3K', 'Pathway', (48, 52))	('improve', 'PosReg', (215, 222))	('inhibition', 'Var', (163, 173))
70653	23146242	The functional export activity of nuclear BCRP was demonstrated by chemical inhibition and siRNA knock down of the nuclear BCRP, which resulted in increased sensitivity to the anti-cancer agent mitoxantrone.	('export', 'MPA', (15, 21))	('increased', 'PosReg', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('BCRP', 'Gene', (123, 127))	('BCRP', 'Gene', '9429', (123, 127))	('knock down', 'Var', (97, 107))	('mitoxantrone', 'Chemical', 'MESH:D008942', (194, 206))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('BCRP', 'Gene', (42, 46))	('BCRP', 'Gene', '9429', (42, 46))	('cancer', 'Disease', (181, 187))
70672	23146242	The NMAC-BCRP column was attached to the chromatographic system Series 1100 Liquid Chromatography/Mass Selective Detector (Agilent Technologies, Palo Alto, CA, USA) equipped with a vacuum de-gasser (G 1322 A), a binary pump (1312 A), an autosampler (G1313 A) with a 20 muL injection loop, a mass selective detector (G1946 B) supplied with atmospheric pressure ionization electrospray and an on-line nitrogen generation system (Whatman, Haverhill, MA, USA).	('nitrogen', 'Chemical', 'MESH:D009584', (399, 407))	('NMAC-BCRP', 'Gene', '9429', (4, 13))	('G 1322 A', 'Var', (199, 207))	('G1946 B', 'Var', (316, 323))	('ionization', 'Disease', (360, 370))	('NMAC-BCRP', 'Gene', (4, 13))	('ionization', 'Disease', 'MESH:D004194', (360, 370))	('G 1322 A', 'Mutation', 'rs1354553769', (199, 207))	('G1313 A', 'Mutation', 'rs758900849', (250, 257))	('1312 A', 'Var', (225, 231))
70674	23146242	Pumps A, C and D were used to apply a series of ligands in the mobile phase: Etoposide (1 muM, 2 muM, 5 muM, 10 muM, 20 muM), FTC (0.125 muM, 0.25 muM, 0.5 muM, 1 muM, 2 muM, 7 muM) and Biochanin A (1 muM, 2 muM, 5 muM, 10 muM, 20 muM).	('muM', 'Gene', '56925', (90, 93))	('muM', 'Gene', (147, 150))	('muM', 'Gene', '56925', (201, 204))	('muM', 'Gene', '56925', (177, 180))	('muM', 'Gene', (90, 93))	('muM', 'Gene', '56925', (170, 173))	('muM', 'Gene', (201, 204))	('muM', 'Gene', (177, 180))	('muM', 'Gene', (170, 173))	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (137, 140))	('muM', 'Gene', '56925', (104, 107))	('muM', 'Gene', '56925', (97, 100))	('muM', 'Gene', '56925', (231, 234))	('muM', 'Gene', (104, 107))	('muM', 'Gene', '56925', (215, 218))	('muM', 'Gene', (97, 100))	('muM', 'Gene', '56925', (208, 211))	('0.125', 'Var', (131, 136))	('muM', 'Gene', (208, 211))	('muM', 'Gene', '56925', (112, 115))	('muM', 'Gene', (231, 234))	('muM', 'Gene', (215, 218))	('muM', 'Gene', '56925', (120, 123))	('muM', 'Gene', (112, 115))	('muM', 'Gene', '56925', (223, 226))	('muM', 'Gene', (120, 123))	('muM', 'Gene', (223, 226))	('Etoposide', 'Chemical', 'MESH:D005047', (77, 86))	('muM', 'Gene', '56925', (163, 166))	('muM', 'Gene', '56925', (156, 159))	('muM', 'Gene', (163, 166))	('muM', 'Gene', (156, 159))	('muM', 'Gene', '56925', (147, 150))
70708	32375839	The results of the automatic segmentation compared to the three different raters were 0.83 (IQR: 0.14), 0.81 (IQR: 0.12), and 0.81 (IQR: 0.13) which was significantly lower compared to the DC among raters (chi-square = 11.63, p = 0.04).	('DC', 'Chemical', '-', (189, 191))	('lower', 'NegReg', (167, 172))	('0.81', 'Var', (104, 108))	('0.81', 'Var', (126, 130))
70734	32375839	Manual contouring was performed slice-wise in Eclipse  version 13.6 (Varian Medical Systems, Inc. Palo Alto, CA, USA) by three independent radiation oncology experts (EH, EE, MB) with with respectively, 9, 3 and 1 years of experience in brain tumor imaging analysis, and familiar with all four MR sequences (T1w, T1w gadolinium, T2w and FLAIR).	('T1w gadolinium', 'Var', (313, 327))	('T2w', 'Var', (329, 332))	('brain tumor', 'Disease', (237, 248))	('brain tumor', 'Disease', 'MESH:D001932', (237, 248))	('T1w', 'Var', (308, 311))	('brain tumor', 'Phenotype', 'HP:0030692', (237, 248))	('gadolinium', 'Chemical', 'MESH:D005682', (317, 327))	('oncology', 'Phenotype', 'HP:0002664', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
70782	32069381	BWA  burrows-wheeler aligner  CNV copy number variation IDH isocitrate dehydrogenase INDELs insertions and deletions SNP single nucleotide polymorphism SP subpopulation SV structure variation TP53 tumor protein p53 WHO World Health Organization Gliomas are the most common central nervous system tumors derived from glial cells.	('Gliomas', 'Phenotype', 'HP:0009733', (245, 252))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('deletions', 'Var', (107, 116))	('IDH', 'Gene', (56, 59))	('Gliomas', 'Disease', (245, 252))	('tumor', 'Disease', (296, 301))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('TP53', 'Gene', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('IDH', 'Gene', '3417', (56, 59))	('p53', 'Gene', '7157', (211, 214))	('nervous system tumors', 'Phenotype', 'HP:0004375', (281, 302))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (273, 302))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('Gliomas', 'Disease', 'MESH:D005910', (245, 252))	('p53', 'Gene', (211, 214))	('tumors', 'Disease', (296, 302))	('TP53', 'Gene', '7157', (192, 196))	('tumor', 'Disease', (197, 202))	('insertions', 'Var', (92, 102))
70784	32069381	Like most cancers, gliomas develop because of genetic aberrations that accumulate with tumor progression [2, 3, 4].	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('genetic aberrations', 'Var', (46, 65))	('tumor', 'Disease', (87, 92))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
70794	32069381	Studies have shown that low-grade astrocytomas usually carry mutations of isocitrate dehydrogenase 1/2 (IDH1/2) and tumor protein p53 (TP53) gene [18, 19, 20].	('astrocytoma', 'Phenotype', 'HP:0009592', (34, 45))	('astrocytomas', 'Disease', 'MESH:D001254', (34, 46))	('TP53', 'Gene', '7157', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutations', 'Var', (61, 70))	('IDH1/2', 'Gene', '3417;3418', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('astrocytomas', 'Disease', (34, 46))	('TP53', 'Gene', (135, 139))	('p53', 'Gene', (130, 133))	('tumor', 'Disease', (116, 121))	('IDH1/2', 'Gene', (104, 110))	('p53', 'Gene', '7157', (130, 133))
70809	32069381	Based on the somatic SNPs and CNVs of the tumor, expands predicts the number of subpopulations (SPs) that coexist in a tumor, the size of the SPs in the tumor bulk and the mutations that mark each SP.	('mutations', 'Var', (172, 181))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
70811	32069381	Compared with the primary tumor, more genetic variants (including the SNPs, INDELs, CNVs and chromosome translocations) were detected in the relapse tumor (Fig.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('INDELs', 'Var', (76, 82))	('detected', 'Reg', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CNVs', 'Var', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('chromosome translocations', 'Var', (93, 118))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
70824	32069381	In this study, the "baseline" background of the patient was a heterozygous NOTCH-1 (NC_000009.11:g.139408966T>C) missense mutation (Table 1).	('NC_000009.11:g.139408966T>C', 'Mutation', 'g.139408966T>C', (84, 111))	('g.139408966T>C', 'Var', (97, 111))	('patient', 'Species', '9606', (48, 55))	('NOTCH-1', 'Gene', '4851', (75, 82))	('NOTCH-1', 'Gene', (75, 82))
70826	32069381	It is difficult to determine whether the astrocytoma cells originated from the Notch-1 mutation, although Notch-1 mutations are among driver mutations in all astrocytomas and glioblastomas, as well as normal tissues.	('astrocytomas', 'Disease', 'MESH:D001254', (158, 170))	('glioblastomas', 'Phenotype', 'HP:0012174', (175, 188))	('Notch-1', 'Gene', (106, 113))	('astrocytoma', 'Disease', (41, 52))	('Notch-1', 'Gene', '4851', (106, 113))	('astrocytoma', 'Disease', 'MESH:D001254', (158, 169))	('astrocytoma', 'Phenotype', 'HP:0009592', (41, 52))	('glioblastomas', 'Disease', 'MESH:D005909', (175, 188))	('astrocytomas', 'Disease', (158, 170))	('Notch-1', 'Gene', '4851', (79, 86))	('glioblastomas', 'Disease', (175, 188))	('Notch-1', 'Gene', (79, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('originated from', 'Reg', (59, 74))	('mutation', 'Var', (87, 95))	('astrocytoma', 'Disease', (158, 169))	('astrocytoma', 'Disease', 'MESH:D001254', (41, 52))	('astrocytoma', 'Phenotype', 'HP:0009592', (158, 169))
70827	32069381	IDH1 and IDH2 genes mutations were hallmarks of gliomas [41].	('IDH2', 'Gene', (9, 13))	('gliomas', 'Disease', (48, 55))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('IDH2', 'Gene', '3418', (9, 13))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (20, 29))	('IDH1', 'Gene', '3417', (0, 4))
70828	32069381	IDH1 gene mutation could be identified in most of the patients with low-grade (grade II-III) astrocytomas and glioblastomas, whereas the gene mutation was rarely detected in patients with primary glioblastomas [18, 19, 42].	('IDH1', 'Gene', '3417', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('glioblastomas', 'Disease', (110, 123))	('astrocytoma', 'Phenotype', 'HP:0009592', (93, 104))	('patients', 'Species', '9606', (54, 62))	('glioblastomas', 'Phenotype', 'HP:0012174', (196, 209))	('mutation', 'Var', (10, 18))	('astrocytomas', 'Disease', 'MESH:D001254', (93, 105))	('patients', 'Species', '9606', (174, 182))	('glioblastomas', 'Disease', 'MESH:D005909', (196, 209))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('glioblastomas', 'Phenotype', 'HP:0012174', (110, 123))	('IDH1', 'Gene', (0, 4))	('glioblastomas', 'Disease', (196, 209))	('astrocytomas', 'Disease', (93, 105))	('glioblastomas', 'Disease', 'MESH:D005909', (110, 123))
70829	32069381	Although the IDH1 mutation has been considered a hallmark of astrocytoma and a good prognosis, an IDH1 mutation was not identified until the late stage (relapse tumor, WHO IV).	('astrocytoma', 'Phenotype', 'HP:0009592', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('IDH1', 'Gene', (13, 17))	('astrocytoma', 'Disease', 'MESH:D001254', (61, 72))	('IDH1', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutation', 'Var', (18, 26))	('IDH1', 'Gene', '3417', (13, 17))	('astrocytoma', 'Disease', (61, 72))	('IDH1', 'Gene', '3417', (98, 102))	('tumor', 'Disease', (161, 166))
70830	32069381	In this case, the IDH1 mutation is likely a secondary change after the accelerated growth of tumor cells and hypoxia.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutation', 'Var', (23, 31))	('hypoxia', 'Disease', (109, 116))	('IDH1', 'Gene', '3417', (18, 22))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('tumor', 'Disease', (93, 98))	('IDH1', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
70831	32069381	TP53 mutations were found in most of the patients with astrocytomas with IDH1 mutations [43].	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (73, 77))	('astrocytomas', 'Disease', 'MESH:D001254', (55, 67))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (78, 87))	('patients', 'Species', '9606', (41, 49))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('found', 'Reg', (20, 25))	('astrocytomas', 'Disease', (55, 67))	('IDH1', 'Gene', (73, 77))
70832	32069381	TP53 mutations could be found in most of the low-grade astrocytomas and secondary glioblastomas, in which the mutation rate in primary glioblastomas was relatively low [16, 20].	('TP53', 'Gene', '7157', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('TP53', 'Gene', (0, 4))	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('glioblastomas', 'Disease', (135, 148))	('glioblastomas', 'Disease', 'MESH:D005909', (82, 95))	('astrocytomas', 'Disease', 'MESH:D001254', (55, 67))	('mutations', 'Var', (5, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('glioblastomas', 'Disease', (82, 95))	('glioblastomas', 'Phenotype', 'HP:0012174', (135, 148))	('astrocytomas', 'Disease', (55, 67))	('found', 'Reg', (24, 29))	('glioblastomas', 'Disease', 'MESH:D005909', (135, 148))
70833	32069381	In our study, a heterozygous nonsense mutation of TP53 (NC_000017.10:g.7578492C>T) was found in the astrocytoma (WHO II, TY-1) sample.	('astrocytoma', 'Disease', 'MESH:D001254', (100, 111))	('astrocytoma', 'Disease', (100, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('TP53', 'Gene', '7157', (50, 54))	('g.7578492C>T', 'Var', (69, 81))	('TP53', 'Gene', (50, 54))	('NC_000017.10:g.7578492C>T', 'Mutation', 'rs1131691026', (56, 81))	('found', 'Reg', (87, 92))
70834	32069381	One of the key mutations found in the WHO stage IV glioblastoma is the homozygous TP53 nonsense mutation.	('TP53', 'Gene', (82, 86))	('glioblastoma', 'Disease', (51, 63))	('glioblastoma', 'Disease', 'MESH:D005909', (51, 63))	('nonsense mutation', 'Var', (87, 104))	('TP53', 'Gene', '7157', (82, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))
70835	32069381	TP53 is a gatekeeper of cell survival after DNA damage; astrocytoma cells with the TP53 mutation have an advantage under selection from radiation and chemotherapy.	('TP53', 'Gene', '7157', (83, 87))	('gatekeeper', 'Species', '111938', (10, 20))	('mutation', 'Var', (88, 96))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('advantage', 'PosReg', (105, 114))	('TP53', 'Gene', (83, 87))	('astrocytoma', 'Disease', 'MESH:D001254', (56, 67))	('astrocytoma', 'Disease', (56, 67))	('astrocytoma', 'Phenotype', 'HP:0009592', (56, 67))
70839	32069381	However, very aggressive radiation (60 Gy) provides selection pressure for TP53 mutation-free cells: cells with TP53 mutations and impaired TP53 function are more likely to survive after radiation therapy.	('very aggressive radiation', 'Disease', 'MESH:D011832', (9, 34))	('mutations', 'Var', (117, 126))	('TP53', 'Gene', '7157', (75, 79))	('survive', 'CPA', (173, 180))	('TP53', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (140, 144))	('TP53', 'Gene', '7157', (112, 116))	('function', 'MPA', (145, 153))	('very aggressive radiation', 'Disease', (9, 34))	('TP53', 'Gene', (75, 79))	('TP53', 'Gene', (112, 116))
70840	32069381	Indeed, the number of mutations and structure variants increased significantly in the relapse tumor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('relapse', 'Disease', (86, 93))	('increased', 'PosReg', (55, 64))	('tumor', 'Disease', (94, 99))	('mutations', 'Var', (22, 31))
70993	32190011	Only few prominent bands migrating at ~ 25-30 kDa were present in these proteomes and TAMRA-FP labeling of these bands was inhibited by PMSF, desthiobiotin-FP and AEBSF, but was largely resistant to MAFP and IDFP, consistent with the pharmacology of the ~ 25 kDa glioma band.	('glioma', 'Disease', 'MESH:D005910', (263, 269))	('glioma', 'Disease', (263, 269))	('AEBSF', 'Chemical', '-', (163, 168))	('TAMRA-FP', 'Chemical', '-', (86, 94))	('desthiobiotin-FP', 'Var', (142, 158))	('inhibited', 'NegReg', (123, 132))	('glioma', 'Phenotype', 'HP:0009733', (263, 269))	('desthiobiotin-FP', 'Chemical', '-', (142, 158))	('PMSF', 'Chemical', 'MESH:D010664', (136, 140))	('rat', 'Species', '10116', (28, 31))
71047	32190011	the principal endocannabinoid hydrolase MAGL using brain sections of wild-type and MAGL-deficient mice, as MAGL knockout does not lead to compensatory changes in the activity of other SHs, as evidenced by gel-based ABPP.	('SH', 'Gene', '17701', (184, 186))	('knockout', 'Var', (112, 120))	('MAGL', 'Gene', (107, 111))	('mice', 'Species', '10090', (98, 102))
71131	32190011	Methionine oxidation (+ 15,995 Da (M)) and TAMRA-FP (+ 659,312 Da (S, Y)) were set as dynamic modifications.	('+ 15,995', 'Var', (22, 30))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('+ 659,312', 'Var', (53, 62))	('TAMRA-FP', 'Chemical', '-', (43, 51))
71144	31483918	Analysis of The Cancer Genome Atlas showed that EPHA6 expression was lower in patients with GBM than in the normal brain, and that high EPHA6 expression was correlated with better prognosis.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('patients', 'Species', '9606', (78, 86))	('lower', 'NegReg', (69, 74))	('EPHA6', 'Protein', (48, 53))	('GBM', 'Disease', (92, 95))	('high', 'Var', (131, 135))	('GBM', 'Disease', 'MESH:D005909', (92, 95))
71148	31483918	In summary, EPHA6 together with BMP-2 signaling led to apoptotic cell death in GIC, and thus is a putative tumor suppressor in GBM.	('GBM', 'Disease', 'MESH:D005909', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('apoptotic cell death', 'CPA', (55, 75))	('EPHA6', 'Var', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('GBM', 'Disease', (127, 130))
71153	31483918	In GBM, EPHA2 and EPHA3 were reported to ligand-independently increase stemness, proliferation, and radiation resistance.14, 15 In a ligand-dependent method, EPHA2 receptor is downregulated and dephosphorylated at Ser897 by ephrin-A1-Fc, thus forming a less invasive GBM tumor with growth inhibition.14, 16 Targeting antibodies against EPHA2 and EPHA3 also blocked oncogenic effects of EPHA2 and EPHA3, and suppressed tumorigenesis.17, 18 Additional studies implicate EPHA4,19 EPHA5,20 and EPHA721 as glioma promoters.	('GBM', 'Disease', (3, 6))	('tumor', 'Disease', (418, 423))	('EPHA2', 'Gene', '1969', (336, 341))	('GBM', 'Disease', 'MESH:D005909', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('EPHA2', 'Gene', (158, 163))	('EPHA3', 'Gene', '2042', (396, 401))	('EPHA721', 'Var', (490, 497))	('tumor', 'Disease', 'MESH:D009369', (418, 423))	('EPHA3', 'Gene', (346, 351))	('EPHA5', 'Gene', (477, 482))	('EPHA2', 'Gene', '1969', (8, 13))	('increase stemness', 'Disease', (62, 79))	('EPHA3', 'Gene', '2042', (346, 351))	('glioma', 'Disease', (501, 507))	('EPHA4', 'Gene', (468, 473))	('EPHA2', 'Gene', '1969', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (418, 423))	('Ser', 'Chemical', 'MESH:C530429', (214, 217))	('EPHA2', 'Gene', (386, 391))	('EPHA2', 'Gene', (336, 341))	('glioma', 'Disease', 'MESH:D005910', (501, 507))	('tumor', 'Disease', (271, 276))	('EPHA3', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('EPHA3', 'Gene', '2042', (18, 23))	('EPHA4', 'Gene', '2043', (468, 473))	('glioma', 'Phenotype', 'HP:0009733', (501, 507))	('EPHA5', 'Gene', '2044', (477, 482))	('EPHA721', 'Chemical', 'MESH:C082152', (490, 497))	('EPHA3', 'Gene', (396, 401))	('EPHA2', 'Gene', '1969', (386, 391))	('GBM', 'Disease', (267, 270))	('EPHA2', 'Gene', (8, 13))	('GBM', 'Disease', 'MESH:D005909', (267, 270))	('increase stemness', 'Disease', 'MESH:D020295', (62, 79))
71166	31483918	The mutation site was based on the corresponding kinase-dead mutant of EPHA8 K666M25 and EPHA3 K653R.26 All sequences were confirmed by Sanger sequencing analysis.	('EPHA8 K666M25', 'Var', (71, 84))	('EPHA3', 'Gene', (89, 94))	('K653R', 'Mutation', 'p.K653R', (95, 100))	('EPHA3', 'Gene', '2042', (89, 94))
71168	31483918	Ad-EPHA6-WT and ad-EPHA6-KD were infected at MOI 120 in TGS-03 and TGS-04 cells, and at MOI 60 in TGS-01 cells.	('MOI', 'Disease', 'MESH:D007239', (88, 91))	('ad-EPHA6-KD', 'Var', (16, 27))	('MOI', 'Disease', (45, 48))	('TGS-01', 'CellLine', 'CVCL:4982', (98, 104))	('MOI', 'Disease', 'MESH:D007239', (45, 48))	('MOI', 'Disease', (88, 91))
71171	31483918	For coimmunoprecipitation, 0.5 mL cell lysate was incubated with 25 or 30 muL precoated Dynabeads protein A or M280 sheep antimouse IgG (both from Invitrogen, Thermo Fisher Scientific), respectively, overnight or for 6 hours at 4 C with gentle rotation.	('mouse', 'Species', '10090', (126, 131))	('gentle rotation', 'Disease', 'MESH:D009069', (237, 252))	('M280', 'Var', (111, 115))	('sheep', 'Species', '9940', (116, 121))	('gentle rotation', 'Disease', (237, 252))
71174	31483918	TGS-01 cells expressing luciferase were transduced with adenovirus to express LacZ (ad-LacZ), EPHA6 WT (ad-EPHA6-WT), or EPHA6 kinase-dead mutant (ad-EPHA6-KD) (MOI 60) together with pretreatment with 200 ng/mL BMP-2 for 2 days prior to intracranial injection in 6-week-old female BALB/c nude mice (Sankyo Labo Service).	('LacZ', 'Gene', (78, 82))	('MOI', 'Disease', 'MESH:D007239', (161, 164))	('EPHA6', 'Var', (121, 126))	('nude mice', 'Species', '10090', (288, 297))	('EPHA6', 'Var', (94, 99))	('TGS-01', 'CellLine', 'CVCL:4982', (0, 6))	('Ser', 'Chemical', 'MESH:C530429', (311, 314))	('MOI', 'Disease', (161, 164))
71189	31483918	Moreover, high EPHA6 expression was significantly correlated with longer disease-free survival of patients with GBM (Figure 1C).	('EPHA6', 'Protein', (15, 20))	('GBM', 'Disease', 'MESH:D005909', (112, 115))	('expression', 'MPA', (21, 31))	('patients', 'Species', '9606', (98, 106))	('disease-free survival', 'CPA', (73, 94))	('high', 'Var', (10, 14))	('longer', 'PosReg', (66, 72))	('GBM', 'Disease', (112, 115))
71199	31483918	The c-Met inhibitor foretinib (also known as EXEL-2880/GSK-1363089) was reported to inhibit EPHA6 with a dissociation constant (K d) of 1.1 nmol/L, whereas dasatinib (Src and EPHA2/3 inhibitor) does not (K d = 2100 nmol/L).35 Consistently, foretinib diminished EPHA6 phosphorylation in TGS-03 and TGS-01 cells overexpressing EPHA6, whereas dasatinib did not (Figures 2D and S1G).	('EPHA6', 'Var', (325, 330))	('dasatinib', 'Chemical', 'MESH:C488369', (340, 349))	('overexpressing EPHA6', 'Var', (310, 330))	('Src', 'Gene', (167, 170))	('diminished', 'NegReg', (250, 260))	('Src', 'Gene', '6714', (167, 170))	('EPHA6 phosphorylation', 'MPA', (261, 282))	('EPHA2', 'Gene', (175, 180))	('foretinib', 'Chemical', 'MESH:C544831', (20, 29))	('dasatinib', 'Chemical', 'MESH:C488369', (156, 165))	('EXEL-2880', 'Chemical', 'MESH:C544831', (45, 54))	('GSK-1363089', 'Chemical', 'MESH:C544831', (55, 66))	('c-Met', 'Gene', (4, 9))	('foretinib', 'Chemical', 'MESH:C544831', (240, 249))	('c-Met', 'Gene', '4233', (4, 9))	('EPHA2', 'Gene', '1969', (175, 180))	('TGS-01', 'CellLine', 'CVCL:4982', (297, 303))
71202	31483918	To assess the role of EPHA6 kinase activity in GIC apoptosis, we introduced a kinase dead (KD) mutant of EPHA6 (K757R).	('EPHA6', 'Gene', (105, 110))	('K757R', 'Mutation', 'p.K757R', (112, 117))	('K757R', 'Var', (112, 117))
71204	31483918	Consistent with previous results, inhibition of BMP type I receptor kinase by LDN193189 blocked apoptosis induced by the cooperation of EPHA6 overexpression and exogenous BMP-2 (Figure 3D,E), showing the importance of BMP type I receptor kinase activity in apoptosis induction.	('EPHA6', 'Gene', (136, 141))	('LDN193189', 'Chemical', 'MESH:C554430', (78, 87))	('LDN193189', 'Var', (78, 87))	('BMP', 'Gene', (48, 51))	('BMP', 'Gene', '649', (218, 221))	('blocked', 'NegReg', (88, 95))	('inhibition', 'NegReg', (34, 44))	('apoptosis', 'CPA', (96, 105))	('BMP', 'Gene', '649', (171, 174))	('BMP', 'Gene', (218, 221))	('BMP', 'Gene', '649', (48, 51))	('BMP', 'Gene', (171, 174))
71205	31483918	Results of the immunoblots further support that EPHA6 and BMP-2 upregulated apoptosis, as indicated by expression of the apoptosis marker cleaved caspase 3 with a concomitant increase in phosphorylated p38 MAPK (Figure 3E), similar to previous observations of ALK-2-induced apoptosis.9 Both effects were suppressed by LDN193189 (compare lane 4 to lane 8, Figure 3E).	('LDN193189', 'Var', (318, 327))	('LDN193189', 'Chemical', 'MESH:C554430', (318, 327))	('p38', 'Gene', '1432', (202, 205))	('p38', 'Gene', (202, 205))
71206	31483918	Furthermore, binding of EPHA6 to the ALK-2-CA receptor was reduced in the presence of LDN193189 (Figure 4C), implying that ALK-2 kinase activity supports binding to EPHA6 and that this interaction is correlated with their cooperative effects in causing apoptosis.	('binding', 'Interaction', (154, 161))	('binding', 'Interaction', (13, 20))	('reduced', 'NegReg', (59, 66))	('ALK-2', 'Enzyme', (123, 128))	('LDN193189', 'Chemical', 'MESH:C554430', (86, 95))	('LDN193189', 'Var', (86, 95))
71208	31483918	BMP-2 signaling alone induced apoptosis in TGS-01 cells infected with ad-LacZ and this effect was augmented by overexpression of EPHA6-WT or EPHA6-KD (Figure 5A), confirming the results observed in TGS-03 and TGS-04 cells.	('EPHA6-KD', 'Var', (141, 149))	('EPHA6-WT', 'Var', (129, 137))	('apoptosis', 'CPA', (30, 39))	('TGS-01', 'CellLine', 'CVCL:4982', (43, 49))
71209	31483918	Additionally, we carried out RNA-sequencing to compare the transcriptome of TGS-01 cells infected with ad-LacZ control, ad-EPHA6-WT, or ad-EPHA6-KD.	('TGS-01', 'CellLine', 'CVCL:4982', (76, 82))	('ad-EPHA6-KD', 'Var', (136, 147))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('ad-EPHA6-WT', 'Var', (120, 131))
71211	31483918	EPHA6 could bind to all ephrin-A ligands (A1-A5)36 and EPHA6-Fc has been used to block endogenous ephrin-A ligands in the mouse brain.37 In TGS-01 cells, EPHA6-Fc treatment minimally affected BMP-2-induced apoptosis compared to the IgG-Fc control (Figure S2C,D).	('BMP-2-induced', 'Gene', (192, 205))	('TGS-01', 'CellLine', 'CVCL:4982', (140, 146))	('mouse', 'Species', '10090', (122, 127))	('EPHA6-Fc', 'Var', (154, 162))
71212	31483918	Tumorigenic abilities of TGS-01 cells overexpressing LacZ control, EPHA6-WT or EPHA6-KD were examined by orthotopic inoculation into nude mice in the presence or absence of BMP-2 pretreatment (Figure 6).	('EPHA6-KD', 'Var', (79, 87))	('Tumorigenic abilities', 'CPA', (0, 21))	('TGS-01', 'CellLine', 'CVCL:4982', (25, 31))	('nude mice', 'Species', '10090', (133, 142))
71213	31483918	BMP-2 pretreatment alone did not delay tumor progression of GIC expressing LacZ; however, EPHA6-KD mutant expression inhibited tumor growth, resulting in extended survival of mice compared to LacZ control (Figure 6A,B).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mice', 'Species', '10090', (175, 179))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('EPHA6-KD mutant', 'Var', (90, 105))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('extended', 'PosReg', (154, 162))	('tumor', 'Disease', (39, 44))	('inhibited', 'NegReg', (117, 126))	('survival', 'CPA', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
71214	31483918	This tumor-suppressive effect was enhanced by BMP-2 pretreatment as observed in the survival curve (Figure 6A), in agreement with the data obtained in cell culture experiments.	('enhanced', 'PosReg', (34, 42))	('BMP-2', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('pretreatment', 'Var', (52, 64))	('tumor', 'Disease', (5, 10))
71215	31483918	TGS-01 cells overexpressing EPHA6-WT with BMP-2 pretreatment also showed smaller tumors and longer survival of mice than the LacZ control with BMP-2 pretreatment (Figure 6C,D).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('survival', 'CPA', (99, 107))	('mice', 'Species', '10090', (111, 115))	('EPHA6-WT', 'Var', (28, 36))	('smaller', 'NegReg', (73, 80))	('TGS-01', 'CellLine', 'CVCL:4982', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('longer', 'PosReg', (92, 98))	('BMP-2', 'Gene', (42, 47))
71216	31483918	Nevertheless, TGS-01 cells overexpressing EPHA6-KD with BMP-2 pretreatment exerted the strongest tumor-suppressive effect compared to both EPHA6-WT and LacZ control (Figure 6C,D).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('BMP-2', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('EPHA6-KD', 'Var', (42, 50))	('tumor', 'Disease', (97, 102))	('TGS-01', 'CellLine', 'CVCL:4982', (14, 20))
71224	31483918	EPHA6 association with ALK-2 might alter its interaction with type II receptors, thus influencing signaling directions and sensitivity to BMP-induced apoptosis.	('EPHA6', 'Var', (0, 5))	('signaling directions', 'MPA', (98, 118))	('ALK-2', 'Gene', (23, 28))	('interaction', 'Interaction', (45, 56))	('BMP', 'Gene', (138, 141))	('association', 'Interaction', (6, 17))	('influencing', 'Reg', (86, 97))	('type', 'Protein', (62, 66))	('alter', 'Reg', (35, 40))	('BMP', 'Gene', '649', (138, 141))
71234	31483918	For example, EPHA4 induces cell death in the absence of ephrin-B3 ligand in subventricular zone neuroblasts during adult neurogenesis50 and in glioblastoma.51 Furthermore, the intrinsically kinase-inactive EPHB6 promotes breast cancer cell death by anoikis mediated by EPHA2 signaling inhibition52 and apoptosis through mitochondrial fragmentation, rendering cells susceptible to death receptor signaling.53 c-Kit RTK, which binds to BMPRII,54 was similarly reported to induce apoptosis in the absence of its ligand and its apoptotic activity was enhanced by the loss of its kinase function.55  Collectively, our data imply that EPHA6 expression is beneficial for GBM inhibition, particularly in combination with activation of BMP-2 signaling.	('EPHB6', 'Gene', (206, 211))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('EPHA2', 'Gene', (269, 274))	('breast cancer', 'Disease', (221, 234))	('EPHA4', 'Gene', '2043', (13, 18))	('EPHB6', 'Gene', '2051', (206, 211))	('RTK', 'Gene', (414, 417))	('BMPRII', 'Gene', (434, 440))	('RTK', 'Gene', '5979', (414, 417))	('EPHA6', 'Gene', (629, 634))	('EPHA2', 'Gene', '1969', (269, 274))	('expression', 'Var', (635, 645))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ephrin-B3', 'Gene', '1949', (56, 65))	('glioblastoma', 'Disease', (143, 155))	('BMPRII', 'Gene', '659', (434, 440))	('inhibition', 'NegReg', (668, 678))	('GBM', 'Disease', (664, 667))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('EPHA4', 'Gene', (13, 18))	('GBM', 'Disease', 'MESH:D005909', (664, 667))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('ephrin-B3', 'Gene', (56, 65))
71242	31072237	Although the proneural subtype had the lowest angiogenin expression, high angiogenin expression was associated with significantly worse overall survival.	('worse', 'NegReg', (130, 135))	('expression', 'MPA', (85, 95))	('angiogenin', 'Gene', (46, 56))	('angiogenin', 'Gene', '283', (74, 84))	('angiogenin', 'Gene', (74, 84))	('angiogenin', 'Gene', '283', (46, 56))	('overall survival', 'MPA', (136, 152))	('high', 'Var', (69, 73))	('lowest', 'NegReg', (39, 45))
71243	31072237	By performing univariate and multivariate analysis using Cox regression model, we observed that high angiogenin expression was an independent indicator of shorter overall survival in proneural glioblastoma (hazard ratio: 1.669, 95% confidence interval: 1.033-2.696, P = .036), after adjustment of age, gender, isocitrate dehydrogenase 1 mutation, temozolomide chemotherapy and radiation therapy.	('overall survival', 'MPA', (163, 179))	('isocitrate dehydrogenase 1', 'Gene', (310, 336))	('glioblastoma', 'Disease', 'MESH:D005909', (193, 205))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('angiogenin', 'Gene', (101, 111))	('shorter', 'NegReg', (155, 162))	('temozolomide', 'Chemical', 'MESH:D000077204', (347, 359))	('angiogenin', 'Gene', '283', (101, 111))	('high', 'Var', (96, 100))	('glioblastoma', 'Disease', (193, 205))	('isocitrate dehydrogenase 1', 'Gene', '3417', (310, 336))	('expression', 'MPA', (112, 122))
71247	31072237	Proneural subtype has a higher frequency of PDGFRA or isocitrate dehydrogenase 1 (IDH1) mutations.	('isocitrate dehydrogenase 1', 'Gene', (54, 80))	('isocitrate dehydrogenase 1', 'Gene', '3417', (54, 80))	('Proneural', 'Disease', (0, 9))	('mutations', 'Var', (88, 97))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (82, 86))	('PDGFRA', 'Gene', '5156', (44, 50))	('PDGFRA', 'Gene', (44, 50))
71248	31072237	Classical subtypes show an abnormally high level of EGFR amplification and homozygous deletions of CDKN2A.	('CDKN2A', 'Gene', (99, 105))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('CDKN2A', 'Gene', '1029', (99, 105))	('deletions', 'Var', (86, 95))	('amplification', 'MPA', (57, 70))
71250	31072237	Although several strong prognostic indicators have been identified in GBM, such as isocitrate dehydrogenase (IDH) mutations and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, the use of these markers in clinical practices still has some limitations due to the heterogeneous properties of GBM.	('isocitrate dehydrogenase', 'Gene', '3417', (83, 107))	('GBM', 'Phenotype', 'HP:0012174', (311, 314))	('mutations', 'Var', (114, 123))	('MGMT', 'Gene', '4255', (170, 174))	('MGMT', 'Gene', (170, 174))	('IDH', 'Gene', (109, 112))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))	('isocitrate dehydrogenase', 'Gene', (83, 107))	('IDH', 'Gene', '3417', (109, 112))	('O(6)-methylguanine-DNA methyltransferase', 'Gene', '4255', (128, 168))
71264	31072237	The following variables were extracted from the database for subsequent analysis: age at initial pathologic diagnosis, gender, IDH1 mutation status, gene expression subtypes, karnofsky performance score, overall survival (OS) status and time, temozolomide chemotherapy status, radiation therapy status, ANG expression, and ANG DNA methylation (quantified by Infinium HumanMethylation27 BeadChip, which includes cg22723026 and cg19211827 in ANG DNA).	('ANG', 'Gene', '283', (303, 306))	('cg19211827', 'Var', (426, 436))	('temozolomide', 'Chemical', 'MESH:D000077204', (243, 255))	('ANG', 'Gene', (440, 443))	('ANG', 'Gene', '283', (323, 326))	('Human', 'Species', '9606', (367, 372))	('cg22723026', 'Var', (411, 421))	('ANG', 'Gene', (303, 306))	('ANG', 'Gene', (323, 326))	('IDH1', 'Gene', (127, 131))	('OS', 'Chemical', '-', (222, 224))	('IDH1', 'Gene', '3417', (127, 131))	('ANG', 'Gene', '283', (440, 443))
71265	31072237	O(6)-methylguanine-DNA methyltransferase promoter methylation status was determined by the mean methylation status of the MGMT-STP2 model, which includes 2 CpG sites (cg12434587 and cg12981137).	('cg12981137', 'Var', (182, 192))	('cg12434587', 'Var', (167, 177))	('STP2', 'Gene', (127, 131))	('STP2', 'Gene', '6799', (127, 131))	('O(6)-methylguanine-DNA methyltransferase', 'Gene', '4255', (0, 40))	('MGMT', 'Gene', (122, 126))	('MGMT', 'Gene', '4255', (122, 126))
71275	31072237	The IDH1 mutation does not only serve as a powerful prognostic marker but also influences the expression of a series of genes via indirectly influencing the activity of DNA demethylases.	('mutation', 'Var', (9, 17))	('IDH1', 'Gene', '3417', (4, 8))	('influences', 'Reg', (79, 89))	('DNA demethylases', 'Enzyme', (169, 185))	('influencing', 'Reg', (141, 152))	('IDH1', 'Gene', (4, 8))	('expression', 'MPA', (94, 104))	('activity', 'MPA', (157, 165))
71276	31072237	In this study, we examined the correlation between IDH1 mutation and ANG expression in proneural subtype.	('ANG', 'Gene', '283', (69, 72))	('ANG', 'Gene', (69, 72))	('IDH1', 'Gene', '3417', (51, 55))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))
71277	31072237	Results showed that among the 60 cases with proneural subtype having IDH1 mutation identified, 13 cases had mutations.	('mutation', 'Var', (74, 82))	('IDH1', 'Gene', '3417', (69, 73))	('IDH1', 'Gene', (69, 73))
71281	31072237	Group comparison showed that the methylated group had significantly lower ANG expression compared to the hypomethylation group (Figure 3D).	('ANG', 'Gene', '283', (74, 77))	('methylated', 'Var', (33, 43))	('ANG', 'Gene', (74, 77))	('lower', 'NegReg', (68, 73))
71283	31072237	Results confirmed that the methylated group had significantly longer OS compared to the hypomethylated group (Figure 4).	('methylated', 'Var', (27, 37))	('longer', 'PosReg', (62, 68))	('OS', 'Chemical', '-', (69, 71))
71286	31072237	By performing univariate analysis, we found that older age, male patients, without IDH1 mutation, without temozolomide chemotherapy, without radiotherapy, and high ANG expression were risk factors of unfavorable OS (Table 2).	('mutation', 'Var', (88, 96))	('IDH1', 'Gene', '3417', (83, 87))	('temozolomide', 'Chemical', 'MESH:D000077204', (106, 118))	('OS', 'Chemical', '-', (212, 214))	('ANG', 'Gene', '283', (164, 167))	('patients', 'Species', '9606', (65, 73))	('ANG', 'Gene', (164, 167))	('IDH1', 'Gene', (83, 87))
71287	31072237	Following multivariate analysis confirmed that high ANG expression was an independent indicator of shorter OS in proneural GBM (hazard ratio [HR]: 1.669, 95% confidence interval [CI]: 1.033-2.696, P = .036) after adjustment of other factors (Table 2).	('shorter', 'NegReg', (99, 106))	('ANG', 'Gene', '283', (52, 55))	('proneural GBM', 'Disease', (113, 126))	('ANG', 'Gene', (52, 55))	('OS', 'Chemical', '-', (107, 109))	('high', 'Var', (47, 51))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))
71293	31072237	Since IDH1 mutation and MGMT promoter methylation are 2 well-established prognostic indicators in GBM, we included these 2 factors in the univariate and multivariate analyses to assess the independent prognostic value of ANG expression.	('IDH1', 'Gene', '3417', (6, 10))	('MGMT', 'Gene', '4255', (24, 28))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('ANG', 'Gene', '283', (221, 224))	('ANG', 'Gene', (221, 224))	('mutation', 'Var', (11, 19))	('IDH1', 'Gene', (6, 10))	('GBM', 'Disease', (98, 101))	('MGMT', 'Gene', (24, 28))
71294	31072237	Results showed that high ANG expression was an independent indicator of shorter OS in proneural GBM (HR: 1.669, 95%CI: 1.033-2.696, P = .036), after adjustment of age, gender, isocitrate dehydrogenase 1(IDH1) mutation, temozolomide chemotherapy, and radiation therapy.	('shorter', 'NegReg', (72, 79))	('OS', 'Chemical', '-', (80, 82))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('temozolomide', 'Chemical', 'MESH:D000077204', (219, 231))	('mutation', 'Var', (209, 217))	('high', 'Var', (20, 24))	('proneural GBM', 'Disease', (86, 99))	('IDH1', 'Gene', (203, 207))	('isocitrate dehydrogenase 1', 'Gene', (176, 202))	('isocitrate dehydrogenase 1', 'Gene', '3417', (176, 202))	('ANG', 'Gene', '283', (25, 28))	('ANG', 'Gene', (25, 28))	('IDH1', 'Gene', '3417', (203, 207))
71296	31072237	Although IDH1 mutation has strong predictive value, they are uncommon in primary GBM.	('GBM', 'Phenotype', 'HP:0012174', (81, 84))	('mutation', 'Var', (14, 22))	('IDH1', 'Gene', '3417', (9, 13))	('IDH1', 'Gene', (9, 13))
71297	31072237	Our study found that ANG expression showed independent prognostic value, even after adjustment of IDH1 mutation.	('ANG', 'Gene', '283', (21, 24))	('IDH1', 'Gene', (98, 102))	('mutation', 'Var', (103, 111))	('ANG', 'Gene', (21, 24))	('IDH1', 'Gene', '3417', (98, 102))
71298	31072237	By checking the association between IDH1 mutation and ANG expression, we found that mutation group had significantly decreased ANG expression.	('IDH1', 'Gene', (36, 40))	('ANG', 'Gene', '283', (54, 57))	('decreased', 'NegReg', (117, 126))	('ANG', 'Gene', (54, 57))	('IDH1', 'Gene', '3417', (36, 40))	('ANG', 'Gene', '283', (127, 130))	('ANG', 'Gene', (127, 130))	('mutation', 'Var', (84, 92))
71299	31072237	Mechanistically, the mutations result in the loss of isocitrate dehydrogenase activity and following enhanced production of 2-hydroxyglutarate (2-HG), which inhibit the enzymic activity of DNA demethylases.	('enzymic activity', 'MPA', (169, 185))	('DNA demethylases', 'Enzyme', (189, 205))	('2-HG', 'Chemical', 'MESH:C019417', (144, 148))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (124, 142))	('loss', 'NegReg', (45, 49))	('isocitrate dehydrogenase', 'Gene', (53, 77))	('production of 2-hydroxyglutarate', 'MPA', (110, 142))	('isocitrate dehydrogenase', 'Gene', '3417', (53, 77))	('inhibit', 'NegReg', (157, 164))	('enhanced', 'PosReg', (101, 109))	('activity', 'MPA', (78, 86))	('mutations', 'Var', (21, 30))
71300	31072237	Therefore, IDH1 mutation could indirectly increase DNA methylation status of a series of genes.	('mutation', 'Var', (16, 24))	('IDH1', 'Gene', '3417', (11, 15))	('IDH1', 'Gene', (11, 15))	('DNA methylation status', 'MPA', (51, 73))	('increase', 'PosReg', (42, 50))
71301	31072237	Considering the effect of IDH1 mutation, we examined whether the DNA methylation status of ANG was altered in proneural subtype.	('ANG', 'Gene', '283', (91, 94))	('IDH1', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('ANG', 'Gene', (91, 94))	('IDH1', 'Gene', '3417', (26, 30))
71305	31072237	In future, it is meaningful to demonstrate that the causative effect of IDH1 mutation or ANG methylation on ANG expression.	('ANG', 'Gene', '283', (108, 111))	('IDH1', 'Gene', (72, 76))	('ANG', 'Gene', (108, 111))	('mutation', 'Var', (77, 85))	('IDH1', 'Gene', '3417', (72, 76))	('ANG', 'Gene', '283', (89, 92))	('ANG', 'Gene', (89, 92))
71397	27248469	Loss-of-function mutations in human TRPML-1 gene cause a neurodegenerative disease, Mucolipidosis Type IV, whereas at present no pathology has been associated to human TRPML-2 channels.	('human', 'Species', '9606', (30, 35))	('neurodegenerative disease', 'Disease', (57, 82))	('TRPML-1', 'Gene', '57192', (36, 43))	('Mucolipidosis Type IV', 'Disease', (84, 105))	('Loss', 'Disease', 'MESH:D015431', (0, 4))	('Mucolipidosis Type IV', 'Disease', 'MESH:D009081', (84, 105))	('TRPML-2', 'Gene', '255231', (168, 175))	('human', 'Species', '9606', (162, 167))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (57, 82))	('mutations', 'Var', (17, 26))	('TRPML-1', 'Gene', (36, 43))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (57, 82))	('TRPML-2', 'Gene', (168, 175))	('Loss', 'Disease', (0, 4))
71402	27248469	In fact, knock-down of TRPML-2 inhibited the viability, altered the cell cycle, reduced the proliferation and induced apoptotic cell death in glioma cell lines.	('apoptotic cell death', 'CPA', (118, 138))	('cell cycle', 'CPA', (68, 78))	('glioma', 'Disease', (142, 148))	('inhibited', 'NegReg', (31, 40))	('viability', 'CPA', (45, 54))	('altered', 'Reg', (56, 63))	('reduced', 'NegReg', (80, 87))	('TRPML-2', 'Gene', (23, 30))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('knock-down', 'Var', (9, 19))	('TRPML-2', 'Gene', '255231', (23, 30))	('induced', 'Reg', (110, 117))	('proliferation', 'CPA', (92, 105))
71403	27248469	The DNA damage and apoptosis induced by TRPML-2 loss increased Ser139 H2AX phosphorylation and induced caspase-3 activation; furthermore, knock-down of TRPML-2 in T98 and U251 glioma cell lines completely abrogated Akt and Erk1/2 phosphorylation, as compared to untreated cells.	('H2AX', 'Gene', '3014', (70, 74))	('caspase-3', 'Gene', '836', (103, 112))	('TRPML-2', 'Gene', '255231', (152, 159))	('Erk1/2', 'Gene', (223, 229))	('TRPML-2', 'Gene', '255231', (40, 47))	('increased', 'PosReg', (53, 62))	('caspase-3', 'Gene', (103, 112))	('glioma', 'Disease', (176, 182))	('abrogated', 'NegReg', (205, 214))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('activation', 'PosReg', (113, 123))	('T98', 'CellLine', 'CVCL:B368', (163, 166))	('Erk1/2', 'Gene', '5595;5594', (223, 229))	('TRPML-2', 'Gene', (152, 159))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('TRPML-2', 'Gene', (40, 47))	('knock-down', 'Var', (138, 148))	('Ser139', 'Chemical', '-', (63, 69))	('phosphorylation', 'MPA', (75, 90))	('loss', 'NegReg', (48, 52))	('Ser139', 'Protein', (63, 69))	('H2AX', 'Gene', (70, 74))	('Akt', 'Gene', (215, 218))	('Akt', 'Gene', '207', (215, 218))
71415	27248469	Loss or function mutations in the human TRPML-1 gene cause Mucolipidosis Type IV (ML4), a devastating neurodegenerative disease; gain-of-function mutations of the mouse TRPML-3 gene result in the varitint-waddler (Va) phenotype.	('TRPML-1', 'Gene', '57192', (40, 47))	('human', 'Species', '9606', (34, 39))	('Loss', 'Disease', 'MESH:D015431', (0, 4))	('TRPML-3', 'Gene', (169, 176))	('mutations', 'Var', (17, 26))	('varitint-waddler', 'Gene', '171166', (196, 212))	('Mucolipidosis Type IV', 'Disease', 'MESH:D009081', (59, 80))	('Loss', 'Disease', (0, 4))	('gain-of-function', 'PosReg', (129, 145))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (102, 127))	('mouse', 'Species', '10090', (163, 168))	('varitint-waddler', 'Gene', (196, 212))	('Mucolipidosis Type IV', 'Disease', (59, 80))	('ML4', 'Gene', '57192', (82, 85))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (102, 127))	('neurodegenerative disease', 'Disease', (102, 127))	('mutations', 'Var', (146, 155))	('ML4', 'Gene', (82, 85))	('TRPML-1', 'Gene', (40, 47))
71440	27248469	The effect of TRPML-2 knock-down in glioma cells viability and proliferation was evaluated by MTT and BrdU assay, respectively.	('knock-down', 'Var', (22, 32))	('TRPML-2', 'Gene', (14, 21))	('BrdU', 'Chemical', 'MESH:D001973', (102, 106))	('TRPML-2', 'Gene', '255231', (14, 21))	('glioma', 'Disease', (36, 42))	('MTT', 'Chemical', 'MESH:C070243', (94, 97))	('glioma', 'Disease', 'MESH:D005910', (36, 42))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))
71442	27248469	Moreover, evaluation of DNA synthesis through BrdU/PI assay showed that TRPML-2 silencing significantly reduced DNA synthesis rate of about 25% in both cell lines after 72 h of transfection (Figure 6B).	('TRPML-2', 'Gene', '255231', (72, 79))	('silencing', 'Var', (80, 89))	('reduced', 'NegReg', (104, 111))	('DNA synthesis rate', 'MPA', (112, 130))	('BrdU', 'Chemical', 'MESH:D001973', (46, 50))	('TRPML-2', 'Gene', (72, 79))
71446	27248469	Knock-down of TRPML-2 gene markedly reduced the activation in both cell lines, compared to siGLO cells (Figure 6C).	('TRPML-2', 'Gene', (14, 21))	('TRPML-2', 'Gene', '255231', (14, 21))	('activation', 'MPA', (48, 58))	('Knock-down', 'Var', (0, 10))	('reduced', 'NegReg', (36, 43))
71449	27248469	Thus, the effect of TRPML-2 gene silencing on histone gamma-H2AX (H2AX) phosphorylation and cell cycle arrest was evaluated by western blot analysis and cell cycle assay.	('TRPML-2', 'Gene', (20, 27))	('TRPML-2', 'Gene', '255231', (20, 27))	('H2AX', 'Gene', (66, 70))	('gamma-H2AX', 'Gene', (54, 64))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (92, 109))	('gene silencing', 'Var', (28, 42))	('H2AX', 'Gene', '3014', (60, 64))	('H2AX', 'Gene', (60, 64))	('gamma-H2AX', 'Gene', '3014', (54, 64))	('cell cycle', 'CPA', (92, 102))	('H2AX', 'Gene', '3014', (66, 70))
71451	27248469	Moreover, knock-down of TRPML-2 increased the percentage of cells arrested at subG0 phase, indicating an elevated percentage of hypodiploid cells with fragmented DNA in U251 and T98 siTRPML-2 cell lines, compared with siGLO cells (Figure 7B).	('TRPML-2', 'Gene', '255231', (24, 31))	('elevated', 'PosReg', (105, 113))	('TRPML-2', 'Gene', (184, 191))	('TRPML-2', 'Gene', '255231', (184, 191))	('hypodiploid', 'Disease', 'None', (128, 139))	('T98', 'CellLine', 'CVCL:B368', (178, 181))	('knock-down', 'Var', (10, 20))	('increased', 'PosReg', (32, 41))	('hypodiploid', 'Disease', (128, 139))	('cells arrested at subG0 phase', 'CPA', (60, 89))	('TRPML-2', 'Gene', (24, 31))
71456	27248469	Immunoblots revealed that the transfection condition increased the LC3-I levels in both cell lines; moreover, in siTRPML-2 U251 cells increased levels of LC3-II were detected under basal conditions (Figure 8A).	('transfection', 'Var', (30, 42))	('TRPML-2', 'Gene', (115, 122))	('increased levels of LC3', 'Phenotype', 'HP:0003141', (134, 157))	('LC3', 'Gene', '84557', (67, 70))	('TRPML-2', 'Gene', '255231', (115, 122))	('increased', 'PosReg', (53, 62))	('LC3', 'Gene', (67, 70))	('LC3', 'Gene', '84557', (154, 157))	('LC3', 'Gene', (154, 157))
71461	27248469	To elucidate the molecular mechanism by which the silencing of TRPML-2 induced apoptotic cell death, the mitochondrial transmembrane potential (DeltaPsim) was analyzed in glioma cells.	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('TRPML-2', 'Gene', (63, 70))	('TRPML-2', 'Gene', '255231', (63, 70))	('apoptotic', 'CPA', (79, 88))	('silencing', 'Var', (50, 59))	('glioma', 'Disease', (171, 177))
71462	27248469	Mitochondrial depolarization was evident after 72 h of transfection in siTRPML-2 cells, as respect to siGLO cells (Figure 9B).	('depolarization', 'NegReg', (14, 28))	('TRPML-2', 'Gene', (73, 80))	('TRPML-2', 'Gene', '255231', (73, 80))	('transfection', 'Var', (55, 67))	('Mitochondrial', 'MPA', (0, 13))
71464	27248469	Taken together, loss of TRPML-2 in glioma cell lines induces DNA damage, reduces cell proliferation, and activates caspase-dependent apoptosis.	('cell proliferation', 'CPA', (81, 99))	('glioma', 'Disease', (35, 41))	('TRPML-2', 'Gene', '255231', (24, 31))	('reduces', 'NegReg', (73, 80))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('DNA damage', 'MPA', (61, 71))	('activates', 'PosReg', (105, 114))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('loss', 'Var', (16, 20))	('caspase-dependent apoptosis', 'CPA', (115, 142))	('TRPML-2', 'Gene', (24, 31))	('induces', 'Reg', (53, 60))
71475	27248469	So, we evaluated the role of TRPML-2 in glioma cell survival, proliferation and death, by silencing the TRPML-2 gene in T98 and U251 GBM cell lines.	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('TRPML-2', 'Gene', (104, 111))	('TRPML-2', 'Gene', '255231', (104, 111))	('silencing', 'Var', (90, 99))	('TRPML-2', 'Gene', '255231', (29, 36))	('TRPML-2', 'Gene', (29, 36))	('glioma', 'Disease', (40, 46))	('T98', 'CellLine', 'CVCL:B368', (120, 123))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
71476	27248469	We found that siTRPML-2 U251 and T98 cells show a reduced viability, compared to siGLO cells, correlated with a decreased cell proliferation.	('viability', 'CPA', (58, 67))	('T98', 'CellLine', 'CVCL:B368', (33, 36))	('TRPML-2', 'Gene', (16, 23))	('TRPML-2', 'Gene', '255231', (16, 23))	('reduced', 'NegReg', (50, 57))	('U251', 'Var', (24, 28))	('decreased', 'NegReg', (112, 121))	('cell proliferation', 'CPA', (122, 140))
71477	27248469	Furthermore, silencing of TRPML-2 resulted in a strong reduction in G1 phase cell populations, with a marked increase of subG0 DNA fragmentation, a sign of an enhanced cell death.	('reduction', 'NegReg', (55, 64))	('increase', 'PosReg', (109, 117))	('subG0 DNA fragmentation', 'CPA', (121, 144))	('TRPML-2', 'Gene', (26, 33))	('G1 phase cell populations', 'CPA', (68, 93))	('TRPML-2', 'Gene', '255231', (26, 33))	('silencing', 'Var', (13, 22))
71478	27248469	Thus, an increased percentage of Ann V+ and PI+/Ann V+ apoptotic cells was evidenced in siTRPML-2 U251 and T98MG cells, respect to relative controls.	('Ann V', 'Gene', (48, 53))	('TRPML-2', 'Gene', (90, 97))	('TRPML-2', 'Gene', '255231', (90, 97))	('T98MG', 'Var', (107, 112))	('Ann V', 'Gene', '308', (48, 53))	('U251', 'Var', (98, 102))	('T98MG', 'CellLine', 'CVCL:B368', (107, 112))	('Ann V', 'Gene', (33, 38))	('Ann V', 'Gene', '308', (33, 38))
71480	27248469	In agreement with our results, knock-down of TRPML-2 expression in HEK-293 cells causes severe cell degeneration, characterized by lysosomal inclusions and mitochondrial fragmentation, suggesting that the presence of functional TRPML-2 channel is necessary to ensure cell viability.	('TRPML-2', 'Gene', (45, 52))	('TRPML-2', 'Gene', '255231', (45, 52))	('TRPML-2', 'Gene', (228, 235))	('TRPML-2', 'Gene', '255231', (228, 235))	('cell degeneration', 'Disease', (95, 112))	('knock-down', 'Var', (31, 41))	('HEK-293', 'CellLine', 'CVCL:0045', (67, 74))	('lysosomal inclusions', 'CPA', (131, 151))	('mitochondrial fragmentation', 'CPA', (156, 183))	('cell degeneration', 'Disease', 'MESH:D009410', (95, 112))
71482	27248469	In agree with previous findings obtained in TRPML-2 silenced HEK-293 and Hela cells, the silencing of TRPML-2 gene in glioma cell lines does not affect the autophagic process.	('glioma', 'Disease', (118, 124))	('Hela cells', 'CellLine', 'CVCL:0030', (73, 83))	('HEK-293', 'CellLine', 'CVCL:0045', (61, 68))	('TRPML-2', 'Gene', (44, 51))	('TRPML-2', 'Gene', '255231', (44, 51))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('autophagic process', 'CPA', (156, 174))	('TRPML-2', 'Gene', (102, 109))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('silencing', 'Var', (89, 98))	('TRPML-2', 'Gene', '255231', (102, 109))
71483	27248469	Changes in the activation and/or expression of TRP calcium channels affect calcium-dependent signalling pathways implicated in tumorigenesis and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('calcium-dependent signalling pathways', 'Pathway', (75, 112))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('TRP', 'Gene', (47, 50))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('affect', 'Reg', (68, 74))
71552	26525104	Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('TEP', 'Chemical', '-', (114, 117))	('EGFR', 'Gene', (45, 49))	('PIK3CA', 'Gene', '5290', (54, 60))	('mutant', 'Var', (32, 38))	('HER2', 'Gene', (13, 17))	('KRAS', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('HER2', 'Gene', '2064', (13, 17))	('KRAS', 'Gene', '3845', (39, 43))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('EGFR', 'Gene', '1956', (45, 49))	('PIK3CA', 'Gene', (54, 60))
71555	26525104	show that mRNA sequencing of tumor-educated blood platelets distinguishes cancer patients from healthy individuals with 96% accuracy, differentiates between six primary tumor types of patients with 71% accuracy, and identifies several genetic alterations found in tumors.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('differentiates', 'Reg', (134, 148))	('primary tumor', 'Disease', 'MESH:D009369', (161, 174))	('cancer', 'Disease', (74, 80))	('tumors', 'Disease', (264, 270))	('primary tumor', 'Disease', (161, 174))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('genetic', 'Var', (235, 242))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor type', 'Disease', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (81, 89))	('tumor type', 'Disease', 'MESH:D009369', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))
71600	26525104	Although the platelet mRNA profiles contained undetectable or low levels of these mutant biomarkers, the TEP mRNA profiles did allow to distinguish patients with KRAS mutant tumors from KRAS wild-type tumors in PAAD, CRC, NSCLC, and HBC patients, and EGFR mutant tumors in NSCLC patients, using algorithms specifically trained on biomarker-specific input gene lists (all p < 0.01 versus random classifiers, Figures 3A-3E; Table S4).	('KRAS', 'Gene', '3845', (162, 166))	('KRAS', 'Gene', '3845', (186, 190))	('NSCLC', 'Disease', (222, 227))	('mutant', 'Var', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patients', 'Species', '9606', (237, 245))	('EGFR', 'Gene', '1956', (251, 255))	('patients', 'Species', '9606', (148, 156))	('KRAS', 'Gene', (162, 166))	('tumors', 'Disease', (174, 180))	('KRAS', 'Gene', (186, 190))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('patients', 'Species', '9606', (279, 287))	('NSCLC', 'Disease', (273, 278))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('EGFR', 'Gene', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('TEP', 'Chemical', '-', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', (263, 269))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
71601	26525104	Even though the number of samples analyzed is relatively low and the risk of algorithm overfitting needs to be taken into account, the TEP profiles distinguished patients with HER2-amplified, PIK3CA mutant or triple-negative BrCa, and NSCLC patients with MET overexpression (all p < 0.01 versus random classifiers, Figures 3F-3I).	('patients', 'Species', '9606', (162, 170))	('HER2', 'Gene', (176, 180))	('TEP', 'Chemical', '-', (135, 138))	('PIK3CA', 'Gene', (192, 198))	('HER2', 'Gene', '2064', (176, 180))	('BrCa', 'Gene', (225, 229))	('NSCLC', 'Disease', (235, 240))	('PIK3CA', 'Gene', '5290', (192, 198))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('BrCa', 'Gene', '672', (225, 229))	('patients', 'Species', '9606', (241, 249))	('mutant', 'Var', (199, 205))
71603	26525104	This method did allow for the detection of individual mutant KRAS and EGFR sequences in both plasma DNA and platelet RNA (Table S7), indicating sequestration and potential education capacity of mutant, tumor-derived RNA biomarkers in TEPs.	('KRAS', 'Gene', '3845', (61, 65))	('tumor', 'Disease', (202, 207))	('EGFR', 'Gene', '1956', (70, 74))	('education', 'MPA', (172, 181))	('EGFR', 'Gene', (70, 74))	('KRAS', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('mutant', 'Var', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('TEP', 'Chemical', '-', (234, 237))	('sequestration', 'MPA', (144, 157))
71604	26525104	Mutant KRAS was detected in 62% and 39%, respectively, of plasma DNA (n = 103, kappa statistics = 0.370, p < 0.05) and platelet RNA (n = 144, kappa statistics = 0.213, p < 0.05) of patients with a KRAS mutation in primary tumor tissue.	('KRAS', 'Gene', '3845', (7, 11))	('platelet RNA', 'MPA', (119, 131))	('mutation', 'Var', (202, 210))	('KRAS', 'Gene', (197, 201))	('plasma DNA', 'MPA', (58, 68))	('primary tumor', 'Disease', (214, 227))	('patients', 'Species', '9606', (181, 189))	('KRAS', 'Gene', '3845', (197, 201))	('Mutant', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('primary tumor', 'Disease', 'MESH:D009369', (214, 227))	('KRAS', 'Gene', (7, 11))
71606	26525104	To discriminate KRAS mutant from wild-type tumors in blood, the TEP mRNA profiles provided superior concordance with tissue molecular status (kappa statistics = 0.795-0.895, p < 0.05) compared to KRAS amplicon sequencing analysis of both plasma DNA and platelet RNA (Table S7).	('mutant', 'Var', (21, 27))	('TEP', 'Chemical', '-', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('KRAS', 'Gene', (196, 200))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('KRAS', 'Gene', '3845', (196, 200))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
71798	26217178	Currently MSCs have been defined, according with the International Society for Cellular Therapy (ISCT) criteria, as multipotent cells (with the ability of at least differentiating towards the osteogenic, chondrogenic and adipogenic lineages), capable of self-renewal, able to adhere to tissue culture plastic and to display the presence of surface markers (CD105, CD73, CD90), as well as the lack of hematopoietic cell surface markers (CD45, CD34, CD14 or CD11b, CD79a or CD19 and Human Leukocyte Antigen DR; Table 1; Dominici et al.,).	('CD90', 'Gene', (370, 374))	('CD14', 'Gene', (448, 452))	('CD73', 'Gene', '4907', (364, 368))	('CD19', 'Gene', (472, 476))	('CD34', 'Gene', (442, 446))	('CD45', 'Gene', '5788', (436, 440))	('CD11b', 'Gene', '3684', (456, 461))	('CD34', 'Gene', '947', (442, 446))	('CD14', 'Gene', '929', (448, 452))	('CD73', 'Gene', (364, 368))	('CD11b', 'Gene', (456, 461))	('CD90', 'Gene', '7070', (370, 374))	('CD19', 'Gene', '930', (472, 476))	('CD79a', 'Gene', (463, 468))	('Human', 'Species', '9606', (481, 486))	('CD79a', 'Gene', '973', (463, 468))	('CD45', 'Gene', (436, 440))	('CD105', 'Var', (357, 362))
71820	26217178	The depletion of SN neurons leads to the loss of DAergic innervations and consequently to striatal DA deficiency, which is responsible for the major sensory-motor symptoms of PD (Dauer and Przedborski,).	('DAergic', 'Protein', (49, 56))	('striatal DA deficiency', 'MPA', (90, 112))	('PD', 'Disease', 'MESH:D010300', (175, 177))	('depletion', 'Var', (4, 13))	('DA', 'Chemical', 'MESH:D004298', (49, 51))	('loss', 'NegReg', (41, 45))	('DA', 'Chemical', 'MESH:D004298', (99, 101))
71833	26217178	Moreover, their presence also revert the loss of nigral DAergic neurons and striatal fibers (Danielyan et al.,).	('DA', 'Chemical', 'MESH:D004298', (56, 58))	('nigral DAergic', 'MPA', (49, 63))	('revert', 'NegReg', (30, 36))	('presence', 'Var', (16, 24))	('loss', 'NegReg', (41, 45))
71846	26217178	suggested that the observed improvements were due to the presence of miRNA-133b in the exosomal fraction of MSCs that were transplanted into a middle cerebral artery occlusion (MCAo) rat model.	('miRNA-133b', 'Var', (69, 79))	('rat', 'Species', '10116', (183, 186))	('middle cerebral artery occlusion', 'Disease', 'MESH:D020244', (143, 175))	('middle cerebral artery occlusion', 'Disease', (143, 175))	('miRNA-133b', 'Chemical', '-', (69, 79))	('artery occlusion', 'Phenotype', 'HP:0025324', (159, 175))	('presence', 'Reg', (57, 65))	('middle cerebral artery occlusion', 'Phenotype', 'HP:0012493', (143, 175))	('improvements', 'PosReg', (28, 40))
71863	26217178	Combinations of sTRAIL-secreting NSCs with anticancer drugs, including bortezomib (a proteasome inhibitor), PI-103 (a dual PI3K/mTOR inhibitor), and lanatoside C (a cardiac glycoside), resulted in synergistic therapeutic effects, emphasizing the potential clinical value of sensitizing glioma cells to TRAIL-induced NSC-mediated cell death (Hingtgen et al.,; Bagci-Onder et al.,; Balyasnikova et al.,; Teng et al.,).	('glioma', 'Disease', (286, 292))	('NSC-mediated cell death', 'Disease', (316, 339))	('mTOR', 'Gene', (128, 132))	('TRAIL', 'Gene', '8743', (17, 22))	('bortezomib', 'Gene', (71, 81))	('mTOR', 'Gene', '2475', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('NSC-mediated cell death', 'Disease', 'OMIM:617394', (316, 339))	('TRAIL', 'Gene', '8743', (302, 307))	('cancer', 'Disease', (47, 53))	('Combinations', 'Var', (0, 12))	('TRAIL', 'Gene', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (286, 292))	('TRAIL', 'Gene', (302, 307))	('PI-103', 'Var', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
71868	26217178	Similarly, MSCs genetically engineered to express a modified IL-12 also prolonged the survival of glioma mice models when injected intratumorally (Ryu et al.,).	('mice', 'Species', '10090', (105, 109))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IL-12', 'Gene', '64546', (61, 66))	('prolonged', 'PosReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('survival', 'CPA', (86, 94))	('glioma', 'Disease', (98, 104))	('rat', 'Species', '10116', (134, 137))	('IL-12', 'Gene', (61, 66))	('modified', 'Var', (52, 60))	('tumor', 'Disease', (136, 141))
71890	25118638	Locally-Delivered T-Cell-Derived Cellular Vehicles Efficiently Track and Deliver Adenovirus Delta24-RGD to Infiltrating Glioma Oncolytic adenoviral vectors are a promising alternative for the treatment of glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('Glioma', 'Disease', 'MESH:D005910', (120, 126))	('Glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Glioma', 'Disease', (120, 126))	('Delta24-RGD', 'Var', (92, 103))	('Adenovirus', 'Species', '28285', (81, 91))	('glioblastoma', 'Disease', (205, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))
71892	25118638	Here, we studied T-cells, often having a natural capacity to target tumors, for their feasibility as a CV to deliver the oncolytic adenovirus, Delta24-RGD, to glioblastoma.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('glioblastoma', 'Disease', (159, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))	('Delta24-RGD', 'Var', (143, 154))	('adenovirus', 'Species', '28285', (131, 141))
71893	25118638	The Jurkat T-cell line was assessed in co-culture with the glioblastoma stem cell (GSC) line, MGG8, for the optimal transfer conditions of Delta24-RGD in vitro.	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('glioblastoma', 'Disease', (59, 71))	('Delta24-RGD', 'Var', (139, 150))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('Jurkat T-cell', 'CellLine', 'CVCL:0065', (4, 17))
71895	25118638	Jurkat T-cells were demonstrated to facilitate the amplification and transfer of Delta24-RGD onto GSCs.	('Jurkat T-cells', 'CellLine', 'CVCL:0065', (0, 14))	('Delta24-RGD', 'Var', (81, 92))	('amplification', 'MPA', (51, 64))
71896	25118638	Injection of Delta24-RGD-loaded T-cells into the brains of GSC-bearing mice led to migration towards the tumor and dispersion of the virus within the tumor core and infiltrative zones.	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('dispersion', 'CPA', (115, 125))	('Delta24-RGD-loaded', 'Var', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (150, 155))
71898	25118638	We found that T-cell-mediated delivery of Delta24-RGD led to the inhibition of tumor growth compared to non-treated controls, resulting in prolonged survival (p = 0.007).	('inhibition', 'NegReg', (65, 75))	('tumor', 'Disease', (79, 84))	('Delta24-RGD', 'Var', (42, 53))	('prolonged', 'PosReg', (139, 148))	('survival', 'CPA', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
71904	25118638	Delta24-RGD is a conditionally replicating oncolytic adenovirus that has demonstrated therapeutic efficacy in preclinical models of glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('adenovirus', 'Species', '28285', (53, 63))	('glioblastoma', 'Disease', (132, 144))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('Delta24-RGD', 'Var', (0, 11))
71905	25118638	The Delta24 mutation consists of a 24-base pair deletion in the E1A gene of the serotype 5 adenovirus.	('E1A', 'Gene', (64, 67))	('adenovirus', 'Species', '28285', (91, 101))	('Delta24', 'Var', (4, 11))
71906	25118638	This alteration facilitates selective viral replication in cells that harbor altered Rb pathway signaling, which is a common (75%) phenomenon in glioblastoma.	('facilitates', 'Reg', (16, 27))	('Rb pathway signaling', 'Pathway', (85, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('viral', 'CPA', (38, 43))	('glioblastoma', 'Disease', (145, 157))	('altered', 'Var', (77, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
71907	25118638	The addition of the RGD motif enhances the potency of Delta24 by targeting the virus to alpha (V)-beta(3) integrins that are frequently expressed on tumor cells and vasculature.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('Delta24', 'Var', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('potency', 'MPA', (43, 50))	('enhances', 'PosReg', (30, 38))	('tumor', 'Disease', (149, 154))	('alpha (V)-beta(3) integrins', 'Protein', (88, 115))
71915	25118638	We have investigated the feasibility of the Jurkat T-cell line as a model for T-cell-based cellular delivery of Delta24-RGD in a glioblastoma stem cell (GSC)-based preclinical xenograft model.	('glioblastoma', 'Disease', (129, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('Jurkat T-cell', 'CellLine', 'CVCL:0065', (44, 57))	('Delta24-RGD', 'Var', (112, 123))
71926	25118638	After removal of the kanamycin resistance gene (by ClaI digestion and re-ligation), PacI + AatII digestion was used to isolate the fragment containing the DeltaE3-Fib.RGD.ADP-EGFP sequence, which was recombined with SpeI-linearized pAdEasy-1, resulting in pAdEasy-DeltaE3-Fib.RGD.ADP-EGFP.	('DeltaE3', 'DELETION', 'None', (155, 162))	('DeltaE3', 'DELETION', 'None', (264, 271))	('EGF', 'Gene', (284, 287))	('EGF', 'Gene', (175, 178))	('EGF', 'Gene', '1950', (284, 287))	('kanamycin', 'Chemical', 'MESH:D007612', (21, 30))	('DeltaE3', 'Var', (155, 162))	('EGF', 'Gene', '1950', (175, 178))	('DeltaE3', 'Var', (264, 271))
71940	25118638	Treatment consisted of 5 microL PBS, Delta24-RGD 5 x 106 IUs in 5 microL PBS or 5 x 104 Jurkat T-cells infected with MOI 100 Delta24-RGD in 5 microL PBS.	('Jurkat T-cells', 'CellLine', 'CVCL:0065', (88, 102))	('Delta24-RGD', 'Var', (125, 136))	('Delta24-RGD', 'Var', (37, 48))	('PBS', 'Chemical', 'MESH:D007854', (149, 152))	('PBS', 'Chemical', 'MESH:D007854', (73, 76))	('PBS', 'Chemical', 'MESH:D007854', (32, 35))
71941	25118638	Jurkat T-cells were incubated in Delta24-RGD (MOI-100) 2 h prior to intratumoral injections.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Jurkat T-cells', 'CellLine', 'CVCL:0065', (0, 14))	('Delta24-RGD', 'Var', (33, 44))	('tumor', 'Disease', (73, 78))
71951	25118638	MGG8 tumor neurospheres were found to be susceptible to Delta24-RGD-induced oncolysis with an IC50 value of MOI 0.89 at 96 h post-infection (R2 = 0.92-0.99).	('oncolysis', 'CPA', (76, 85))	('Delta24-RGD-induced', 'Var', (56, 75))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
71980	25118638	As expected, hexon staining was demonstrated within the Jurkat T-cell injection site, suggestive of the T-cell-based Delta24-RGD distribution, which left a necrotic cavity (Figure 4E).	('Jurkat T-cell', 'CellLine', 'CVCL:0065', (56, 69))	('hexon', 'Chemical', '-', (13, 18))	('necrotic', 'Disease', (156, 164))	('necrotic', 'Disease', 'MESH:D009336', (156, 164))	('left', 'Reg', (149, 153))	('Delta24-RGD', 'Var', (117, 128))
71983	25118638	Therapeutic effect of Jurkat T-cell-mediated Delta24-RGD delivery was compared to both PBS and Delta24-RGD intratumoral injections.	('Delta24-RGD', 'Var', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Jurkat T-cell', 'CellLine', 'CVCL:0065', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PBS', 'Chemical', 'MESH:D007854', (87, 90))	('tumor', 'Disease', (112, 117))
71984	25118638	Delta24-RGD-loaded T-cells (CV) prolonged the overall survival of mice bearing MGG8 orthotopic xenografts to a similar extent as direct intratumoral injection of Delta24-RGD.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('prolonged', 'PosReg', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Delta24-RGD-loaded', 'Var', (0, 18))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Disease', (141, 146))	('MGG8', 'Gene', (79, 83))
71985	25118638	When compared to PBS-treated controls (mean: 38.6 days), both treatment conditions prolonged survival significantly (CV mean survival: 46.2 days, Log Rank p = 0.007; and Delta24-RGD mean: 49.6 days, Log Rank p < 0.001) (Figure 5A).	('prolonged', 'PosReg', (83, 92))	('survival', 'CPA', (93, 101))	('Delta24-RGD', 'Var', (170, 181))	('PBS', 'Chemical', 'MESH:D007854', (17, 20))
71991	25118638	Analyses of the brains revealed that direct intravenous injection of Delta24-RGD did not lead to infection of MGG8 tumors in any of the analyzed animals, with the exception of a small vascular structure in one animal at 144 h post-injection (Figure 5B, upper left).	('infection of MGG8 tumors', 'Disease', 'MESH:D009369', (97, 121))	('Delta24-RGD', 'Var', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('infection of MGG8 tumors', 'Disease', (97, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
71994	25118638	In the current study we investigated the feasibility of T-cell-mediated delivery of Delta24-RGD to glioblastoma.	('glioblastoma', 'Disease', (99, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('Delta24-RGD', 'Var', (84, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))
71997	25118638	Based on these in vitro findings, we set-up a proof of concept study, which demonstrated that intratumoral CV-based delivery of Delta24-RGD yields comparable results to direct Delta24-RGD injections with regard to therapeutic efficacy.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Delta24-RGD', 'Var', (128, 139))
71998	25118638	Importantly, delivery of Delta24-RGD into peripheral tumor regions was demonstrated after injections of cellular vehicles into the contralateral hemisphere in GSC xenografts.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Delta24-RGD', 'Var', (25, 36))
72000	25118638	Moreover, systemically delivered Delta24-RGD-loaded CVs were detected in small numbers within the orthotopic xenografts within 48-96 h, although efficient virus handover to the tumor was not observed in this setting.	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('Delta24-RGD-loaded', 'Var', (33, 51))
72001	25118638	We conclude that T-cells have the ability to serve as cellular vehicles to deliver Delta24-RGD to glioblastoma at a distance, in particular to infiltrating tumor cells in the brain parenchyma.	('brain parenchyma', 'Disease', (175, 191))	('Delta24-RGD', 'Var', (83, 94))	('glioblastoma', 'Disease', (98, 110))	('brain parenchyma', 'Disease', 'MESH:D010195', (175, 191))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))
72006	25118638	As shown, tail vein injections in orthotopic xenograft-bearing mice did not lead to widespread intratumoral delivery of Delta24-RGD.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (63, 67))	('Delta24-RGD', 'Var', (120, 131))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
72007	25118638	The administration of L1210 leukemic cells in a syngeneic CV model did yield appreciable intracerebral carrier cell infiltration in a VSV delivery model for lung cancer, indicating that the choice of oncolytic virus or tumor type may influence intracranial tropism.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('leukemic', 'Disease', 'MESH:D007938', (28, 36))	('yield', 'Reg', (71, 76))	('tumor', 'Disease', (219, 224))	('lung cancer', 'Disease', (157, 168))	('L1210', 'Var', (22, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('influence', 'Reg', (234, 243))	('intracranial tropism', 'Disease', (244, 264))	('leukemic', 'Disease', (28, 36))	('VSV', 'Species', '11276', (134, 137))	('intracerebral carrier', 'MPA', (89, 110))	('intracranial tropism', 'Disease', 'MESH:D001932', (244, 264))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('L1210', 'CellLine', 'CVCL:0382', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))
72016	23433400	HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines.	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('malignant glioma lines', 'Disease', 'MESH:D005910', (114, 136))	('51Cr', 'Chemical', 'MESH:C000615375', (86, 90))	('U251MG', 'CellLine', 'CVCL:0021', (157, 163))	('EGFR', 'Gene', '1956', (15, 19))	('HER2', 'Gene', '2064', (0, 4))	('AT', 'Disease', 'None', (28, 30))	('U87MG', 'Var', (138, 143))	('glioblastoma lines', 'Disease', (177, 195))	('malignant glioma lines', 'Disease', (114, 136))	('U118MG', 'Var', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('MTT', 'Chemical', 'MESH:C070243', (78, 81))	('U251MG', 'Var', (157, 163))	('EGFR', 'Gene', (15, 19))	('HER2', 'Gene', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (177, 189))	('cytotoxicity', 'Disease', (59, 71))	('glioblastoma lines', 'Disease', 'MESH:D005909', (177, 195))	('U87MG', 'CellLine', 'CVCL:0022', (138, 143))
72030	23433400	Arming ex vivo expanded T cells with BiAbs may not only improve clinical responses but also minimize toxicity by avoiding the cytokine storm that can occur by systemic infusion of BiAb alone.	('clinical responses', 'CPA', (64, 82))	('cytokine storm', 'MPA', (126, 140))	('BiAb', 'Chemical', 'MESH:D018033', (180, 184))	('avoiding', 'NegReg', (113, 121))	('minimize', 'NegReg', (92, 100))	('improve', 'PosReg', (56, 63))	('BiAb', 'Chemical', 'MESH:D018033', (37, 41))	('BiAbs', 'Var', (37, 42))	('toxicity', 'Disease', (101, 109))	('BiAbs', 'Chemical', 'MESH:D018033', (37, 42))	('toxicity', 'Disease', 'MESH:D064420', (101, 109))
72059	23433400	Glioma cell lines U87MG, U118MG, and U251MG were also cultured as adherent monolayers in the DMEM-F12-based medium.	('DMEM', 'Chemical', '-', (93, 97))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('U87MG', 'CellLine', 'CVCL:0022', (18, 23))	('U251MG', 'Var', (37, 43))	('U251MG', 'CellLine', 'CVCL:0021', (37, 43))
72075	23433400	We established in the glioma cell lines U251MG (Figure 1) as well as glioma U118MG (data not shown) and breast cancer line SKBR3 (data not shown), that absorbance (A570-A650) is a linear function (R2 = 0.9930) of the cell number up to 4 x 104 cells similar to counts per minute (CPM) as a linear function (R2 = 1.0) of cytotoxicity (Figure 1, lower panel).	('glioma', 'Disease', (69, 75))	('A570-A650', 'Var', (164, 173))	('U251MG', 'CellLine', 'CVCL:0021', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('glioma', 'Disease', (22, 28))	('cytotoxicity', 'Disease', (319, 331))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('breast cancer', 'Disease', (104, 117))	('SKBR3', 'CellLine', 'CVCL:0033', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('glioma', 'Phenotype', 'HP:0009733', (22, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (319, 331))	('glioma', 'Disease', 'MESH:D005910', (22, 28))
72085	23433400	The data with the three donors in all three cell lines (U87MG, U118MG and U251MG) using unarmed ATC or armed ATC at 50 ng dose are shown in Figure 2B.	('U87MG', 'Var', (56, 61))	('U251MG', 'Var', (74, 80))	('U251MG', 'CellLine', 'CVCL:0021', (74, 80))	('AT', 'Disease', 'None', (109, 111))	('U118MG', 'Var', (63, 69))	('AT', 'Disease', 'None', (96, 98))	('U87MG', 'CellLine', 'CVCL:0022', (56, 61))
72086	23433400	Flow cytometry analysis of U87MG, U118MG, and U251MG confirmed that all 3 lines show high surface expression of EGFR (80-100% cell positivity) while only the latter two expressed low levels of surface HER2/neu (U118MG: 17.6% and U251MG: 32.5% positive cells).	('EGFR', 'Gene', (112, 116))	('U251MG', 'Var', (229, 235))	('U251MG', 'CellLine', 'CVCL:0021', (46, 52))	('U251MG', 'CellLine', 'CVCL:0021', (229, 235))	('HER2/neu', 'Gene', (201, 209))	('EGFR', 'Gene', '1956', (112, 116))	('U87MG', 'CellLine', 'CVCL:0022', (27, 32))	('U118MG', 'Var', (211, 217))	('HER2/neu', 'Gene', '2064', (201, 209))
72092	23433400	U118MG and U251MG viabilities were reduced by HER2Bi-armed ATC (middle and right columns), consistent with the surface expression data, whereas HER2Bi-armed ATC (left column) failed to reduce the viability of U87MG cells below 100%.	('HER2', 'Gene', (46, 50))	('reduced', 'NegReg', (35, 42))	('HER2', 'Gene', '2064', (144, 148))	('HER2', 'Gene', '2064', (46, 50))	('U118MG', 'CPA', (0, 6))	('U251MG', 'CellLine', 'CVCL:0021', (11, 17))	('HER2', 'Gene', (144, 148))	('U251MG', 'Var', (11, 17))	('AT', 'Disease', 'None', (157, 159))	('U87MG', 'CellLine', 'CVCL:0022', (209, 214))	('AT', 'Disease', 'None', (59, 61))
72116	23433400	Our preliminary experiments show that the TMZ-resistant U251MG could be killed by armed ATC in the absence of TMZ (unpublished data) and other studies showing radioresistance of armed ATC effector function, we tested whether irradiation and TMZ would inhibit cytotoxicity mediated by unarmed and both HER2Bi- and EGFRBi-armed ATC.	('EGFR', 'Gene', '1956', (313, 317))	('EGFR', 'Gene', (313, 317))	('TMZ', 'Chemical', 'MESH:D000077204', (110, 113))	('cytotoxicity', 'Disease', 'MESH:D064420', (259, 271))	('TMZ', 'Chemical', 'MESH:D000077204', (42, 45))	('HER2', 'Gene', (301, 305))	('AT', 'Disease', 'None', (88, 90))	('AT', 'Disease', 'None', (326, 328))	('inhibit', 'NegReg', (251, 258))	('HER2', 'Gene', '2064', (301, 305))	('U251MG', 'Var', (56, 62))	('tested', 'Reg', (210, 216))	('U251MG', 'CellLine', 'CVCL:0021', (56, 62))	('TMZ', 'Chemical', 'MESH:D000077204', (241, 244))	('AT', 'Disease', 'None', (184, 186))	('cytotoxicity', 'Disease', (259, 271))
72127	23433400	We then tested unarmed or armed ATC from these co-cultures for their ability to kill U118MG and U251MG target cells.	('U118MG', 'Var', (85, 91))	('AT', 'Disease', 'None', (32, 34))	('U251MG', 'CellLine', 'CVCL:0021', (96, 102))	('U251MG', 'Var', (96, 102))
72128	23433400	Exposure of ATC or armed ATC to conditioned medium from normal astrocytes or gliomas did not inhibit their cytotoxic activity towards U118MG or U251MG target cells compared to the ability of control effectors that were not treated with conditioned medium (data not shown).	('inhibit', 'NegReg', (93, 100))	('AT', 'Disease', 'None', (12, 14))	('gliomas', 'Disease', (77, 84))	('U251MG', 'CellLine', 'CVCL:0021', (144, 150))	('U251MG', 'Var', (144, 150))	('gliomas', 'Disease', 'MESH:D005910', (77, 84))	('gliomas', 'Phenotype', 'HP:0009733', (77, 84))	('AT', 'Disease', 'None', (25, 27))	('cytotoxic activity', 'CPA', (107, 125))	('U118MG', 'Var', (134, 140))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
72131	23433400	After removal of the non-adherent ATC, the viability via MTT was <10% (>90% killing) for HER2Bi on SK-BR-3 and U251MG targets (Culture 1 in Figure 7).	('MTT', 'Chemical', 'MESH:C070243', (57, 60))	('SK-BR-3', 'CellLine', 'CVCL:0033', (99, 106))	('AT', 'Disease', 'None', (34, 36))	('U251MG', 'Var', (111, 117))	('HER2', 'Gene', (89, 93))	('U251MG', 'CellLine', 'CVCL:0021', (111, 117))	('HER2', 'Gene', '2064', (89, 93))
72176	23433400	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/13/83/prepub This work was funded by National Cancer Institute (R01 CA 92344 and R01 CA 140314 to LGL); Leukemia and Lymphoma Society (Grant # 6092-09 and #6066-06 to LGL); Susan G. Komen Foundation Translational Award (BCTR0707125 to LGL); Cancer Center Support Grant (P30 CA022453-25 to LGL); and Wayne State University School of Medicine Startup Funds (to SM); and Karmanos Cancer Institute Strategic Research Initiative Grant (to SM).	('Leukemia', 'Phenotype', 'HP:0001909', (208, 216))	('Cancer', 'Disease', 'MESH:D009369', (150, 156))	('Cancer', 'Disease', (150, 156))	('Lymphoma', 'Phenotype', 'HP:0002665', (221, 229))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Cancer', 'Phenotype', 'HP:0002664', (345, 351))	('P30 CA022453-25', 'Var', (374, 389))	('Cancer', 'Phenotype', 'HP:0002664', (481, 487))	('Cancer', 'Disease', (481, 487))	('Cancer', 'Disease', (345, 351))	('Cancer', 'Disease', 'MESH:D009369', (481, 487))	('Cancer', 'Disease', 'MESH:D009369', (345, 351))	('R01', 'Var', (168, 171))	('Leukemia and Lymphoma Society', 'Disease', 'MESH:D007938', (208, 237))
72194	33275159	The MCF10CA single-cell RNA-Seq dataset is available at the EGA database with sample ID SAMEA4666651 and SAMEA4666652.	('MCF10CA', 'Gene', (4, 11))	('SAMEA4666652', 'Var', (105, 117))	('MCF10', 'CellLine', 'CVCL:5555', (4, 9))	('SAMEA4666651', 'Var', (88, 100))
72214	33275159	Figure 4C visualizes the proportion of stable partitions (1-PAC > 0.9) for a given best number of subgroups for each method, and as expected, methods with ATC or skmeans gave more stable partitions while methods with hclust gave fewer stable partitions.	('PAC', 'Phenotype', 'HP:0006699', (60, 63))	('skmeans', 'Var', (162, 169))	('kmeans', 'Chemical', '-', (163, 169))	('stable partitions', 'MPA', (180, 197))
72268	32024090	Aberrant S1P metabolism, receptor expression, and signaling emerged as relevant contributors to initiation, progression, and malignant properties of different tumors, and, among them, glioblastoma (GBM), one of the most aggressive neoplasms in humans.	('GBM', 'Disease', 'MESH:D005909', (198, 201))	('S1P', 'Gene', '13609', (9, 12))	('aggressive neoplasms', 'Disease', 'MESH:D001523', (220, 240))	('neoplasms', 'Phenotype', 'HP:0002664', (231, 240))	('Aberrant', 'Var', (0, 8))	('S1P', 'Gene', (9, 12))	('GBM', 'Phenotype', 'HP:0012174', (198, 201))	('glioblastoma', 'Phenotype', 'HP:0012174', (184, 196))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('humans', 'Species', '9606', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('neoplasm', 'Phenotype', 'HP:0002664', (231, 239))	('aggressive neoplasms', 'Disease', (220, 240))	('GBM', 'Disease', (198, 201))	('glioblastoma', 'Disease', (184, 196))	('glioblastoma', 'Disease', 'MESH:D005909', (184, 196))
72269	32024090	After introducing the key features of S1P signaling and of GBM, we here review our current understanding of how different tumor and normal cells in cancer niches contribute to alterations of S1P homeostasis and signaling, and impact cancer hallmarks, progression and properties.	('GBM', 'Disease', (59, 62))	('signaling', 'MPA', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('GBM', 'Disease', 'MESH:D005909', (59, 62))	('tumor', 'Disease', (122, 127))	('S1P', 'Gene', '13609', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('impact cancer hallmarks', 'Disease', 'MESH:D004834', (226, 249))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('homeostasis', 'MPA', (195, 206))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('properties', 'CPA', (267, 277))	('rat', 'Species', '10116', (180, 183))	('S1P', 'Gene', (191, 194))	('impact cancer hallmarks', 'Disease', (226, 249))	('alterations', 'Var', (176, 187))	('progression', 'CPA', (251, 262))	('S1P', 'Gene', '13609', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (233, 239))	('S1P', 'Gene', (38, 41))
72314	32024090	High SphK1 expression has been found to be correlated with a significant poor prognosis in patients with GBM by some studies, but such a relation was not detected in more recent reports.	('patients', 'Species', '9606', (91, 99))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('GBM', 'Disease', 'MESH:D005909', (105, 108))	('GBM', 'Disease', (105, 108))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))	('SphK1', 'Gene', '8877', (5, 10))	('SphK1', 'Gene', (5, 10))
72333	32024090	Besides reducing ceramide, the variations (in opposite directions) of ceramide synthase and acid ceramidase (Figure 1) appear to concur in favoring the availability of sphingosine as a substrate for SphKs, and thus the overproduction of S1P in GBM.	('overproduction', 'PosReg', (219, 233))	('GBM', 'Disease', (244, 247))	('sphingosine', 'Chemical', 'MESH:D013110', (168, 179))	('ceramide', 'MPA', (17, 25))	('rat', 'Species', '10116', (190, 193))	('ceramide', 'Chemical', 'MESH:D002518', (70, 78))	('favoring', 'PosReg', (139, 147))	('acid ceramidase', 'Gene', (92, 107))	('variations', 'Var', (31, 41))	('S1P', 'Gene', '13609', (237, 240))	('GBM', 'Disease', 'MESH:D005909', (244, 247))	('acid ceramidase', 'Gene', '427', (92, 107))	('GBM', 'Phenotype', 'HP:0012174', (244, 247))	('S1P', 'Gene', (237, 240))	('SphK', 'Gene', (199, 203))	('SphK', 'Gene', '8877', (199, 203))	('ceramide', 'Chemical', 'MESH:D002518', (17, 25))
72334	32024090	In addition to SphK variations, two enzymes involved in S1P degradation are altered in GBM, further potentiating the metabolic events leading to high levels of S1P in this cancer.	('variations', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('SphK', 'Gene', (15, 19))	('S1P', 'Gene', (56, 59))	('GBM', 'Disease', (87, 90))	('potentiating', 'PosReg', (100, 112))	('S1P', 'Gene', (160, 163))	('SphK', 'Gene', '8877', (15, 19))	('altered', 'Reg', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('cancer', 'Disease', (172, 178))	('metabolic events', 'MPA', (117, 133))	('S1P', 'Gene', '13609', (56, 59))	('S1P', 'Gene', '13609', (160, 163))
72365	32024090	Further studies reported that different human GBM cell lines, including U87MG, CCF-STTG, and T98G, can all constitutively secrete S1P, underlying the relevance of GBM cells in the secretion of S1P in the extracellular TME.	('T98G', 'Var', (93, 97))	('S1P', 'Gene', (193, 196))	('GBM', 'Disease', (163, 166))	('S1P', 'Gene', '13609', (130, 133))	('GBM', 'Disease', (46, 49))	('GBM', 'Disease', 'MESH:D005909', (46, 49))	('S1P', 'Gene', (130, 133))	('GBM', 'Disease', 'MESH:D005909', (163, 166))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('secrete', 'MPA', (122, 129))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('human', 'Species', '9606', (40, 45))	('S1P', 'Gene', '13609', (193, 196))
72422	32024090	It was reported that exogenous S1P elicits glutamate secretion, and potentiated depolarization-evoked secretion from neurons, suggesting that a depolarization/S1P secretion cycle occurs.	('S1P', 'Gene', (31, 34))	('glutamate secretion', 'MPA', (43, 62))	('elicits', 'Reg', (35, 42))	('potentiated', 'PosReg', (68, 79))	('S1P', 'Gene', '13609', (31, 34))	('S1P', 'Gene', '13609', (159, 162))	('exogenous', 'Var', (21, 30))	('glutamate', 'Chemical', 'MESH:D018698', (43, 52))	('depolarization-evoked secretion from neurons', 'MPA', (80, 124))	('S1P', 'Gene', (159, 162))
72428	32024090	Of note, the ABCA1 inhibitor glyburide was reported to induce an accumulation of intracellular S1P and exogenously added S1P partially restored astrocyte proliferation in the presence of this inhibitor.	('S1P', 'Gene', (121, 124))	('S1P', 'Gene', '13609', (95, 98))	('astrocyte proliferation', 'CPA', (144, 167))	('glyburide', 'Chemical', 'MESH:D005905', (29, 38))	('ABCA1', 'Gene', '19', (13, 18))	('S1P', 'Gene', (95, 98))	('ABCA1', 'Gene', (13, 18))	('accumulation', 'MPA', (65, 77))	('rat', 'Species', '10116', (161, 164))	('S1P', 'Gene', '13609', (121, 124))	('inhibitor', 'Var', (19, 28))
72444	32024090	S1P1 is known to be coupled exclusively to Gi protein, leading to cAMP reduction and activation of Ras, MAPK, PI3K, Akt, and PLC pathways.	('Ras', 'Pathway', (99, 102))	('reduction', 'NegReg', (71, 80))	('cAMP', 'MPA', (66, 70))	('PI3K', 'Pathway', (110, 114))	('Akt', 'Gene', '207', (116, 119))	('activation', 'PosReg', (85, 95))	('S1P1', 'Var', (0, 4))	('PLC pathways', 'Pathway', (125, 137))	('Akt', 'Gene', (116, 119))	('cAMP', 'Chemical', '-', (66, 70))	('MAPK', 'Pathway', (104, 108))
72467	32024090	Moreover, SphK2 knockdown was found to inhibit GBM cell growth more potently than SphK1 knockdown, suggesting that both SphKs can participate to promote GBM cell growth.	('SphK2', 'Gene', '56848', (10, 15))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('SphK2', 'Gene', (10, 15))	('SphK1', 'Gene', (82, 87))	('inhibit', 'NegReg', (39, 46))	('SphK', 'Gene', '8877', (82, 86))	('GBM', 'Disease', (153, 156))	('SphK', 'Gene', (82, 86))	('SphK', 'Gene', '8877', (10, 14))	('GBM', 'Disease', 'MESH:D005909', (153, 156))	('SphK', 'Gene', (10, 14))	('SphK', 'Gene', (120, 124))	('SphK', 'Gene', '8877', (120, 124))	('GBM', 'Disease', (47, 50))	('GBM', 'Phenotype', 'HP:0012174', (153, 156))	('GBM', 'Disease', 'MESH:D005909', (47, 50))	('knockdown', 'Var', (16, 25))	('promote', 'PosReg', (145, 152))	('SphK1', 'Gene', '8877', (82, 87))
72470	32024090	The proliferative role of extracellular S1P in GBM is further substantiated by several reports demonstrating that human GBM cells respond mitogenically to nanomolar concentrations of S1P, and that extracellular S1P antagonized the inhibition of cell proliferation induced by inhibition of the S1P transporter ABCA1.	('extracellular', 'Var', (197, 210))	('S1P', 'Gene', (211, 214))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('human', 'Species', '9606', (114, 119))	('S1P', 'Gene', '13609', (183, 186))	('S1P', 'Gene', '13609', (40, 43))	('ABCA1', 'Gene', '19', (309, 314))	('rat', 'Species', '10116', (102, 105))	('rat', 'Species', '10116', (172, 175))	('S1P', 'Gene', '13609', (293, 296))	('cell proliferation', 'CPA', (245, 263))	('GBM', 'Disease', (120, 123))	('S1P', 'Gene', (183, 186))	('GBM', 'Disease', 'MESH:D005909', (120, 123))	('S1P', 'Gene', (40, 43))	('rat', 'Species', '10116', (11, 14))	('rat', 'Species', '10116', (257, 260))	('GBM', 'Disease', (47, 50))	('S1P', 'Gene', (293, 296))	('S1P', 'Gene', '13609', (211, 214))	('GBM', 'Disease', 'MESH:D005909', (47, 50))	('GBM', 'Phenotype', 'HP:0012174', (120, 123))	('ABCA1', 'Gene', (309, 314))	('antagonized', 'NegReg', (215, 226))
72483	32024090	The signal transducer and activator of transcription 3 (Stat3) is constitutively activated by phosphorylation in GSCs, promotes GSC proliferation, and is indispensable for GSC-induced tumor formation.	('promotes', 'PosReg', (119, 127))	('Stat3', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('rat', 'Species', '10116', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('GSC proliferation', 'CPA', (128, 145))	('activated', 'PosReg', (81, 90))	('tumor', 'Disease', (184, 189))	('signal transducer and activator of transcription 3', 'Gene', '6774', (4, 54))	('Stat3', 'Gene', '6774', (56, 61))	('phosphorylation', 'Var', (94, 109))
72497	32024090	Indeed, S1P1 and S1P3 signal migratory responses and amplify those exerted by other growth factors, whereas S1P2 signals inhibition of growth factor-evoked migration.	('migratory responses', 'CPA', (29, 48))	('S1P1', 'Var', (8, 12))	('rat', 'Species', '10116', (32, 35))	('S1P3', 'Gene', '1903', (17, 21))	('S1P2', 'Gene', (108, 112))	('S1P2', 'Gene', '9294', (108, 112))	('S1P3', 'Gene', (17, 21))	('inhibition', 'NegReg', (121, 131))	('rat', 'Species', '10116', (159, 162))
72498	32024090	The possible reason of this antagonistic effect appears to reside in the fact that S1P1 and S1P3 stimulate the small GTPase Rac, whereas S1P2 inhibits it.	('Rac', 'Gene', '207', (124, 127))	('S1P2', 'Gene', '9294', (137, 141))	('Rac', 'Gene', (124, 127))	('inhibits', 'NegReg', (142, 150))	('S1P3', 'Gene', '1903', (92, 96))	('S1P1', 'Var', (83, 87))	('S1P3', 'Gene', (92, 96))	('stimulate', 'PosReg', (97, 106))	('S1P2', 'Gene', (137, 141))
72510	32024090	Moreover, it was found that gene silencing of not only the G6T but also the membrane-type 1 MMP (MT1-MMP) decreased the extent of S1P-induced Ca2+ mobilization, unrevealing these signaling pathways that are required in GBM cells for efficient Ca2+ mobilization, and invasive effects in response to S1P.	('decreased', 'NegReg', (106, 115))	('GBM', 'Disease', (219, 222))	('membrane-type 1 MMP', 'Gene', '4323', (76, 95))	('GBM', 'Disease', 'MESH:D005909', (219, 222))	('S1P', 'Gene', '13609', (298, 301))	('S1P', 'Gene', '13609', (130, 133))	('Ca2+', 'Chemical', 'MESH:D000069285', (142, 146))	('membrane-type 1 MMP', 'Gene', (76, 95))	('gene silencing', 'Var', (28, 42))	('Ca2+ mobilization', 'MPA', (142, 159))	('S1P', 'Gene', (298, 301))	('MT1-MMP', 'Gene', '4323', (97, 104))	('GBM', 'Phenotype', 'HP:0012174', (219, 222))	('S1P', 'Gene', (130, 133))	('MT1-MMP', 'Gene', (97, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (243, 247))	('G6T', 'Mutation', 'c.6G>T', (59, 62))
72518	32024090	The dysregulation of the ceramide/S1P rheostat appears crucial in the death-resistance features of GBM.	('GBM', 'Disease', 'MESH:D005909', (99, 102))	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('ceramide', 'Chemical', 'MESH:D002518', (25, 33))	('dysregulation', 'Var', (4, 17))	('S1P', 'Gene', '13609', (34, 37))	('GBM', 'Disease', (99, 102))	('S1P', 'Gene', (34, 37))
72524	32024090	Several studies support a key role of SphKs in the promotion of S1P-induced survival in GBM, and SphK inhibition/genetic ablation sensitizes GBM cells to chemotherapeutics, and slows GBM growth in mice.	('promotion', 'PosReg', (51, 60))	('slows', 'NegReg', (177, 182))	('mice', 'Species', '10090', (197, 201))	('S1P', 'Gene', '13609', (64, 67))	('inhibition/genetic ablation', 'Var', (102, 129))	('GBM', 'Disease', (183, 186))	('GBM', 'Disease', 'MESH:D005909', (183, 186))	('GBM', 'Phenotype', 'HP:0012174', (141, 144))	('GBM', 'Disease', (88, 91))	('GBM', 'Disease', 'MESH:D005909', (88, 91))	('SphK', 'Gene', (97, 101))	('GBM', 'Disease', (141, 144))	('SphK', 'Gene', '8877', (97, 101))	('GBM', 'Disease', 'MESH:D005909', (141, 144))	('S1P', 'Gene', (64, 67))	('GBM', 'Phenotype', 'HP:0012174', (183, 186))	('survival', 'CPA', (76, 84))	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('sensitizes', 'Reg', (130, 140))	('SphK', 'Gene', '8877', (38, 42))	('SphK', 'Gene', (38, 42))
72525	32024090	A pivotal study reported that SphK1 expression correlates with poor survival of patients with GBM, and the following investigations revealed the importance of this enzyme.	('patients', 'Species', '9606', (80, 88))	('SphK1', 'Gene', (30, 35))	('GBM', 'Disease', (94, 97))	('expression', 'Var', (36, 46))	('GBM', 'Disease', 'MESH:D005909', (94, 97))	('poor', 'NegReg', (63, 67))	('GBM', 'Phenotype', 'HP:0012174', (94, 97))	('SphK1', 'Gene', '8877', (30, 35))
72526	32024090	In particular, it was found that SphK1 inhibition: (1) leads to cell death by inducing apoptosis of human GBM cells and xenografts, and reduces survival in orthotopic GBM; (2) sensitizes GBM cells, and different cancer cells, to several cytotoxic drugs; (3) is effective in potentiating the cytotoxicity of both TMZ and radiation therapy in various human GBM cell lines; and (4) induces apoptosis and inhibits colony formation in TMZ-resistant GBM cells.	('GBM', 'Phenotype', 'HP:0012174', (444, 447))	('apoptosis', 'CPA', (387, 396))	('induces', 'Reg', (379, 386))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('SphK1', 'Gene', '8877', (33, 38))	('GBM', 'Phenotype', 'HP:0012174', (187, 190))	('reduces', 'NegReg', (136, 143))	('GBM', 'Phenotype', 'HP:0012174', (355, 358))	('GBM', 'Disease', (106, 109))	('GBM', 'Disease', 'MESH:D005909', (106, 109))	('colony formation', 'CPA', (410, 426))	('SphK1', 'Gene', (33, 38))	('inhibits', 'NegReg', (401, 409))	('GBM', 'Disease', (167, 170))	('inhibition', 'Var', (39, 49))	('human', 'Species', '9606', (349, 354))	('GBM', 'Disease', 'MESH:D005909', (167, 170))	('GBM', 'Phenotype', 'HP:0012174', (106, 109))	('inducing', 'PosReg', (78, 86))	('cancer', 'Disease', (212, 218))	('GBM', 'Disease', (444, 447))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('GBM', 'Disease', 'MESH:D005909', (444, 447))	('cytotoxicity', 'Disease', (291, 303))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('human', 'Species', '9606', (100, 105))	('GBM', 'Disease', (187, 190))	('GBM', 'Disease', (355, 358))	('GBM', 'Disease', 'MESH:D005909', (187, 190))	('GBM', 'Disease', 'MESH:D005909', (355, 358))	('cytotoxicity', 'Disease', 'MESH:D064420', (291, 303))	('TMZ', 'Chemical', 'MESH:D000077204', (312, 315))	('TMZ', 'Chemical', 'MESH:D000077204', (430, 433))
72534	32024090	Indeed, targeting SphK1 in GBM cells with SK1-I rapidly reduced Akt phosphorylation, inhibited JNK, and finally reduced death in GBM cells in vivo.	('GBM', 'Disease', 'MESH:D005909', (129, 132))	('SK1-I', 'Var', (42, 47))	('inhibited', 'NegReg', (85, 94))	('JNK', 'Gene', '5599', (95, 98))	('reduced', 'NegReg', (56, 63))	('GBM', 'Disease', 'MESH:D005909', (27, 30))	('SphK1', 'Gene', '8877', (18, 23))	('JNK', 'Gene', (95, 98))	('SphK1', 'Gene', (18, 23))	('Akt', 'Gene', '207', (64, 67))	('GBM', 'Phenotype', 'HP:0012174', (129, 132))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('Akt', 'Gene', (64, 67))	('GBM', 'Disease', (129, 132))	('reduced', 'NegReg', (112, 119))	('death', 'CPA', (120, 125))	('GBM', 'Disease', (27, 30))
72547	32024090	Since S1P1 expression is increased in GSCs from U87MG GBM cells, and promotes cell survival in cultured cells and in a murine model of intracranial GBM, it appears reasonable that S1P1 might be involved in the pro-survival effect of extracellular S1P in TMZ-treated GSCs.	('S1P', 'Gene', (180, 183))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('expression', 'MPA', (11, 21))	('S1P', 'Gene', '13609', (247, 250))	('promotes', 'PosReg', (69, 77))	('murine', 'Species', '10090', (119, 125))	('GBM', 'Phenotype', 'HP:0012174', (148, 151))	('TMZ', 'Chemical', 'MESH:D000077204', (254, 257))	('S1P', 'Gene', (247, 250))	('S1P', 'Gene', '13609', (6, 9))	('cell survival', 'CPA', (78, 91))	('GBM', 'Disease', (54, 57))	('S1P', 'Gene', '13609', (180, 183))	('GBM', 'Disease', 'MESH:D005909', (54, 57))	('U87MG', 'Var', (48, 53))	('increased', 'PosReg', (25, 34))	('GBM', 'Disease', (148, 151))	('GBM', 'Disease', 'MESH:D005909', (148, 151))	('S1P', 'Gene', (6, 9))
72548	32024090	In support, it was reported that administration of the functional S1P antagonist FTY720 to nude mice led to downregulation of S1P receptors, induced apoptosis in GSCs, and was synergistic with TMZ in promoting cytotoxicity.	('apoptosis', 'CPA', (149, 158))	('FTY720', 'Var', (81, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (210, 222))	('TMZ', 'Chemical', 'MESH:D000077204', (193, 196))	('nude mice', 'Species', '10090', (91, 100))	('S1P', 'Gene', '13609', (126, 129))	('S1P', 'Gene', '13609', (66, 69))	('rat', 'Species', '10116', (41, 44))	('S1P', 'Gene', (126, 129))	('downregulation', 'NegReg', (108, 122))	('cytotoxicity', 'Disease', (210, 222))	('induced', 'Reg', (141, 148))	('S1P', 'Gene', (66, 69))
72552	32024090	Consistently, in both animal xenografts and surgical resections, the invasive front of GBM, where GSCs reside, contains abundantly infiltrating TAMs, and in in vivo GBM models, depletion of microglia/macrophages significantly reduces tumor growth.	('depletion', 'Var', (177, 186))	('GBM', 'Disease', (165, 168))	('reduces', 'NegReg', (226, 233))	('tumor', 'Disease', (234, 239))	('GBM', 'Disease', 'MESH:D005909', (165, 168))	('GBM', 'Disease', (87, 90))	('TAMs', 'Chemical', '-', (144, 148))	('GBM', 'Phenotype', 'HP:0012174', (165, 168))	('rat', 'Species', '10116', (137, 140))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
72553	32024090	It is believed that tumor-associated macrophages are mainly M2 macrophages, and more likely contribute to tumor growth, rather than exerting effective antitumor protection, and M2 abundance is associated with poor prognosis for patients with different tumors including GBM.	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('rat', 'Species', '10116', (120, 123))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('patients', 'Species', '9606', (228, 236))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('M2 abundance', 'Var', (177, 189))	('tumors', 'Disease', (252, 258))	('GBM', 'Disease', (269, 272))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('GBM', 'Disease', 'MESH:D005909', (269, 272))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('GBM', 'Phenotype', 'HP:0012174', (269, 272))	('tumor', 'Disease', (252, 257))	('associated', 'Reg', (193, 203))	('tumor', 'Disease', (20, 25))
72611	32024090	Multiple studies strongly support that cancers undergo metabolic adaptation and reprogramming, with factors intrinsic to cancer cells such as oncogenic mutations, and cell-extrinsic microenvironmental factors substantially contributing to the metabolic phenotype of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', (39, 45))	('mutations', 'Var', (152, 161))	('contributing', 'Reg', (223, 235))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('reprogramming', 'CPA', (80, 93))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('metabolic adaptation', 'CPA', (55, 75))	('cancer', 'Disease', (121, 127))
72627	32024090	In this context, it is worth mentioning that, among different metabolic deregulations, aberrant lipid metabolism has emerged as crucial, not only as an energy source and in providing substrates for membrane synthesis, but also for its role in cellular signaling in both GBM cells and GSCs.	('lipid', 'Chemical', 'MESH:D008055', (96, 101))	('aberrant', 'Var', (87, 95))	('lipid metabolism', 'MPA', (96, 112))	('GBM', 'Phenotype', 'HP:0012174', (270, 273))	('rat', 'Species', '10116', (188, 191))	('GBM', 'Disease', (270, 273))	('aberrant lipid metabolism', 'Phenotype', 'HP:0003119', (87, 112))	('GBM', 'Disease', 'MESH:D005909', (270, 273))
72640	32024090	Of particular interest is the S1P receptor antagonist FTY720 (Gilenya/Fingolimod), which demonstrated efficacy in multiple sclerosis and has been used in numerous animal experiments and clinical trials for different diseases and cancers, including GBM (, NCT02490930, sponsored by Sidney Kimmel Comprehensive Cancer).	('S1P', 'Gene', '13609', (30, 33))	('multiple sclerosis', 'Disease', 'MESH:D009103', (114, 132))	('GBM', 'Disease', (248, 251))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('Sidney Kimmel Comprehensive Cancer', 'Disease', 'MESH:D001308', (281, 315))	('GBM', 'Disease', 'MESH:D005909', (248, 251))	('S1P', 'Gene', (30, 33))	('diseases and cancers', 'Disease', 'MESH:D009369', (216, 236))	('rat', 'Species', '10116', (96, 99))	('GBM', 'Phenotype', 'HP:0012174', (248, 251))	('Cancer', 'Phenotype', 'HP:0002664', (309, 315))	('Sidney Kimmel Comprehensive Cancer', 'Disease', (281, 315))	('multiple sclerosis', 'Disease', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('FTY720', 'Var', (54, 60))
72779	26766590	MiR-215 is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence.	('iron', 'Chemical', 'MESH:D007501', (168, 172))	('MiR-215', 'Gene', (0, 7))	('glioblastoma', 'Disease', (268, 280))	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (268, 280))	('MiR-215', 'Gene', '406997', (0, 7))	('KDM1B', 'Gene', (136, 141))	('HIF-Drosha', 'Disease', (46, 56))	('GBM', 'Phenotype', 'HP:0012174', (282, 285))	('targeting', 'Var', (126, 135))	('glioma', 'Disease', (215, 221))	('HIF-Drosha', 'Disease', 'None', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('glioma', 'Disease', 'MESH:D005910', (215, 221))	('hypoxic tumor', 'Disease', 'MESH:D009369', (146, 159))	('glioma', 'Disease', (78, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (268, 280))	('glioma', 'Phenotype', 'HP:0009733', (215, 221))	('hypoxia', 'Disease', (115, 122))	('glioma', 'Disease', 'MESH:D005910', (78, 84))	('hypoxic tumor', 'Disease', (146, 159))
72812	26766590	As displayed in Figure 1A, antagonizing the function of miR-215, rather than other miRNAs, in GICs significantly alleviated GBM progression in mice bearing the intracranial tumor in comparison to controls.	('antagonizing', 'Var', (27, 39))	('intracranial tumor', 'Disease', (160, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('alleviated', 'NegReg', (113, 123))	('GBM progression', 'CPA', (124, 139))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (56, 59))	('miR', 'Gene', '220972', (56, 59))	('GBM', 'Phenotype', 'HP:0012174', (124, 127))	('intracranial tumor', 'Disease', 'MESH:D001932', (160, 178))	('mice', 'Species', '10090', (143, 147))
72829	26766590	In contrast, the level of unprocessed pri-miR-215 was found to increase under hypoxia when HIF1alpha was knocked down, suggesting a blockage of the pri-miR-215 processing into pre-miR-215.	('increase', 'PosReg', (63, 71))	('HIF1alpha', 'Gene', (91, 100))	('blockage', 'NegReg', (132, 140))	('hypoxia', 'Disease', (78, 85))	('processing', 'MPA', (160, 170))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('level', 'MPA', (17, 22))	('HIF1alpha', 'Gene', '3091', (91, 100))	('knocked down', 'Var', (105, 117))
72832	26766590	Since portions of pri-miR-215 are embedded in the 3'UTR of the firefly luciferase gene, cleavage of pri-miR-215 by the Drosha complex is expected to destabilize the mRNA of firefly luciferase and in turn to decrease the firefly luminescence.	('Drosha', 'Gene', '29102', (119, 125))	('pri-miR-215', 'Gene', (100, 111))	('mRNA of', 'MPA', (165, 172))	('Drosha', 'Gene', (119, 125))	('firefly luciferase', 'Enzyme', (173, 191))	('cleavage', 'Var', (88, 96))	('destabilize', 'NegReg', (149, 160))	('decrease', 'NegReg', (207, 215))	('firefly luminescence', 'MPA', (220, 240))
72848	26766590	RNA-Chromatin Immunoprecipitation (RNA-ChIP) analysis was performed on HEK293T cells transfected with pri-miR-215 and Flag-tagged HIF1alpha and an enhanced association of HIF1alpha with pri-miR-215 was detected (Figure S3E).	('enhanced', 'PosReg', (147, 155))	('HIF1alpha', 'Gene', (171, 180))	('HEK293T', 'CellLine', 'CVCL:0063', (71, 78))	('HIF1alpha', 'Gene', '3091', (130, 139))	('pri-miR-215', 'Var', (102, 113))	('HIF1alpha', 'Gene', '3091', (171, 180))	('association', 'Interaction', (156, 167))	('HIF1alpha', 'Gene', (130, 139))
72859	26766590	Interestingly, knocking down either HIF1alpha or HIF2alpha by shRNA could abolish the enhancement of miR-215 expression by hypoxia (Figure S4F), suggesting that a threshold of combined protein amount of HIF1alpha and HIF2alpha might be critical to promote the Drosha-mediated pri-miRNA processing.	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('HIF1alpha', 'Gene', '3091', (36, 45))	('HIF1alpha', 'Gene', (203, 212))	('HIF2alpha', 'Gene', '2034', (49, 58))	('miR', 'Gene', '220972', (280, 283))	('miR', 'Gene', (101, 104))	('HIF1alpha', 'Gene', (36, 45))	('enhancement', 'PosReg', (86, 97))	('HIF2alpha', 'Gene', (217, 226))	('miR', 'Gene', (280, 283))	('knocking', 'Var', (15, 23))	('abolish', 'NegReg', (74, 81))	('HIF2alpha', 'Gene', (49, 58))	('expression', 'MPA', (109, 119))	('Drosha', 'Gene', (260, 266))	('HIF2alpha', 'Gene', '2034', (217, 226))	('hypoxia', 'Disease', (123, 130))	('HIF1alpha', 'Gene', '3091', (203, 212))	('Drosha', 'Gene', '29102', (260, 266))	('miR', 'Gene', '220972', (101, 104))
72862	26766590	Although over-expression of miR-215 impedes the progression of colon and renal cancer, miR-215 is shown to serve as an onco-mir in the development of gastric cancer and hepatoma.	('mir', 'Gene', (124, 127))	('impedes', 'NegReg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('hepatoma', 'Disease', (169, 177))	('colon and renal cancer', 'Disease', 'MESH:D007680', (63, 85))	('gastric cancer', 'Disease', (150, 164))	('miR-215', 'Var', (87, 94))	('mir', 'Gene', '220972', (124, 127))	('renal cancer', 'Phenotype', 'HP:0009726', (73, 85))	('hepatoma', 'Disease', 'MESH:D006528', (169, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('miR-215', 'Gene', (28, 35))	('progression', 'CPA', (48, 59))	('over-expression', 'PosReg', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
72863	26766590	Since miR-215 is induced in GICs under hypoxia and attenuation of its function significantly delayed tumor progression (Figure 1A), we further examined the role of miR-215 in GICs.	('attenuation', 'Var', (51, 62))	('hypoxia', 'Disease', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('miR-215', 'Gene', (6, 13))	('delayed', 'NegReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
72864	26766590	Attenuating the function of miR-215 by miR-215-sponge or a specific LNA inhibitor in GICs significantly reduced their growth rate as well as ability to form neurospheres under hypoxia (Figure 4A-B and Figure S5A-F).	('reduced', 'NegReg', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (176, 183))	('miR-215-sponge', 'Var', (39, 53))	('Attenuating', 'NegReg', (0, 11))	('miR-215', 'Gene', (28, 35))	('growth rate', 'CPA', (118, 129))	('hypoxia', 'Disease', (176, 183))	('function', 'MPA', (16, 24))
72865	26766590	In consistency with the observation in Figure 1A, miR-215-sponge also rendered a significant delay in GBM progression in mice bearing intracranial tumors derived from GICs isolated from the glioma line 110040 (Figure 4C).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('intracranial tumors', 'Disease', 'MESH:D001932', (134, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('GBM progression', 'CPA', (102, 117))	('glioma', 'Disease', (190, 196))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('delay', 'NegReg', (93, 98))	('intracranial tumors', 'Disease', (134, 153))	('mice', 'Species', '10090', (121, 125))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('miR-215-sponge', 'Var', (50, 64))
72877	26766590	Alterations related with histone modification processes in GBM, such as mutations of KDM6A, MLL2 and SETD2 have been reported.	('mutations', 'Var', (72, 81))	('SETD2', 'Gene', (101, 106))	('MLL2', 'Gene', '9757', (92, 96))	('KDM6A', 'Gene', '7403', (85, 90))	('MLL2', 'Gene', (92, 96))	('GBM', 'Phenotype', 'HP:0012174', (59, 62))	('SETD2', 'Gene', '29072', (101, 106))	('KDM6A', 'Gene', (85, 90))
72878	26766590	These mutations result in disruption of the epigenetic processes and promotion of cancer progression.	('promotion', 'PosReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('epigenetic processes', 'MPA', (44, 64))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('disruption', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
72882	26766590	Indeed, the luciferase expression was repressed by miR-215 in a dose-dependent manner in HEK293T cells, whereas expression of the luciferase with mutated 3'UTR was not altered significantly (Figure 5D).	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('miR-215', 'Var', (51, 58))	('expression', 'MPA', (23, 33))	('luciferase', 'Enzyme', (12, 22))
72885	26766590	Expression of KDM1B could recapitulate phenotypes of miR-215 knockdown in GICs under hypoxia as demonstrated by the impaired cell growth and neurosphere formation (Figure 5E-G and Figure S6D-F).	('miR-215', 'Gene', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (85, 92))	('cell growth', 'CPA', (125, 136))	('hypoxia', 'Disease', (85, 92))	('impaired', 'NegReg', (116, 124))	('knockdown', 'Var', (61, 70))	('KDM1B', 'Var', (14, 19))	('neurosphere formation', 'CPA', (141, 162))
72890	26766590	As shown in Figure S7A-B, the analysis revealed that multiple pathways related to cellular response to hypoxia emerged in a prominent pattern, indicating that KDM1B might reprogram GICs for hypoxia-adaptation through affecting those pathways.	('hypoxia', 'Disease', 'MESH:D000860', (190, 197))	('hypoxia', 'Disease', (190, 197))	('affecting', 'Reg', (217, 226))	('KDM1B', 'Var', (159, 164))	('hypoxia', 'Disease', (103, 110))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))
72892	26766590	As shown in Figure 6A-B, expression of these genes increased when KDM1B was knocked down and no longer elevated by hypoxia when the function of miR-215 was attenuated, indicating that they serve as downstream targets of miR-215-KDM1B under hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('knocked', 'Var', (76, 83))	('increased', 'PosReg', (51, 60))	('expression', 'MPA', (25, 35))	('KDM1B', 'Gene', (66, 71))	('hypoxia', 'Disease', (240, 247))	('hypoxia', 'Disease', 'MESH:D000860', (240, 247))	('hypoxia', 'Disease', (115, 122))
72894	26766590	On the other hand, the elevation of glucose uptake in response to hypoxia was abolished in GICs with blockage of miR-215 (Figure 6D).	('miR-215', 'Gene', (113, 120))	('blockage', 'Var', (101, 109))	('glucose uptake', 'MPA', (36, 50))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('abolished', 'NegReg', (78, 87))
72898	26766590	In addition, we found the expression of two enzymes catalyzing the biosynthesis of the chondroitin sulfate chain, chondroitin polymerizing factor (CHPF) and carbohydrate (Chondroitin 4) sulfotransferase 11 (CHST11), induced under hypoxia mediated by miR-215-KDM1B (Figure 6A-B), suggesting a potential role of the modification process of chondroitin sulfate proteoglycan (CSPG) chain during hypoxic responses.	('CHPF', 'Gene', '79586', (147, 151))	('CHST11', 'Gene', '50515', (207, 213))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (87, 106))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (338, 357))	('hypoxia', 'Disease', (230, 237))	('hypoxia', 'Disease', 'MESH:D000860', (230, 237))	('CHST11', 'Gene', (207, 213))	('chondroitin polymerizing factor', 'Gene', '79586', (114, 145))	('CHPF', 'Gene', (147, 151))	('chondroitin polymerizing factor', 'Gene', (114, 145))	('miR-215-KDM1B', 'Var', (250, 263))	('carbohydrate', 'Chemical', 'MESH:D002241', (157, 169))
72899	26766590	CSPG is composed of a core protein with modification of chondroitin sulfate chains, which is a main component of extracellular matrix (ECM).	('chondroitin sulfate chains', 'Protein', (56, 82))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (56, 75))	('modification', 'Var', (40, 52))
72904	26766590	Taken together, these data illustrate that repression of KDM1B via enhancement of the miR-215 signal under hypoxia could activate multiple signaling pathways, which function together to mediate adaptation of GICs to the hypoxic stress.	('hypoxic stress', 'Disease', (220, 234))	('hypoxic stress', 'Disease', 'MESH:D004194', (220, 234))	('repression', 'Var', (43, 53))	('enhancement', 'PosReg', (67, 78))	('miR-215 signal', 'MPA', (86, 100))	('activate', 'PosReg', (121, 129))	('signaling pathways', 'Pathway', (139, 157))	('hypoxia', 'Disease', (107, 114))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))	('KDM1B', 'Gene', (57, 62))
72924	26766590	Genetic knockout of KDM1B in mice was embryonic lethal due to its critical roles in maintaining the maternal genomic imprints of specific genes.	('KDM1B', 'Gene', (20, 25))	('embryonic', 'Disease', 'MESH:D009373', (38, 47))	('mice', 'Species', '10090', (29, 33))	('knockout', 'Var', (8, 16))	('embryonic', 'Disease', (38, 47))
72931	26766590	Indeed, this assumption is supported by a report demonstrating that the level of C4S is accumulated during hypoxia, which further mediates the effects of hypoxia through regulating its binding with galectin-3 in human bronchial epithelial cells.	('regulating', 'Reg', (170, 180))	('galectin-3', 'Gene', (198, 208))	('human', 'Species', '9606', (212, 217))	('binding', 'Interaction', (185, 192))	('hypoxia', 'Disease', (154, 161))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('C4S', 'Chemical', 'MESH:D002809', (81, 84))	('C4S', 'Var', (81, 84))	('galectin-3', 'Gene', '3958', (198, 208))	('hypoxia', 'Disease', (107, 114))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))
72932	26766590	Although we have observed that disruption of the chondroitin sulfate chain by chondroitinase impairs the GIC growth under hypoxic stress, the exact activities of the chondroitin sulfate chain in affecting GIC function at the mechanistic level remain to be further explored.	('chondroitin', 'Chemical', 'MESH:D002807', (49, 60))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (49, 68))	('GIC growth', 'CPA', (105, 115))	('chondroitin', 'Chemical', 'MESH:D002807', (166, 177))	('hypoxic stress', 'Disease', 'MESH:D004194', (122, 136))	('chondroitin sulfate chain', 'Protein', (49, 74))	('hypoxic stress', 'Disease', (122, 136))	('impairs', 'NegReg', (93, 100))	('disruption', 'Var', (31, 41))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (166, 185))	('chondroitin', 'Chemical', 'MESH:D002807', (78, 89))
72941	26766590	Unlike Smad proteins that bind to a subset of pri-miRNAs directly through association of their DNA binding domain and consensus binding sequences embedded in the pri-miRNAs, it appears that HIFs interact with the pri-miRNAs independently from their DNA binding domains, since a HIF1alpha mutant with mutations in its bHLH domain was still able to promote the incorporation of pri-miR-215 into HIF1alpha complex or affecting the processing activity of miR-215 by Drosha (data not shown).	('HIF1alpha', 'Gene', '3091', (393, 402))	('incorporation', 'MPA', (359, 372))	('HIF1alpha', 'Gene', (393, 402))	('mutant', 'Var', (288, 294))	('miR', 'Gene', '220972', (50, 53))	('Drosha', 'Gene', (462, 468))	('Drosha', 'Gene', '29102', (462, 468))	('miR', 'Gene', '220972', (217, 220))	('HIF1alpha', 'Gene', '3091', (278, 287))	('miR', 'Gene', (50, 53))	('miR', 'Gene', '220972', (380, 383))	('mutations', 'Var', (300, 309))	('HIF1alpha', 'Gene', (278, 287))	('bHLH', 'Gene', (317, 321))	('promote', 'PosReg', (347, 354))	('miR', 'Gene', (217, 220))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', '220972', (451, 454))	('affecting', 'Reg', (414, 423))	('miR', 'Gene', (380, 383))	('processing activity', 'MPA', (428, 447))	('miR', 'Gene', (166, 169))	('miR', 'Gene', (451, 454))
72943	26766590	GBM xenografted lines (D456MG, 110040, 080695 and 080326) were isolated from patient specimen and passaged in nude mice as subcutaneous xenografts.	('D456MG', 'Var', (23, 29))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('080326', 'Var', (50, 56))	('080695', 'Var', (39, 45))	('patient', 'Species', '9606', (77, 84))	('nude mice', 'Species', '10090', (110, 119))
73005	25712125	The following primary antibodies were used: AKT, phospho-AKT (Ser473), pS6K (Thr421/Ser424), GAPDH, phospho-ERK1/2 (Thr202/Tyr204), phospho-RSK2 (Ser227) (Cell Signaling).	('RSK2', 'Gene', (140, 144))	('ERK', 'Gene', (108, 111))	('Thr202/Tyr204', 'Var', (116, 129))	('Thr202', 'Chemical', '-', (116, 122))	('AKT', 'Gene', '207', (57, 60))	('RSK2', 'Gene', '6197', (140, 144))	('Ser424', 'Chemical', '-', (84, 90))	('AKT', 'Gene', (44, 47))	('Ser227', 'Chemical', '-', (146, 152))	('GAPDH', 'Gene', '2597', (93, 98))	('Tyr204', 'Chemical', '-', (123, 129))	('pS6K', 'Gene', '6198', (71, 75))	('pS6K', 'Gene', (71, 75))	('ERK', 'Gene', '5594', (108, 111))	('Ser473', 'Chemical', '-', (62, 68))	('Thr421', 'Chemical', '-', (77, 83))	('GAPDH', 'Gene', (93, 98))	('Thr421/Ser424', 'Var', (77, 90))	('AKT', 'Gene', '207', (44, 47))	('AKT', 'Gene', (57, 60))
73028	25712125	The dose-modifying factor (DMF, ratio of radiation dose with hyperthermia to radiation alone to achieve 90% cell kill) was 0.66 and 0.62 for GSC 387 and GSC 3691, respectively, showing a considerable enhancement in cell killing with hyperthermia.	('GSC 3691', 'Var', (153, 161))	('enhancement', 'PosReg', (200, 211))	('hyperthermia', 'Disease', (233, 245))	('hyperthermia', 'Phenotype', 'HP:0001945', (233, 245))	('DMF', 'Chemical', '-', (27, 30))	('hyperthermia', 'Disease', 'MESH:D005334', (61, 73))	('hyperthermia', 'Disease', 'MESH:D005334', (233, 245))	('hyperthermia', 'Phenotype', 'HP:0001945', (61, 73))	('hyperthermia', 'Disease', (61, 73))	('GSC', 'Var', (141, 144))	('cell killing', 'CPA', (215, 227))
73057	25712125	We next tested the ability of constitutively active AKT to rescue hyperthermic radiosensitization of GSCs using cells that stably expressed myristoylated AKT (MYR-AKT) or control GFP (Figure 4C).	('tested', 'Reg', (8, 14))	('myristoylated', 'Var', (140, 153))	('AKT', 'Gene', (163, 166))	('AKT', 'Gene', (52, 55))	('AKT', 'Gene', '207', (154, 157))	('hyperthermic radiosensitization', 'Phenotype', 'HP:0010997', (66, 97))	('AKT', 'Gene', (154, 157))	('AKT', 'Gene', '207', (163, 166))	('AKT', 'Gene', '207', (52, 55))
73059	25712125	Treatment of GSCs with the PI3K inhibitor LY294002 further reduced GSC colony formation (Figure 4E).	('GSC colony formation', 'CPA', (67, 87))	('reduced', 'NegReg', (59, 66))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('LY294002', 'Var', (42, 50))
73078	25712125	These results are consistent with results of gold nanoshell-mediated hyperthermia in improving the radiosensitivity of breast cancer stem cells and suggest that maximizing PI3K-AKT inhibition with hyperthermia and pharmacologic inhibition may further improve radiosensitization of cancer stem cells.	('AKT', 'Gene', '207', (177, 180))	('hyperthermia', 'Disease', (69, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('improving', 'PosReg', (85, 94))	('inhibition', 'NegReg', (181, 191))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('hyperthermia', 'Disease', 'MESH:D005334', (197, 209))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('breast cancer', 'Disease', (119, 132))	('improve', 'PosReg', (251, 258))	('cancer', 'Disease', (126, 132))	('hyperthermia', 'Disease', 'MESH:D005334', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hyperthermia', 'Phenotype', 'HP:0001945', (197, 209))	('AKT', 'Gene', (177, 180))	('radiosensitivity', 'CPA', (99, 115))	('radiosensitization', 'CPA', (259, 277))	('hyperthermia', 'Phenotype', 'HP:0001945', (69, 81))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('maximizing', 'Var', (161, 171))	('hyperthermia', 'Disease', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
73090	25712125	Our data suggest that maximizing AKT inhibition with pharmacologic inhibitors and hyperthermia may enhance cancer control and potentially overcome resistance mechanisms.	('maximizing', 'Var', (22, 32))	('inhibition', 'NegReg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('AKT', 'Gene', '207', (33, 36))	('hyperthermia', 'Disease', 'MESH:D005334', (82, 94))	('hyperthermia', 'Phenotype', 'HP:0001945', (82, 94))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('hyperthermia', 'Disease', (82, 94))	('AKT', 'Gene', (33, 36))	('cancer', 'Disease', (107, 113))	('enhance', 'PosReg', (99, 106))
73095	23936469	Here, we investigated the roles of Lyn, a SFK, in promoting the survival of human glioblastoma tumor (GBM) cells in vitro and in vivo using lentiviral vector-mediated expression of constitutively-active Lyn (CA-Lyn) or dominant-negative Lyn (DN-Lyn).	('dominant-negative', 'Var', (219, 236))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('human', 'Species', '9606', (76, 81))	('promoting', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (82, 100))	('glioblastoma tumor', 'Disease', (82, 100))
73096	23936469	In contrast, under nutrient-deprived conditions (absence of supplementation with L-glutamine, which is essential for growth of GBM cells, and FBS) CA-Lyn expression enhanced survival and promoted autophagy as well as inhibiting cell death and promoting proliferation.	('CA-Lyn', 'Protein', (147, 153))	('autophagy', 'CPA', (196, 205))	('FBS', 'Disease', (142, 145))	('L-glutamine', 'Chemical', 'MESH:D005973', (81, 92))	('survival', 'CPA', (174, 182))	('enhanced', 'PosReg', (165, 173))	('inhibiting', 'NegReg', (217, 227))	('expression', 'Var', (154, 164))	('FBS', 'Disease', 'MESH:D005198', (142, 145))	('promoting', 'PosReg', (243, 252))	('promoted', 'PosReg', (187, 195))	('cell death', 'CPA', (228, 238))
73100	23936469	The DN-Lyn xenografts formed smaller tumors and contained more apoptotic cells.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('apoptotic cells', 'CPA', (63, 78))	('DN-Lyn', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('smaller', 'NegReg', (29, 36))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
73121	23936469	CA-Lyn (Y508F) and DN-Lyn (Y397F) cDNAs were kind gifts from Dr. Evan Ingley at the Western Australian Institute for Medical Research.	('Y508F', 'Var', (8, 13))	('Y397F', 'Mutation', 'p.Y397F', (27, 32))	('Y508F', 'Mutation', 'p.Y508F', (8, 13))	('Y397F', 'Var', (27, 32))
73125	23936469	Antibodies were purchased as follows: rabbit anti-pY397FAK and anti-total FAK (Upstate Biotechnology, Inc.), rabbit anti-Fyn, anti-Lyn and anti-cSrc (Santa Cruz International); monoclonal antibody (mAb) anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and mAb anti-actin (Sigma Chemical Co.); rabbit anti-LC3B, anti-phospho-Akt and anti-total Akt, and antibodies to pS6 kinase and total S6 kinase (Cell Signaling); rabbit anti-LC3B (Nanotools); rabbit polyclonal IgG (sc-25575) (Santa Cruz Biotechnology); anti-phospho-AMPK (Thr172) and anti-total AMPK (Cell Signaling Technology) and anti-phospho-a1-AMPK (Thr172) (Millipore).	('rabbit', 'Species', '9986', (299, 305))	('Akt', 'Gene', '207', (349, 352))	('LC3B', 'Gene', (433, 437))	('pS6', 'Gene', (372, 375))	('LC3B', 'Gene', '81631', (433, 437))	('Akt', 'Gene', (330, 333))	('GAPDH', 'Gene', (250, 255))	('FAK', 'Gene', (74, 77))	('Fyn', 'Gene', (121, 124))	('Akt', 'Gene', '207', (330, 333))	('pS6', 'Gene', '338413', (372, 375))	('LC3B', 'Gene', (311, 315))	('anti-phospho-a1-AMPK', 'Var', (591, 611))	('rabbit', 'Species', '9986', (421, 427))	('FAK', 'Gene', '5747', (74, 77))	('anti-phospho-AMPK', 'Var', (512, 529))	('LC3B', 'Gene', '81631', (311, 315))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (208, 248))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (208, 248))	('FAK', 'Gene', (55, 58))	('rabbit', 'Species', '9986', (38, 44))	('anti-total AMPK', 'CPA', (543, 558))	('Y397F', 'Mutation', 'p.Y397F', (51, 56))	('rabbit', 'Species', '9986', (451, 457))	('rabbit', 'Species', '9986', (109, 115))	('cSrc', 'Gene', '6714', (144, 148))	('Fyn', 'Gene', '2534', (121, 124))	('cSrc', 'Gene', (144, 148))	('FAK', 'Gene', '5747', (55, 58))	('Akt', 'Gene', (349, 352))	('GAPDH', 'Gene', '2597', (250, 255))
73126	23936469	Activation of Lyn was assessed by immunoblotting to detect autophosphorylation of Y418.	('Y418', 'Chemical', '-', (82, 86))	('Lyn', 'Protein', (14, 17))	('Y418', 'Var', (82, 86))
73131	23936469	A random sampling of tumor cells was performed and examined by EM from 5 tumors expressing LV, 5 expressing DN-Lyn, and 4 expressing CA-Lyn.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (21, 26))	('DN-Lyn', 'Var', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
73137	23936469	The SFKs, including Lyn, are maintained in an inactive state by the C-terminal Src kinase (Csk), which phosphorylates the C-terminal negative regulatory peptide (Y508 in Lyn).	('Csk', 'Gene', '1445', (91, 94))	('C-terminal Src kinase', 'Gene', '1445', (68, 89))	('C-terminal Src kinase', 'Gene', (68, 89))	('Csk', 'Gene', (91, 94))	('Y508', 'Var', (162, 166))
73146	23936469	Fyn protein was decreased by approximately 30% in U87 cells expressing CA-Lyn or DN-Lyn (Fig.	('Fyn', 'Gene', (0, 3))	('Fyn', 'Gene', '2534', (0, 3))	('DN-Lyn', 'Var', (81, 87))	('CA-Lyn', 'Var', (71, 77))	('decreased', 'NegReg', (16, 25))
73157	23936469	Western blotting for LC3 protein further indicated the normalized levels of the lipid-modified LC3B-II protein, which is generated during autophagy, were higher in the U87-CA-Lyn cells than in the U87-LV cells at days 5 and 7 (Fig.	('LC3B', 'Gene', (95, 99))	('levels', 'MPA', (66, 72))	('LC3', 'Gene', '84557', (21, 24))	('LC3', 'Gene', (21, 24))	('higher', 'PosReg', (154, 160))	('lipid', 'Chemical', 'MESH:D008055', (80, 85))	('LC3B', 'Gene', '81631', (95, 99))	('LC3', 'Gene', '84557', (95, 98))	('U87-CA-Lyn', 'Var', (168, 178))	('LC3', 'Gene', (95, 98))
73158	23936469	At days 2, 3 and 5, lower levels of LC3B-II were present in the cells expressing DN-Lyn than in the U87-LV cells (Fig.	('lower', 'NegReg', (20, 25))	('LC3B', 'Gene', (36, 40))	('LC3B', 'Gene', '81631', (36, 40))	('DN-Lyn', 'Var', (81, 87))
73163	23936469	Fyn protein was decreased by approximately 30% in SNB19 cells expressing CA-Lyn or DN-Lyn (Fig.	('Fyn', 'Gene', (0, 3))	('DN-Lyn', 'Var', (83, 89))	('Fyn', 'Gene', '2534', (0, 3))	('SNB19', 'CellLine', 'CVCL:0535', (50, 55))	('CA-Lyn', 'Var', (73, 79))	('decreased', 'NegReg', (16, 25))
73164	23936469	In addition, the level of normalized LC3B-II protein was higher in nutrient-deprived SNB19 cells expressing CA-Lyn at day 7 than in the SNB19 cells expressing the lentivirus vector alone (Fig.	('higher', 'PosReg', (57, 63))	('LC3B', 'Gene', '81631', (37, 41))	('level', 'MPA', (17, 22))	('SNB19', 'CellLine', 'CVCL:0535', (85, 90))	('CA-Lyn', 'Var', (108, 114))	('SNB19', 'CellLine', 'CVCL:0535', (136, 141))	('LC3B', 'Gene', (37, 41))
73166	23936469	4A), consistent with accumulation of lipid-modified LC3B-II protein on blockade of fusion of the autophagosome with the lysosome.	('lipid-modified', 'Var', (37, 51))	('accumulation', 'PosReg', (21, 33))	('LC3B', 'Gene', (52, 56))	('lipid', 'Chemical', 'MESH:D008055', (37, 42))	('LC3B', 'Gene', '81631', (52, 56))
73168	23936469	Furthermore, treatment of the U87 cells expressing LV, CA-Lyn or DN-Lyn with chloroquine or 3-MA for 5 or 7 days under the same nutrient deprivation conditions resulted in a dramatic reduction in cell viability in all cell populations (Fig.	('reduction', 'NegReg', (183, 192))	('DN-Lyn', 'Var', (65, 71))	('cell viability in all cell populations', 'CPA', (196, 234))	('3-MA', 'Chemical', '-', (92, 96))	('chloroquine', 'Chemical', 'MESH:D002738', (77, 88))
73170	23936469	After 5 days of nutrient-deprivation, the levels of pS6 kinase were lower in U87-CA-Lyn and higher in U87-DN-Lyn cells than in U87-LV cells (Fig.	('levels', 'MPA', (42, 48))	('higher', 'PosReg', (92, 98))	('lower', 'NegReg', (68, 73))	('pS6', 'Gene', (52, 55))	('U87-CA-Lyn', 'Var', (77, 87))	('U87-DN-Lyn', 'Var', (102, 112))	('pS6', 'Gene', '338413', (52, 55))
73177	23936469	Perifosine, an Akt inhibitor, enhanced the levels of LC3B-II protein in all cell populations (Fig.	('Akt', 'Gene', '207', (15, 18))	('Perifosine', 'Chemical', 'MESH:C105905', (0, 10))	('enhanced', 'PosReg', (30, 38))	('LC3B', 'Gene', '81631', (53, 57))	('levels', 'MPA', (43, 49))	('Akt', 'Gene', (15, 18))	('Perifosine', 'Var', (0, 10))	('LC3B', 'Gene', (53, 57))
73180	23936469	We therefore transduced primary human GSCs with GFP-CA-Lyn, GFP-DN-Lyn or GFP-LV, sorted for GFP-expressing cells, and plated the cells on laminin in NBM.	('GFP-DN-Lyn', 'Var', (60, 70))	('GFP-CA-Lyn', 'Var', (48, 58))	('human', 'Species', '9606', (32, 37))
73181	23936469	Higher Src activity was confirmed in the GSCs expressing CA-Lyn than those expressing LV (data not shown).	('CA-Lyn', 'Var', (57, 63))	('Src', 'Gene', (7, 10))	('Higher', 'PosReg', (0, 6))	('Src', 'Gene', '6714', (7, 10))
73182	23936469	Immunofluorescent staining for LC3 protein in the GSCs starved of EGF and bFGF for 6 h indicated that the numbers of autophagosomes per cell was significantly higher in the GSCs expressing CA-Lyn as compared to those expressing LV, and significantly lower in the GSCs expressing DN-Lyn as compared to those expressing LV (Fig.	('lower', 'NegReg', (250, 255))	('bFGF', 'Gene', (74, 78))	('LC3', 'Gene', '84557', (31, 34))	('LC3', 'Gene', (31, 34))	('CA-Lyn', 'Var', (189, 195))	('EGF', 'Gene', (66, 69))	('numbers of autophagosomes per cell', 'CPA', (106, 140))	('bFGF', 'Gene', '2247', (74, 78))	('EGF', 'Gene', '1950', (66, 69))	('higher', 'PosReg', (159, 165))
73188	23936469	Detection of proliferating cells by Ki67 mAb labeling showed a significant increase in the CA-Lyn versus the LV tumors, indicating that the larger tumor size with expression of CA-Lyn was due in part to increased proliferation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (112, 117))	('expression', 'Var', (163, 173))	('LV tumors', 'Disease', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('LV tumors', 'Disease', 'MESH:C535509', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('larger', 'PosReg', (140, 146))	('CA-Lyn', 'Gene', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('increased', 'PosReg', (203, 212))
73200	23936469	The tyrosine phosphorylation of the known SFK substrates, FAK(Y397 and Y925) (Fig.	('tyrosine phosphorylation', 'MPA', (4, 28))	('FAK', 'Gene', (58, 61))	('FAK', 'Gene', '5747', (58, 61))	('Y925', 'Var', (71, 75))	('tyrosine', 'Chemical', 'MESH:D014443', (4, 12))
73203	23936469	Similarly, although SFKs can promote survival through the FAK/p130CAS or PI3K/Akt pro-survival pathways, neither FAK nor Akt activity was altered in the nutrient-deprived GBM cells expressing CA-Lyn or DN-Lyn.	('DN-Lyn', 'Var', (202, 208))	('promote', 'PosReg', (29, 36))	('Akt', 'Gene', (121, 124))	('p130CAS', 'Gene', (62, 69))	('FAK', 'Gene', (113, 116))	('CA-Lyn', 'Var', (192, 198))	('FAK', 'Gene', '5747', (113, 116))	('Akt', 'Gene', '207', (78, 81))	('FAK', 'Gene', (58, 61))	('FAK', 'Gene', '5747', (58, 61))	('Akt', 'Gene', (78, 81))	('p130CAS', 'Gene', '9564', (62, 69))	('Akt', 'Gene', '207', (121, 124))	('survival', 'CPA', (37, 45))
73205	23936469	Our in vivo studies in which GBM cells expressing DN-Lyn were propagated in the nude mouse brain showed a significant reduction in tumor size that was associated with increased tumor cell death, suggesting Lyn is important for tumor survival in vivo.	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('reduction', 'NegReg', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (131, 136))	('increased', 'PosReg', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('DN-Lyn', 'Var', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
73213	23936469	Hydroxychloroquine, an inhibitor of autophagy, has been entered into a phase II clinical trial involving patients with multiple types of cancer including GBM (reviewed in), and blockade of autophagy has been shown to result in the sensitization of prostate cancer cells, multi-drug resistant v-Ha-ras transformed NIH-3T3 cells and other cells to a SFK inhibitor in nutrient-rich conditions.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('blockade', 'Var', (177, 185))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Hydroxychloroquine', 'Chemical', 'MESH:D006886', (0, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (248, 263))	('sensitization', 'MPA', (231, 244))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (248, 263))	('NIH-3T3', 'CellLine', 'CVCL:0594', (313, 320))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('prostate cancer', 'Disease', (248, 263))	('cancer', 'Disease', (257, 263))	('autophagy', 'CPA', (189, 198))
73218	23533263	De-repression of PDGFRbeta transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy.	('PDGFRbeta', 'Gene', (17, 26))	('De-repression', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('EGFR', 'Gene', '1956', (73, 77))	('cancer', 'Disease', (232, 238))	('EGFR', 'Gene', (73, 77))	('promotes', 'PosReg', (41, 49))	('PDGFRbeta', 'Gene', '5159', (17, 26))	('tyrosine', 'Chemical', 'MESH:D014443', (78, 86))	('tyrosine', 'Chemical', 'MESH:D014443', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('glioblastoma', 'Disease', (108, 120))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
73221	23533263	Here we demonstrate the first example of this alternate mechanism in brain tumors by showing that EGFR-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing PDGFRbeta.	('PDGFRbeta', 'Gene', (182, 191))	('de-repressing', 'NegReg', (168, 181))	('glioblastomas', 'Disease', (110, 123))	('glioblastomas', 'Disease', 'MESH:D005909', (110, 123))	('evade', 'NegReg', (131, 136))	('brain tumors', 'Phenotype', 'HP:0030692', (69, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('glioblastomas', 'Phenotype', 'HP:0012174', (110, 123))	('EGFR-mutant', 'Var', (98, 109))	('brain tumors', 'Disease', 'MESH:D001932', (69, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))	('EGFR-mutant', 'Gene', (98, 109))	('brain tumors', 'Disease', (69, 81))
73225	23533263	The epidermal growth factor receptor, EGFR, is commonly amplified and/or mutated in many types of solid cancer including a variety of epithelial cancers and glioblastoma (GBM).	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('mutated', 'Var', (73, 80))	('glioblastoma', 'Disease', (157, 169))	('epithelial cancers', 'Disease', 'MESH:D000077216', (134, 152))	('epidermal growth factor receptor', 'Gene', (4, 36))	('EGFR', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('glioblastoma', 'Disease', 'MESH:D005909', (157, 169))	('epithelial cancers', 'Disease', (134, 152))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('epidermal growth factor receptor', 'Gene', '1956', (4, 36))	('solid cancer', 'Disease', 'MESH:D009369', (98, 110))	('solid cancer', 'Disease', (98, 110))
73227	23533263	Multiple genetic resistance mechanisms enable cancer cells to maintain signal flux to critical downstream effector pathways, and thus evade EGFR-targeted therapy, including: 1) acquisition and/or selection for secondary EGFR mutations conferring EGFR TKI-resistance; 2) additional activating mutations in downstream effectors like PTEN, PIK3CA or KRAS, and 3) co-occurrence of other amplified or mutated RTKs, including C-MET and PDGFRalpha.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('KRAS', 'Gene', (347, 351))	('PTEN', 'Gene', (331, 335))	('PIK3CA', 'Gene', (337, 343))	('PDGFRalpha', 'Gene', '5156', (430, 440))	('PTEN', 'Gene', '5728', (331, 335))	('C-MET', 'Gene', '4233', (420, 425))	('mutations', 'Var', (292, 301))	('cancer', 'Disease', (46, 52))	('RTK', 'Gene', (404, 407))	('co-occurrence', 'Reg', (360, 373))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PIK3CA', 'Gene', '5290', (337, 343))	('activating', 'PosReg', (281, 291))	('RTK', 'Gene', '13867', (404, 407))	('EGFR', 'Gene', (220, 224))	('mutations', 'Var', (225, 234))	('KRAS', 'Gene', '3845', (347, 351))	('PDGFRalpha', 'Gene', (430, 440))	('C-MET', 'Gene', (420, 425))
73228	23533263	In addition to these genetic resistance-promoting mutations, it is suspected that EGFR-dependent cancers may escape targeted therapy by developing dependence on other non-amplified, non-mutated RTKs.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('EGFR-dependent', 'Gene', (82, 96))	('cancers', 'Disease', (97, 104))	('RTK', 'Gene', '13867', (194, 197))	('mutations', 'Var', (50, 59))	('RTK', 'Gene', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('dependence', 'MPA', (147, 157))
73230	23533263	Herein, we integrate studies in cell lines, patient-derived tumor cultures, xenotransplants, and tumor tissue from GBM patients in a phase II clinical trial to provide the first demonstration of EGFR TKI resistance mediated by transcriptional de-repression of PDGFRbeta.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('clinical', 'Species', '191496', (142, 150))	('patient', 'Species', '9606', (119, 126))	('patient', 'Species', '9606', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('EGFR', 'Var', (195, 199))	('tumor', 'Disease', (60, 65))	('de-repression', 'NegReg', (243, 256))	('PDGFRbeta', 'Gene', (260, 269))
73234	23533263	To better understand how malignant glioma acquires resistance to EGFR inhibitors in vivo, U87 glioma cells expressing the EGFRvIII gain-of-function mutation (designated U87-EGFRvIII herein) were placed in the flank of SCID mice.	('SCID', 'Disease', 'MESH:D053632', (218, 222))	('glioma', 'Disease', (94, 100))	('SCID', 'Disease', (218, 222))	('mice', 'Species', '10090', (223, 227))	('glioma', 'Disease', 'MESH:D005910', (35, 41))	('gain-of-function', 'PosReg', (131, 147))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (35, 41))	('malignant glioma', 'Disease', 'MESH:D005910', (25, 41))	('EGFRvIII', 'Gene', (122, 130))	('mutation', 'Var', (148, 156))	('malignant glioma', 'Disease', (25, 41))	('glioma', 'Disease', (35, 41))
73254	23533263	Taken together, these data indicate that EGFRvIII/EGFR signaling negatively regulates PDGFRbeta expression in glioma models, and that inhibition of EGFRvIII/EGFR signaling results in upregulation of PDGFRbeta.	('upregulation', 'PosReg', (183, 195))	('PDGFRbeta', 'Gene', (86, 95))	('glioma', 'Disease', (110, 116))	('negatively', 'NegReg', (65, 75))	('inhibition', 'Var', (134, 144))	('expression', 'MPA', (96, 106))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('regulates', 'Reg', (76, 85))	('PDGFRbeta', 'Gene', (199, 208))
73261	23533263	These clinical data support a model where highly active EGFR signaling negatively regulates PDGFRbeta expression in primary brain tumors, and indicates that pharmacologic inhibition of EGFR signaling results in an RTK switch to PDGFRbeta.	('results in', 'Reg', (200, 210))	('inhibition', 'Var', (171, 181))	('regulates', 'Reg', (82, 91))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('RTK', 'Gene', '13867', (214, 217))	('expression', 'MPA', (102, 112))	('RTK', 'Gene', (214, 217))	('PDGFRbeta', 'Gene', (92, 101))	('negatively', 'NegReg', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('brain tumors', 'Phenotype', 'HP:0030692', (124, 136))	('brain tumors', 'Disease', 'MESH:D001932', (124, 136))	('brain tumors', 'Disease', (124, 136))	('clinical', 'Species', '191496', (6, 14))
73262	23533263	EGFRvIII, and to a lesser extent wild-type EGFR, have been shown to potently activate PI3K signaling in GBM, resulting in phosphorylation of AKT and its downstream effector mTORC1.	('activate', 'PosReg', (77, 85))	('mTORC1', 'Gene', (173, 179))	('phosphorylation', 'MPA', (122, 137))	('PI3K signaling', 'Pathway', (86, 100))	('mTORC1', 'Gene', '382056', (173, 179))	('EGFRvIII', 'Var', (0, 8))	('AKT', 'Pathway', (141, 144))
73264	23533263	To examine whether EGFRvIII suppresses PDGFRbeta through AKT, U87-EGFRvIII cells were transfected with the constitutively active AKT1 E17K allele.	('E17K', 'Var', (134, 138))	('suppresses', 'NegReg', (28, 38))	('PDGFRbeta', 'Gene', (39, 48))	('AKT1', 'Gene', '207', (129, 133))	('E17K', 'Mutation', 'rs121434592', (134, 138))	('AKT1', 'Gene', (129, 133))
73265	23533263	Ectopic expression of AKT1 E17K fully abrogated the upregulation of PDGFRbeta in response to erlotinib, confirming that EGFRvIII suppresses PDGFRbeta through AKT (Fig.	('erlotinib', 'Chemical', 'MESH:D000069347', (93, 102))	('AKT1', 'Gene', '207', (22, 26))	('E17K', 'Var', (27, 31))	('suppresses', 'NegReg', (129, 139))	('AKT', 'Pathway', (158, 161))	('response to erlotinib', 'MPA', (81, 102))	('E17K', 'Mutation', 'rs121434592', (27, 31))	('abrogated', 'NegReg', (38, 47))	('PDGFRbeta', 'Gene', (140, 149))	('PDGFRbeta', 'Gene', (68, 77))	('AKT1', 'Gene', (22, 26))
73268	23533263	Immunoblot analysis of U87-EGFRvIII cells transiently transfected with siRNA targeting the mTORC proteins, Raptor and Rictor, indicated that inhibition of mTORC1, and to a lesser extent mTORC2, led to increased levels of PDGFRbeta expression (Fig.	('increased', 'PosReg', (201, 210))	('mTORC proteins, Raptor and Rictor', 'Gene', '74370;78757', (91, 124))	('inhibition', 'Var', (141, 151))	('mTORC1', 'Gene', '382056', (155, 161))	('PDGFRbeta expression', 'MPA', (221, 241))	('mTORC2', 'Gene', (186, 192))	('mTORC1', 'Gene', (155, 161))	('mTORC2', 'Gene', '74343', (186, 192))
73269	23533263	Conversely, transfection of a constitutively active mTOR (S2215Y) allele abrogated erlotinib-dependent upregulation of PDGFRbeta (Fig.	('upregulation', 'PosReg', (103, 115))	('abrogated', 'NegReg', (73, 82))	('S2215Y', 'Mutation', 'rs587777894', (58, 64))	('erlotinib-dependent', 'MPA', (83, 102))	('S2215Y', 'Var', (58, 64))	('erlotinib', 'Chemical', 'MESH:D000069347', (83, 92))	('PDGFRbeta', 'Gene', (119, 128))
73270	23533263	Further, genetic depletion of the mTORC1 effector p70 S6Kinase by siRNA knockdown similarly upregulated PDGFRbeta (Fig.	('upregulated', 'PosReg', (92, 103))	('mTORC1', 'Gene', '382056', (34, 40))	('PDGFRbeta', 'Gene', (104, 113))	('mTORC1', 'Gene', (34, 40))	('genetic depletion', 'Var', (9, 26))	('siRNA', 'Gene', (66, 71))	('knockdown', 'Var', (72, 81))
73276	23533263	Correspondingly, transcriptional reporter studies using the PDGFRbeta promoter upstream of luciferase indicated that knockdown of EGFR or Raptor significantly increased luciferase activity in U87-EGFRvIII cells (Fig.	('luciferase', 'Enzyme', (169, 179))	('activity', 'MPA', (180, 188))	('increased', 'PosReg', (159, 168))	('Raptor', 'Gene', (138, 144))	('Raptor', 'Gene', '57521', (138, 144))	('EGFR', 'Gene', (130, 134))	('knockdown', 'Var', (117, 126))
73280	23533263	The MEK inhibitor U0126 upregulated PDGFRbeta expression, although to a lesser extent than erlotinib (Fig.	('U0126', 'Chemical', 'MESH:C113580', (18, 23))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('erlotinib', 'Chemical', 'MESH:D000069347', (91, 100))	('U0126', 'Var', (18, 23))	('PDGFRbeta', 'Gene', (36, 45))	('upregulated', 'PosReg', (24, 35))	('expression', 'MPA', (46, 56))
73293	23533263	Next, we asked whether PDGFRbeta signaling was required for tumor growth in vivo in GBM cells expressing EGFRvIII, and whether abrogation of EGFRvIII rendered these tumor cells PDGFRbeta-dependent.	('EGFRvIII', 'Gene', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('abrogation', 'Var', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (165, 170))
73295	23533263	Consistent with our in vitro studies, silencing of PDGFRbeta had little effect on U87-EGFRvIII tumor growth (Fig.	('PDGFRbeta', 'Gene', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('silencing', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
73296	23533263	In contrast, silencing PDGFRbeta significantly attenuated the growth of tumors expressing kinase dead-EGFRvIII (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('growth', 'CPA', (62, 68))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('PDGFRbeta', 'Gene', (23, 32))	('attenuated', 'NegReg', (47, 57))	('silencing', 'Var', (13, 22))
73299	23533263	The PDGFR kinase inhibitor AG1295 (2muM) alone had no anti-proliferative effect on GBM39 (EGFRvIII positive, PTEN intact), or HK250 (high level wild-type EGFR, PTEN deficient) cells (Fig.	('anti-proliferative effect', 'MPA', (54, 79))	('PTEN', 'Gene', (160, 164))	('PTEN', 'Gene', '5728', (160, 164))	('PTEN', 'Gene', (109, 113))	('PTEN', 'Gene', '5728', (109, 113))	('PDGFR', 'Gene', (4, 9))	('AG1295', 'Chemical', 'MESH:C407689', (27, 33))	('PDGFR', 'Gene', '5159', (4, 9))	('AG1295', 'Var', (27, 33))
73303	23533263	Acquired drug resistance presents a significant challenge for personalized cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Acquired', 'Var', (0, 8))	('drug resistance', 'Phenotype', 'HP:0020174', (9, 24))
73304	23533263	In principle, upfront sequencing may guide successful combination TKI therapy by defining both the drugable kinase mutations, and the potential "seeds" of resistance - second site mutations, downstream effector mutations and co-amplification of multiple RTKs.	('RTK', 'Gene', (254, 257))	('mutations', 'Var', (115, 124))	('RTK', 'Gene', '13867', (254, 257))	('mutations', 'Var', (180, 189))
73308	23533263	In colorectal cancer cells bearing the BRAF v600E mutation, resistance to the BRAF inhibitor PLX-4032 (vemurafenib) is mediated by reactivation of EGFR signaling through the MAPK pathway, although upregulation of EGFR itself does not appear to be involved.	('v600E', 'Var', (44, 49))	('BRAF', 'Gene', '673', (78, 82))	('MAPK', 'Gene', (174, 178))	('BRAF', 'Gene', '673', (39, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('reactivation', 'PosReg', (131, 143))	('BRAF', 'Gene', (39, 43))	('BRAF', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('vemurafenib', 'Chemical', 'MESH:D000077484', (103, 114))	('colorectal cancer', 'Disease', (3, 20))	('EGFR signaling', 'MPA', (147, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('PLX-4032', 'Chemical', 'MESH:D000077484', (93, 101))	('MAPK', 'Gene', '5594', (174, 178))
73309	23533263	In breast cancer cells, AKT and mTOR inhibition reactivates PI3K signaling through release of an inhibitory feedback loop in a process that appears to involve multiple RTKs.	('PI3K signaling', 'Pathway', (60, 74))	('inhibition', 'Var', (37, 47))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('reactivates', 'MPA', (48, 59))	('mTOR', 'Protein', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('RTK', 'Gene', '13867', (168, 171))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('release of an inhibitory feedback loop', 'MPA', (83, 121))	('AKT', 'Pathway', (24, 27))	('RTK', 'Gene', (168, 171))
73321	23533263	Our data definitively demonstrate that EGFR inhibitors de-repress PDGFRbeta transcription, providing a potent mechanism underlying RTK switching.	('RTK', 'Gene', '13867', (131, 134))	('PDGFRbeta', 'Gene', (66, 75))	('inhibitors', 'Var', (44, 54))	('RTK', 'Gene', (131, 134))	('transcription', 'MPA', (76, 89))	('de-repress', 'NegReg', (55, 65))
73324	23533263	Here, we have identified a transcriptional repressive mechanism by which EGFRvIII regulates PDGFRbeta; shown that EGFR-inhibited GBMs become PDGFRbeta-dependent for survival through mTOR-dependent transcriptional de-repression; and demonstrated that abrogation of EGFRvIII and PDGFRbeta stop tumor growth, providing strong rationale for combination therapy.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('regulates', 'Reg', (82, 91))	('PDGFRbeta stop tumor', 'Disease', 'MESH:D009369', (277, 297))	('de-repression', 'NegReg', (213, 226))	('abrogation', 'Var', (250, 260))	('PDGFRbeta stop tumor', 'Disease', (277, 297))	('PDGFRbeta', 'Gene', (92, 101))	('EGFRvIII', 'Gene', (264, 272))
73340	23533263	Transient knockdown of EGFRvIII, S6K1, Raptor, and Rictor (Ambion) were performed as follows.	('S6K1, Raptor, and Rictor', 'Gene', '6198;57521;253260', (33, 57))	('knockdown', 'Var', (10, 19))	('EGFRvIII', 'Gene', (23, 31))
73343	23533263	Plasmids used were pcDNA control, wildtype mTOR, mTOR S2215Y, and AKT E17K (mTOR constructs were a gift from Fuyu Tamanoi, E17K was a gift from Ingo Mellinghoff, pcDNA control was from Addgene).	('E17K', 'Var', (123, 127))	('S2215Y', 'Mutation', 'rs587777894', (54, 60))	('E17K', 'Mutation', 'rs121434592', (70, 74))	('S2215Y', 'Var', (54, 60))	('E17K', 'Mutation', 'rs121434592', (123, 127))
73350	23533263	Plasmids used were pcDNA control, EES6K1 and T412D/T401D S6K1/2 (S6 kinase plasmids were a gift from Ivan Gout) Cultured cells or snap-frozen tissue samples were lysed and homogenized with RIPA buffer (buffer, Boston Bioproducts; protease and phosphatase inhibitor, Thermoscientific).	('S6K1', 'Gene', (36, 40))	('S6K1', 'Gene', '6198', (36, 40))	('T401D', 'Var', (51, 56))	('S6K1/2', 'Gene', '6198;6199', (57, 63))	('T401D', 'SUBSTITUTION', 'None', (51, 56))	('T412D', 'SUBSTITUTION', 'None', (45, 50))	('S6K1', 'Gene', '6198', (57, 61))	('Gout', 'Phenotype', 'HP:0001997', (106, 110))	('T412D', 'Var', (45, 50))	('RIPA buffer', 'Chemical', '-', (189, 200))	('S6K1', 'Gene', (57, 61))	('S6K1/2', 'Gene', (57, 63))
73353	23533263	Antibodies used in the study include p-EGFR1086 (Epitomics), p-EGFR1068, p-AKT473, p-AKTT308, AKT, p-S6Ser235/236, p-PDGFRbetaY751, p-ERKT202/Y204, ERK, p-MetY1234, p-S6K1T389, S6K1, PathScan cocktail, p-NDRG1T346, beta-actin, PDGFRbeta, PDGFRalpha (Cell Signaling), alpha-tubulin (Sigma); EGFR (Upstate).	('PDGFRbeta', 'Gene', (227, 236))	('ERK', 'Gene', (148, 151))	('p-AKT473', 'Var', (73, 81))	('p-MetY1234', 'Var', (153, 163))	('alpha-tubulin (Sigma', 'Gene', (267, 287))	('p-NDRG1T346', 'Var', (202, 213))	('beta-actin', 'Gene', '728378', (215, 225))	('PDGFRalpha', 'Gene', '5156', (238, 248))	('S6K1', 'Gene', (177, 181))	('S6K1', 'Gene', (167, 171))	('p-EGFR1086', 'Var', (37, 47))	('p-S6Ser235/236', 'Var', (99, 113))	('p-EGFR1068', 'Var', (61, 71))	('p-AKTT308', 'Var', (83, 92))	('ERK', 'Gene', '5594', (134, 137))	('ERK', 'Gene', '5594', (148, 151))	('S6K1', 'Gene', '6198', (177, 181))	('S6K1', 'Gene', '6198', (167, 171))	('beta-actin', 'Gene', (215, 225))	('p-PDGFRbetaY751', 'Var', (115, 130))	('alpha-tubulin (Sigma)', 'Gene', '10376', (267, 288))	('PDGFRalpha', 'Gene', (238, 248))	('ERK', 'Gene', (134, 137))
73364	23533263	Tissue microarrays (TMAs) were used to analyze PDGFRbeta and p-EGFR Tyr1086 immunohistochemical staining in 140 GBM patient samples.	('Tyr1086', 'Var', (68, 75))	('patient', 'Species', '9606', (116, 123))	('TMAs', 'Chemical', '-', (20, 24))	('PDGFRbeta', 'Gene', (47, 56))	('Tyr1086', 'Chemical', '-', (68, 75))
73366	23533263	These cores were placed in a grid pattern into two recipient paraffin blocks, from which tissue sections were cut for immunohistochemical analysis of p-EGFR Y1086 and PDGFRbeta.	('PDGFRbeta', 'Gene', (167, 176))	('paraffin', 'Chemical', 'MESH:D010232', (61, 69))	('p-EGFR Y1086', 'Var', (150, 162))
73380	23533263	The following day, media was changed to serum-free media (U0126), 2% FBS-containing media (U87EGFRvIII, PHA 665752), or DMEM/F12 (GBM39, PHA 665752).	('U87EGFRvIII', 'Var', (91, 102))	('DMEM/F12', 'Gene', '2161', (120, 128))	('DMEM/F12', 'Gene', (120, 128))	('U0126', 'Var', (58, 63))	('U0126', 'Chemical', 'MESH:C113580', (58, 63))
73409	23467584	Although new studies have revealed additional unexpected heterogeneity of severe combined immunodeficiency leukemia-initiating cells, CD34-, Lin+, CD38+, and CD45RA+ fractions have the capacity to form xenografted tumors.	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('CD38', 'Gene', '952', (147, 151))	('immunodeficiency', 'Phenotype', 'HP:0002721', (90, 106))	('CD45RA+', 'Var', (158, 165))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (81, 106))	('CD34', 'Gene', (134, 138))	('CD34', 'Gene', '947', (134, 138))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('immunodeficiency leukemia', 'Disease', (90, 115))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (74, 106))	('immunodeficiency leukemia', 'Disease', 'MESH:D007938', (90, 115))	('CD38', 'Gene', (147, 151))
73432	23467584	Further, a previous report showed that the hedgehog pathway is associated with NF-kB signaling, indicating that sonic hedgehog might be activated by the transcription factor NF-kB.	('sonic hedgehog', 'Gene', '6469', (112, 126))	('sonic hedgehog', 'Gene', (112, 126))	('NF-kB', 'Var', (174, 179))	('activated', 'PosReg', (136, 145))
73445	23467584	Furthermore, Oct1 knockdown specifically decreases the number of SP cells among A549 cells.	('knockdown', 'Var', (18, 27))	('SP', 'Chemical', '-', (65, 67))	('decreases', 'NegReg', (41, 50))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('Oct1', 'Gene', (13, 17))	('Oct1', 'Gene', '5451', (13, 17))
73450	23467584	In a third model of acquired resistance, drug-resistant variants of CSCs or their close descendants arise, which produce a population of DNA-repairing tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CSCs', 'Gene', (68, 72))	('tumor', 'Disease', (151, 156))	('produce', 'Reg', (113, 120))	('variants', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
73510	23467584	As such, disruption of the cross-talk between CSCs and their niches is an attractive approach for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cross-talk', 'Interaction', (27, 37))	('cancer', 'Disease', (98, 104))	('disruption', 'Var', (9, 19))
73560	33976938	Taken together, it can be concluded that the inhibitors of the SP/NK1R system, such as aprepitant, might be considered as a part of therapeutic protocols in patients with glioblastoma multiforme.	('inhibitors', 'Var', (45, 55))	('glioblastoma multiforme', 'Disease', (171, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (171, 183))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (171, 194))
73570	31766326	Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003).	('T2-dominant', 'Var', (54, 65))	('better', 'PosReg', (28, 34))	('patients', 'Species', '9606', (38, 46))	('Median OS', 'CPA', (0, 9))
73585	31766326	Additionally, we describe distinct MRI alterations that might correlate with a survival benefit in patients undergoing REG treatment.	('survival benefit', 'CPA', (79, 95))	('REG', 'Chemical', 'MESH:C559147', (119, 122))	('patients', 'Species', '9606', (99, 107))	('alterations', 'Var', (39, 50))	('MRI alterations', 'Var', (35, 50))
73684	31766326	However, those patients with a T2-dominant growth pattern showed a significantly better median OS of 27 weeks from initiation of REG treatment in contrast to patients with classic PD that had a median OS of 10 weeks (p = 0.003) (Figure 3).	('REG', 'Chemical', 'MESH:C559147', (129, 132))	('patients', 'Species', '9606', (15, 23))	('better', 'PosReg', (81, 87))	('T2-dominant', 'Var', (31, 42))	('patients', 'Species', '9606', (158, 166))
73685	31766326	This effect was still detectable when excluding the patient with the 1p19q co-deleted oligodendroglioma.	('1p19q co-deleted', 'Var', (69, 85))	('oligodendroglioma', 'Disease', (86, 103))	('oligodendroglioma', 'Disease', 'MESH:D009837', (86, 103))	('patient', 'Species', '9606', (52, 59))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
73758	31750250	The new standards required the presence of both IDH-mt and 1p19q co-deletion for the diagnosis of AO, otherwise it could only be regarded as NOS (Not Otherwise Specified).	('AO', 'Disease', 'MESH:D009837', (98, 100))	('IDH', 'Gene', '3417', (48, 51))	('IDH', 'Gene', (48, 51))	('1p19q co-deletion', 'Var', (59, 76))
73825	31508371	The 1p/19q co-deletion is a molecular signature of oligodendroglial tumors and a predictive marker for the response of anaplastic gliomas to vincristine (PCV) chemotherapy.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('gliomas', 'Disease', 'MESH:D005910', (130, 137))	('1p/19q co-deletion', 'Var', (4, 22))	('gliomas', 'Disease', (130, 137))	('vincristine', 'Chemical', 'MESH:D014750', (141, 152))	('gliomas', 'Phenotype', 'HP:0009733', (130, 137))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (51, 74))	('oligodendroglial tumors', 'Disease', (51, 74))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))
73826	31508371	High WT-1 expression is significantly associated with worse outcomes in diffuse astrocytic tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('High', 'Var', (0, 4))	('WT-1', 'Gene', '7490', (5, 9))	('astrocytic tumors', 'Disease', (80, 97))	('astrocytic tumors', 'Disease', 'MESH:D001254', (80, 97))	('WT-1', 'Gene', (5, 9))
73827	31508371	IDH1/IDH2 mutations have a strong favorable prognostic value across all glioma histopathological grades.	('glioma', 'Disease', (72, 78))	('IDH2', 'Gene', (5, 9))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('IDH2', 'Gene', '3418', (5, 9))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('IDH1', 'Gene', '3417', (0, 4))
73858	31508371	Due to the lack of IDH1 mutation information in the REMBRANDT cohorts, the calibration curves for the 1- and 3-year OS rates were well-predicted in only the TCGA and GSE16011 cohorts (C-index: 0.65 for the TCGA cohort and 0.68 for the GSE16011 cohort; Figures 5C,D).	('IDH1', 'Gene', (19, 23))	('GS', 'Disease', 'MESH:D011125', (166, 168))	('GS', 'Disease', 'MESH:D011125', (235, 237))	('IDH1', 'Gene', '3417', (19, 23))	('mutation', 'Var', (24, 32))
73869	31508371	In low-grade gliomas, the presence of activated MAPK was also a predictor of favorable patient outcome, regardless of fusion or hotspot mutation events.	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('activated MAPK', 'Protein', (38, 52))	('presence', 'Var', (26, 34))	('patient', 'Species', '9606', (87, 94))	('gliomas', 'Disease', (13, 20))	('gliomas', 'Disease', 'MESH:D005910', (13, 20))	('gliomas', 'Phenotype', 'HP:0009733', (13, 20))
73875	31508371	Additionally, anti-CLEC5A mAb could repair the blood-brain barrier, attenuate neuroinflammation, and protect mice from JEV-induced lethality.	('anti-CLEC5A', 'Var', (14, 25))	('protect', 'Reg', (101, 108))	('attenuate neuroinflammation', 'Disease', (68, 95))	('attenuate neuroinflammation', 'Disease', 'MESH:C538265', (68, 95))	('JEV', 'Species', '11072', (119, 122))	('mice', 'Species', '10090', (109, 113))
73890	31508371	By constructing a Cox proportional hazards regression model, four genes were finally identified and used in univariate and multivariate Cox analyses, thereby composing a four-gene module with the risk score = (0.00889 x EXPCLEC5A) + (0.0681 x EXPFMOD) + (0.1724 x EXPFKBP9) + (0.1557 x EXPLGALS8).	('Cox', 'Gene', '1351', (136, 139))	('Cox', 'Gene', (136, 139))	('Cox', 'Gene', '1351', (18, 21))	('0.00889 x', 'Var', (210, 219))	('Cox', 'Gene', (18, 21))
73902	29431617	In vitro, the ability AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKKC1 knockdown.	('knockdown', 'Var', (98, 107))	('NKKC1', 'Gene', (92, 97))	('GBM', 'Phenotype', 'HP:0012174', (35, 38))	('bumetanide', 'Chemical', 'MESH:D002034', (77, 87))	('reduce', 'NegReg', (28, 34))	('GBM cell proliferation', 'CPA', (35, 57))	('AF', 'Disease', 'MESH:D001281', (22, 24))
73905	29431617	Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM.	('increase', 'PosReg', (86, 94))	('GBM', 'Phenotype', 'HP:0012174', (130, 133))	('AF', 'Disease', 'MESH:D001281', (6, 8))	('outcome', 'MPA', (119, 126))	('inhibition', 'Var', (18, 28))	('drug uptake', 'MPA', (95, 106))	('improve', 'PosReg', (111, 118))	('GBM', 'Disease', (130, 133))
73931	29431617	Using a compression force bioreactor, we show that AF peptide, bumetanide, and NKCC1 knockdown blocked compression-induced proliferation of GBM tumorspheres.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('bumetanide', 'Chemical', 'MESH:D002034', (63, 73))	('blocked', 'NegReg', (95, 102))	('AF', 'Disease', 'MESH:D001281', (51, 53))	('GBM tumorspheres', 'Disease', (140, 156))	('NKCC1', 'Gene', (79, 84))	('GBM tumorspheres', 'Disease', 'MESH:D005910', (140, 156))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('knockdown', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
73999	29431617	Briefly, cells on coverslips either coated with poly-L-lysine (50 mug/ml) (GC22) or polyornithine (50 mug/ml) and laminin (5 mug/ml) (GBM43) were incubated with 0.5 muM calcein-AM for 30 min at 37 C. The cells were placed in a heated (37 C) imaging chamber (Warner Instruments) on a Nikon Ti Eclipse inverted epifluorescence microscope equipped with perfect focus, a 40x Super Fluor oil immersion objective lens, and a Princeton Instruments MicroMax CCD camera.	('muM', 'Gene', '56925', (165, 168))	('calcein-AM', 'Chemical', 'MESH:C085925', (169, 179))	('muM', 'Gene', (165, 168))	('polyornithine', 'Chemical', 'MESH:C008973', (84, 97))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('polyornithine', 'Var', (84, 97))	('GC22', 'CellLine', 'CVCL:8872', (75, 79))	('poly-L-lysine', 'Var', (48, 61))
74005	29431617	Clophensor can uniquely compensate for pH changes that are known to influence chloride levels.	('influence', 'Reg', (68, 77))	('chloride', 'Chemical', 'MESH:D002712', (78, 86))	('changes', 'Var', (42, 49))	('chloride levels', 'MPA', (78, 93))
74021	29431617	Administration of SPC diet suppressed IFP levels compared to animals administered control diet (Fig.	('IFP levels', 'MPA', (38, 48))	('SPC', 'Chemical', '-', (18, 21))	('suppressed', 'NegReg', (27, 37))	('SPC diet', 'Var', (18, 26))
74039	29431617	In contrast to mesenchymal GBM43 tumors that display NF1 mutations, proliferative GBM6 tumors express EGFRvIII.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('NF1', 'Gene', (53, 56))	('GBM', 'Phenotype', 'HP:0012174', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('GBM', 'Phenotype', 'HP:0012174', (27, 30))	('mutations', 'Var', (57, 66))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('NF1', 'Gene', '18015', (53, 56))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', (33, 39))	('EGFR', 'Gene', (102, 106))	('EGFR', 'Gene', '13649', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
74051	29431617	Using an antibody that recognizes residues 198-217 of human NKCC1, including the Thr203, Thr207, and Thr212 phosphorylation sites, we found reduced immunoreactivity in tumor cells of SPC treated GBM43 xenografts (Fig.	('human', 'Species', '9606', (54, 59))	('immunoreactivity', 'MPA', (148, 164))	('NKCC1', 'Gene', (60, 65))	('tumor', 'Disease', (168, 173))	('Thr212', 'Var', (101, 107))	('Thr203', 'Chemical', '-', (81, 87))	('SPC', 'Chemical', '-', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('GBM', 'Phenotype', 'HP:0012174', (195, 198))	('Thr207', 'Chemical', '-', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Thr212', 'Chemical', '-', (101, 107))	('reduced', 'NegReg', (140, 147))
74065	29431617	Similarly, shRNA-mediated knockdown of NKCC1 or the FDA-approved NKCC1 inhibitor bumetanide restored compression-induced expansion of GBM tumorspheres (Fig.	('compression-induced expansion', 'CPA', (101, 130))	('GBM tumorspheres', 'Disease', (134, 150))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('GBM tumorspheres', 'Disease', 'MESH:D005910', (134, 150))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('knockdown', 'Var', (26, 35))	('bumetanide', 'Chemical', 'MESH:D002034', (81, 91))	('restored', 'PosReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
74087	29431617	NKCC1 knockdown or bumetanide treatment inhibits GABAAR-induced depolarization and reduced proliferation of neural progenitors.	('reduced', 'NegReg', (83, 90))	('GABAAR-induced depolarization', 'MPA', (49, 78))	('NKCC1', 'Gene', (0, 5))	('GABA', 'Chemical', 'MESH:D005680', (49, 53))	('bumetanide', 'Chemical', 'MESH:D002034', (19, 29))	('inhibits', 'NegReg', (40, 48))	('proliferation', 'CPA', (91, 104))	('knockdown', 'Var', (6, 15))
74092	29431617	Previous studies showed that NKCC1 knockdown or bumetanide-treatment disrupted migration of GBM cells.	('knockdown', 'Var', (35, 44))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('disrupted', 'NegReg', (69, 78))	('migration of GBM cells', 'CPA', (79, 101))	('bumetanide', 'Chemical', 'MESH:D002034', (48, 58))	('NKCC1', 'Gene', (29, 34))
74110	29152664	In conclusion, the results of the present study indicated the tumor suppressive role of miR-194-5p.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-194-5p', 'Var', (88, 98))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
74129	29152664	miR-194-5p was overexpressed and inhibited in vitro by transfection with miR-194-5p mimics and an miR-194-5p antisense oligonucleotide (ASO), respectively.	('oligonucleotide', 'Chemical', 'MESH:D009841', (119, 134))	('miR-194-5p', 'Gene', (73, 83))	('miR-194-5p', 'Var', (98, 108))	('ASO', 'Chemical', 'MESH:D016376', (136, 139))	('inhibited', 'NegReg', (33, 42))
74146	29152664	miR-194-5p mimics were subsequently transfected into U373 cells and the IGF-1R protein level was observed to be reduced 48 h following transfection (Fig.	('miR-194-5p', 'Var', (0, 10))	('IGF-1R', 'Gene', (72, 78))	('IGF-1R', 'Gene', '3480', (72, 78))	('reduced', 'NegReg', (112, 119))
74147	29152664	MTT analysis revealed that the miR-194-5p mimics inhibited the growth of U373 and U118 cells (Fig.	('growth', 'CPA', (63, 69))	('inhibited', 'NegReg', (49, 58))	('miR-194-5p mimics', 'Var', (31, 48))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))
74148	29152664	miR-194-5p was successfully downregulated in U373 and U118 cells by miR-194-5p ASO transfection.	('ASO', 'Chemical', 'MESH:D016376', (79, 82))	('downregulated', 'NegReg', (28, 41))	('miR-194-5p', 'Var', (68, 78))	('miR-194-5p', 'Gene', (0, 10))
74149	29152664	Cellular proliferation in the two cell lines was analyzed using the MTT assay, and it was observed that miR-194-5p ASO promoted the cellular proliferation of U373 and U118 cells (Fig.	('cellular proliferation', 'CPA', (132, 154))	('ASO', 'Chemical', 'MESH:D016376', (115, 118))	('promoted', 'PosReg', (119, 127))	('MTT', 'Chemical', 'MESH:C070243', (68, 71))	('miR-194-5p ASO', 'Var', (104, 118))
74150	29152664	miR-194-5p inhibited cellular proliferation, invasion and migration in non-small cell lung cancer by targeting forkhead box A1.	('miR-194-5p', 'Var', (0, 10))	('cellular proliferation', 'CPA', (21, 43))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('non-small cell lung cancer', 'Disease', (71, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('forkhead box A1', 'Gene', '3169', (111, 126))	('forkhead box A1', 'Gene', (111, 126))	('invasion', 'CPA', (45, 53))	('inhibited', 'NegReg', (11, 20))	('targeting', 'Reg', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('migration', 'CPA', (58, 67))
74154	29152664	It was hypothesized that overexpression of miR-194-5p may inhibit tumor cell growth and promote cell apoptosis, and that inhibition of IGF1R may promote the effect of the macrophage-targeted immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('promote', 'PosReg', (145, 152))	('tumor', 'Disease', (66, 71))	('promote', 'PosReg', (88, 95))	('inhibition', 'Var', (121, 131))	('miR-194-5p', 'Var', (43, 53))	('cell apoptosis', 'CPA', (96, 110))	('inhibit', 'NegReg', (58, 65))	('macrophage-targeted immunotherapy', 'CPA', (171, 204))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('overexpression', 'PosReg', (25, 39))	('IGF1R', 'Gene', (135, 140))
74173	28481241	When using pSMAD2 as a marker for TGF-beta signaling activation in glioblastoma patients, it appears that patients with high pSMAD2 expression have more aggressive and treatment-resistant tumors associated with low overall survival (OS).	('OS', 'Chemical', '-', (233, 235))	('patients', 'Species', '9606', (80, 88))	('high', 'Var', (120, 124))	('overall survival', 'MPA', (215, 231))	('aggressive', 'CPA', (153, 163))	('TGF-beta', 'Gene', '7040', (34, 42))	('SMAD2', 'Gene', (12, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('TGF-beta', 'Gene', (34, 42))	('SMAD2', 'Gene', '4087', (126, 131))	('glioblastoma', 'Disease', (67, 79))	('tumors', 'Disease', (188, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('patients', 'Species', '9606', (106, 114))	('SMAD2', 'Gene', (126, 131))	('low', 'NegReg', (211, 214))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('SMAD2', 'Gene', '4087', (12, 17))
74174	28481241	Thus, inhibitors of TGF-beta signaling were postulated to improve OS by modifying tumor cell growth and restoring anti-tumor immunity.	('TGF-beta', 'Gene', (20, 28))	('OS', 'Chemical', '-', (66, 68))	('tumor', 'Disease', (119, 124))	('restoring', 'PosReg', (104, 113))	('modifying', 'Reg', (72, 81))	('improve', 'PosReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibitors', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('TGF-beta', 'Gene', '7040', (20, 28))	('tumor', 'Disease', (82, 87))
74175	28481241	The small molecule inhibitor (SMI) galunisertib (LY2157299 monohydrate) showed anti-tumor effects in glioblastoma animal models and also in patients.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('galunisertib', 'Chemical', 'MESH:C557799', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('LY2157299 monohydrate', 'Chemical', '-', (49, 70))	('LY2157299', 'Var', (49, 58))	('tumor', 'Disease', (84, 89))	('patients', 'Species', '9606', (140, 148))	('glioblastoma', 'Disease', (101, 113))
74191	28481241	IDH1 R132H mutation was detected in eight specimens.	('IDH1', 'Gene', (0, 4))	('R132H', 'Mutation', 'rs121913500', (5, 10))	('R132H', 'Var', (5, 10))	('IDH1', 'Gene', '3417', (0, 4))
74203	28481241	Tissue CD3+ staining was greater in patients with IDH1 mutation-negative tumors compared to patients with IDH1 mutation-positive tumors (p = 0.0260).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('IDH1', 'Gene', (50, 54))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('patients', 'Species', '9606', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('greater', 'PosReg', (25, 32))	('mutation-negative', 'NegReg', (55, 72))	('IDH1', 'Gene', '3417', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patients', 'Species', '9606', (92, 100))	('mutation-negative', 'Var', (55, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('IDH1', 'Gene', (106, 110))	('tumors', 'Disease', (73, 79))	('IDH1', 'Gene', '3417', (106, 110))
74205	28481241	Additionally, plasma levels of MDC/CCL22, TGF-beta1, and CD4+ T cells were numerically higher in IDH1 positive patients compared to IDH1 negative patients (not statistically significant).	('IDH1', 'Gene', (132, 136))	('positive', 'Var', (102, 110))	('IDH1', 'Gene', (97, 101))	('CD4', 'Gene', '920', (57, 60))	('TGF-beta1', 'Gene', (42, 51))	('TGF-beta1', 'Gene', '7040', (42, 51))	('IDH1', 'Gene', '3417', (132, 136))	('IDH1', 'Gene', '3417', (97, 101))	('CCL22', 'Gene', '6367', (35, 40))	('patients', 'Species', '9606', (111, 119))	('MDC', 'Gene', (31, 34))	('MDC', 'Gene', '6367', (31, 34))	('CCL22', 'Gene', (35, 40))	('patients', 'Species', '9606', (146, 154))	('plasma levels', 'MPA', (14, 27))	('CD4', 'Gene', (57, 60))	('higher', 'PosReg', (87, 93))
74221	28481241	Genetic variants (substitutions, short insertions and deletions, and copy number alterations) across 287 cancer related genes were identified for 70 tumor samples (~45% of the patients).	('patients', 'Species', '9606', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('copy number alterations', 'Var', (69, 92))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('deletions', 'Var', (54, 63))
74224	28481241	For example, epidermal growth factor receptor (EGFR) amplification/mutation was observed in 32 tumors (46%), CDKN2A deletion detected in 39 (56%), and cyclin-dependent kinase-4 (CDK4) amplification in 10 (14%).	('epidermal growth factor receptor', 'Gene', (13, 45))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('CDKN2A', 'Gene', (109, 115))	('amplification/mutation', 'Var', (53, 75))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('deletion', 'Var', (116, 124))	('cyclin-dependent kinase-4', 'Gene', (151, 176))	('CDKN2A', 'Gene', '1029', (109, 115))	('cyclin-dependent kinase-4', 'Gene', '1019', (151, 176))	('EGFR', 'Gene', '1956', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CDK4', 'Gene', '1019', (178, 182))	('CDK4', 'Gene', (178, 182))	('tumors', 'Disease', (95, 101))	('EGFR', 'Gene', (47, 51))	('amplification/mutation', 'PosReg', (53, 75))
74225	28481241	However, in contrast with previous observations in a smaller galunisertib-treated glioblastoma patient population, genetic variants in these three genes were identified in both galunisertib responsive and non-responsive tumors.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('patient', 'Species', '9606', (95, 102))	('glioblastoma', 'Disease', (82, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('galunisertib responsive', 'MPA', (177, 200))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('identified', 'Reg', (158, 168))	('galunisertib', 'Chemical', 'MESH:C557799', (177, 189))	('galunisertib', 'Chemical', 'MESH:C557799', (61, 73))	('variants', 'Var', (123, 131))
74226	28481241	Previously, four of five IDH1 mutated tumors benefitted from galunisertib treatment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutated', 'Var', (30, 37))	('benefitted', 'PosReg', (45, 55))	('galunisertib', 'Chemical', 'MESH:C557799', (61, 73))	('IDH1', 'Gene', (25, 29))	('IDH1', 'Gene', '3417', (25, 29))
74227	28481241	Here, five of the sequenced tumors contained an IDH1 mutation.	('mutation', 'Var', (53, 61))	('IDH1', 'Gene', '3417', (48, 52))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('IDH1', 'Gene', (48, 52))	('contained', 'Reg', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
74228	28481241	These five tumors were also determined to be IDH1 mutated by IDH1 R132H IHC assessment, and an additional three IDH1 mutated tumors were identified by IHC (sequence data not available).	('IDH1', 'Gene', '3417', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('R132H', 'Var', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('IDH1', 'Gene', (112, 116))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', (11, 17))	('mutated', 'Var', (50, 57))	('IDH1', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('R132H', 'Mutation', 'rs121913500', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1', 'Gene', (45, 49))	('IDH1', 'Gene', '3417', (112, 116))
74239	28481241	In tumor tissue, the presence of CD3+ T cells in the parenchyma appeared to be numerically associated with reduced survival but were not statistically significant.	('tumor', 'Disease', (3, 8))	('reduced', 'NegReg', (107, 114))	('CD3+ T cells', 'Var', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('survival', 'CPA', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
74241	28481241	The association of tumor-infiltrating CD3+ T cells with poor survival is different from other reports in which CD3+ tumor-infiltrating lymphocytes (TILs) are associated with improved OS, such as colorectal.	('CD3+', 'Var', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('colorectal', 'Disease', 'MESH:D015179', (195, 205))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('OS', 'Chemical', '-', (183, 185))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (19, 24))	('colorectal', 'Disease', (195, 205))	('tumor', 'Disease', (116, 121))
74242	28481241	However, for glioblastoma, the association between CD3+ TILs and OS is less clear and mostly reported as inconclusive.	('OS', 'Chemical', '-', (65, 67))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('CD3+ TILs', 'Var', (51, 60))
74250	28481241	Previous studies, however, found that high pSMAD2 staining was associated with poor survival, and perhaps these discrepancies may be explained by differences in staining protocols, assessment of cellular compartment (cytoplasmic versus nuclear staining), stage of tumor, and time interval since initial diagnosis.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (264, 269))	('high', 'Var', (38, 42))	('survival', 'MPA', (84, 92))	('staining', 'Var', (50, 58))	('SMAD2', 'Gene', '4087', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('poor', 'NegReg', (79, 83))	('SMAD2', 'Gene', (44, 49))
74258	28481241	In this subgroup of patients, we observed concordance (5/5) of the IDH1 R132H staining and DNA sequencing methods.	('R132H', 'Var', (72, 77))	('IDH1', 'Gene', (67, 71))	('R132H', 'Mutation', 'rs121913500', (72, 77))	('IDH1', 'Gene', '3417', (67, 71))	('patients', 'Species', '9606', (20, 28))
74280	28481241	Additional staining was performed to assess the expression of glial fibrillary acidic protein (GFAP), Ki67, isocitrate dehydrogenase 1 (IDH1), R132H, pSMAD2, and CD3.	('isocitrate dehydrogenase 1', 'Gene', '3417', (108, 134))	('R132H', 'Mutation', 'rs121913500', (143, 148))	('glial fibrillary acidic protein', 'Gene', (62, 93))	('SMAD2', 'Gene', (151, 156))	('GFAP', 'Gene', (95, 99))	('IDH1', 'Gene', (136, 140))	('CD3', 'Gene', (162, 165))	('Ki67', 'Gene', (102, 106))	('glial fibrillary acidic protein', 'Gene', '2670', (62, 93))	('SMAD2', 'Gene', '4087', (151, 156))	('IDH1', 'Gene', '3417', (136, 140))	('GFAP', 'Gene', '2670', (95, 99))	('isocitrate dehydrogenase 1', 'Gene', (108, 134))	('R132H', 'Var', (143, 148))
74292	28481241	David Capper and Andreas von Deimling report income from a patent held by the German cancer research center on an Antibody to detect R132H mutant IDH1 in fixed glioma samples, licensed to DIANOVA, Hamburg, Germany.	('IDH1', 'Gene', (146, 150))	('glioma', 'Disease', 'MESH:D005910', (160, 166))	('IDH1', 'Gene', '3417', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('glioma', 'Disease', (160, 166))	('cancer', 'Disease', (85, 91))	('Andreas von Deimling', 'Disease', (17, 37))	('R132H', 'Var', (133, 138))	('Andreas von Deimling', 'Disease', 'MESH:D014842', (17, 37))	('R132H', 'Mutation', 'rs121913500', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
74303	27119230	Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through reducing Sox2 translation.	('reducing', 'NegReg', (123, 131))	('tunicamycin', 'Chemical', 'MESH:D014415', (16, 27))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('self-renewal', 'CPA', (43, 55))	('tunicamycin', 'Var', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('suppresses', 'NegReg', (28, 38))	('glioma', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Sox2 translation', 'MPA', (132, 148))	('tumor', 'Disease', (60, 65))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
74312	27119230	Several groups have reported that tunicamycin inhibits tumor cell growth and angiogenesis and enhances tumor cell apoptosis, offering a possibility for developing a new drug regimen for treating cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('enhances', 'PosReg', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', (195, 201))	('angiogenesis', 'CPA', (77, 89))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('inhibits', 'NegReg', (46, 54))	('tumor', 'Disease', (55, 60))	('tunicamycin', 'Chemical', 'MESH:D014415', (34, 45))	('tunicamycin', 'Var', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
74323	27119230	Similarly, the rates of Brdu incorporation in T698968 and T19002 GICs were obviously reduced by tunicamycin (Figure 1L).	('T19002 GICs', 'Var', (58, 69))	('Brdu', 'Chemical', 'MESH:D001973', (24, 28))	('Brdu incorporation', 'CPA', (24, 42))	('tunicamycin', 'Chemical', 'MESH:D014415', (96, 107))	('reduced', 'NegReg', (85, 92))	('T698968', 'Var', (46, 53))
74327	27119230	Colony formation assay showed that tunicamycin substantially reduced the number of colony formed by SHG44 GICs (Figure 2A and 2B) and by T19002 GICs (Figure 2C).	('tunicamycin', 'Chemical', 'MESH:D014415', (35, 46))	('SHG44', 'Gene', (100, 105))	('reduced', 'NegReg', (61, 68))	('T19002 GICs', 'Var', (137, 148))
74329	27119230	TM-treated SHG44 GICs generated tumors with lower growth rate (Figure 2D), resulting in roughly 80-fold smaller tumor volume compared with DMSO-treated cells (Figure 2E).	('lower', 'NegReg', (44, 49))	('DMSO', 'Chemical', 'MESH:D004121', (139, 143))	('lower growth', 'Phenotype', 'HP:0001510', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('growth rate', 'MPA', (50, 61))	('GICs', 'Var', (17, 21))	('tumors', 'Disease', (32, 38))	('smaller', 'NegReg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('TM', 'Chemical', 'MESH:D014415', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('SHG44', 'Gene', (11, 16))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
74330	27119230	We further found that tunicamycin reduced the tumor-initiating potential of T698968 and T19002 GICs using intracranial tumor formation assay (Figure 2F-2H).	('tumor', 'Disease', (119, 124))	('reduced', 'NegReg', (34, 41))	('tunicamycin', 'Chemical', 'MESH:D014415', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('intracranial tumor', 'Disease', 'MESH:D001932', (106, 124))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('intracranial tumor', 'Disease', (106, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('T19002 GICs', 'Var', (88, 99))	('T698968', 'Var', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
74350	27119230	Down-regulation of Sox2 expression by tunicamycin was also observed in T698968 and T19002 GICs (Figure 4C and 4D).	('expression', 'MPA', (24, 34))	('T19002 GICs', 'Var', (83, 94))	('tunicamycin', 'Chemical', 'MESH:D014415', (38, 49))	('Down-regulation', 'NegReg', (0, 15))	('Sox2', 'Gene', (19, 23))	('T698968', 'Var', (71, 78))
74351	27119230	Furthermore, western blot analysis of xenografts resected from nude mice treated with or without tunicamycin showed that tunicamycin reduced the expression of Sox2 in vivo (Figure 4E).	('Sox2', 'Protein', (159, 163))	('nude mice', 'Species', '10090', (63, 72))	('expression', 'MPA', (145, 155))	('tunicamycin', 'Chemical', 'MESH:D014415', (121, 132))	('tunicamycin', 'Var', (121, 132))	('reduced', 'NegReg', (133, 140))	('tunicamycin', 'Chemical', 'MESH:D014415', (97, 108))
74366	27119230	Altered N-glycosylation during tumor progression promotes tumor cell growth and invasion.	('invasion', 'CPA', (80, 88))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('promotes', 'PosReg', (49, 57))	('Altered', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('N-glycosylation', 'Protein', (8, 23))	('N', 'Chemical', 'MESH:D009584', (8, 9))
74381	27119230	showed that Sox2 silencing in glioblastoma tumor-initiating cells inhibited its proliferation and tumorigenic ability.	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('proliferation', 'CPA', (80, 93))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (30, 48))	('Sox2', 'Gene', (12, 16))	('inhibited', 'NegReg', (66, 75))	('tumor', 'Disease', (98, 103))	('glioblastoma tumor', 'Disease', (30, 48))	('silencing', 'Var', (17, 26))
74382	27119230	showed that knockdown of the Sox2 gene in LN229 GBM cells reduced cell proliferation and colony formation.	('LN229', 'CellLine', 'CVCL:0393', (42, 47))	('cell proliferation', 'CPA', (66, 84))	('knockdown', 'Var', (12, 21))	('Sox2 gene', 'Gene', (29, 38))	('colony formation', 'CPA', (89, 105))	('reduced', 'NegReg', (58, 65))
74395	27119230	In conclusion, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through down-regulation of Sox2 translation.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tunicamycin', 'Chemical', 'MESH:D014415', (15, 26))	('glioma', 'Disease', (84, 90))	('tunicamycin', 'Var', (15, 26))	('self-renewal', 'CPA', (42, 54))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('suppresses', 'NegReg', (27, 37))	('Sox2', 'Protein', (141, 145))	('down-regulation', 'NegReg', (122, 137))	('glioma', 'Disease', 'MESH:D005910', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
74441	26981133	The accumulation of molecular errors in CSCs initiates tumorigenesis, and these CSCs aggregate with stromal cells, which synergistically aggravate the disease.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('initiates', 'PosReg', (45, 54))	('tumor', 'Disease', (55, 60))	('molecular errors', 'Var', (20, 36))	('errors', 'Var', (30, 36))	('aggravate', 'PosReg', (137, 146))
74444	26981133	Several molecular markers have been shown to be related to survival benefits in patients with GBM, including O-6-methylguanine-DNA methyltransferase (MGMT) methylation and the isocitrate dehydrogenase (IDH) 1/2 mutation.	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (176, 208))	('patients', 'Species', '9606', (80, 88))	('GBM', 'Disease', (94, 97))	('benefits', 'PosReg', (68, 76))	('survival', 'CPA', (59, 67))	('MGMT', 'Gene', (150, 154))	('methylation', 'Var', (156, 167))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (109, 148))	('MGMT', 'Gene', '4255', (150, 154))	('mutation', 'Var', (211, 219))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (109, 148))
74447	26981133	We hypothesized that the presence of tMSLCs may aggravate the natural course of pGBM.	('pGBM', 'Disease', (80, 84))	('aggravate', 'PosReg', (48, 57))	('natural', 'MPA', (62, 69))	('pGBM', 'Chemical', '-', (80, 84))	('presence', 'Var', (25, 33))
74474	26981133	Among clinically deemed primary glioblastomas, 5 patients (6%) had mutation on IDH1.	('IDH1', 'Gene', '3417', (79, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (32, 44))	('primary glioblastoma', 'Disease', (24, 44))	('mutation', 'Var', (67, 75))	('primary glioblastoma', 'Disease', 'MESH:D005909', (24, 44))	('glioblastomas', 'Disease', 'MESH:D005909', (32, 45))	('had', 'Reg', (63, 66))	('glioblastomas', 'Disease', (32, 45))	('patients', 'Species', '9606', (49, 57))	('IDH1', 'Gene', (79, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (32, 45))
74475	26981133	Because of small number of patients with IDH1 mutation and previous reports about different clinical characteristics, they were not eligible for survival analysis and excluded from multivariate cox regression model.	('cox', 'Gene', '1351', (194, 197))	('cox', 'Gene', (194, 197))	('patients', 'Species', '9606', (27, 35))	('IDH1', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('IDH1', 'Gene', '3417', (41, 45))
74480	26981133	The 6-, 12-, and 24-month actuarial rates were 86%, 60%, and 21%, respectively, in patients positive for tMSLCs and 93%, 79%, and 61%, respectively, in patients negative for tMSLCs.	('tMSLCs', 'Var', (105, 111))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (152, 160))	('positive', 'Reg', (92, 100))
74482	26981133	We included extent of resection, codeletion of 1p19q, MGMT methylation, and Ki 67 index to a multivariate cox model with a result that isolation of tMSLCs (OR = 2.5, 95% CI = 1.1~5.6, P = 0.021) was associated with poorer outcome and larger extent of resection had association with better prognosis (OR = 0.5, 95% CI = 0.2~0.8, P = 0.011) while codeletion of 1p19q, MGMT methylation, and Ki 67 index does not differentiate survival of patients.	('1p19q', 'Var', (47, 52))	('isolation', 'Var', (135, 144))	('cox', 'Gene', '1351', (106, 109))	('patients', 'Species', '9606', (435, 443))	('MGMT', 'Gene', (54, 58))	('MGMT', 'Gene', '4255', (54, 58))	('MGMT', 'Gene', (366, 370))	('tMSLCs', 'Var', (148, 154))	('cox', 'Gene', (106, 109))	('MGMT', 'Gene', '4255', (366, 370))
74491	26981133	As our analysis does not show different prognosis in overall survival that was determined by MGMT methylation or LOH of 1p19q which was shown in more inclusive larger patient set, cautious interpretation of our result is required.	('MGMT', 'Gene', (93, 97))	('patient', 'Species', '9606', (167, 174))	('MGMT', 'Gene', '4255', (93, 97))	('LOH', 'Var', (113, 116))
74492	26981133	In addition, our study included IDH1 mutant patients and unknown patients, although we described pGBM.	('patients', 'Species', '9606', (44, 52))	('IDH1', 'Gene', (32, 36))	('IDH1', 'Gene', '3417', (32, 36))	('mutant', 'Var', (37, 43))	('patients', 'Species', '9606', (65, 73))	('pGBM', 'Chemical', '-', (97, 101))
74493	26981133	IDH1 mutant patients should be secondary GBM but these patients were allocated to both groups without statistical significance, so we included all IDH1 mutants patients and unknown patients in this study.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (160, 168))	('mutants', 'Var', (152, 159))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (181, 189))	('IDH1', 'Gene', (147, 151))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (147, 151))	('IDH1', 'Gene', '3417', (0, 4))
74494	26981133	From original group of 82 patients, only five of 70 patients tested (7.1%) had IDH1 mutations, including one from 27 tMSLC-negative (3.7%) patients and four from 43 tMSLC-positive (9.3%) patients.	('IDH1', 'Gene', '3417', (79, 83))	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (26, 34))	('mutations', 'Var', (84, 93))	('IDH1', 'Gene', (79, 83))	('patients', 'Species', '9606', (52, 60))
74496	26981133	Patients with mutated IDH1 were younger than those with wild type IDH1 (45.3 versus 60.7 years).	('IDH1', 'Gene', '3417', (66, 70))	('mutated', 'Var', (14, 21))	('IDH1', 'Gene', (22, 26))	('Patients', 'Species', '9606', (0, 8))	('IDH1', 'Gene', '3417', (22, 26))	('IDH1', 'Gene', (66, 70))
74497	26981133	Although LOH at 1p or 19q was found to correlate with longer OS in patients with oligodendroglioma, the association in patients with pGBM remains unclear.	('oligodendroglioma', 'Disease', 'MESH:D009837', (81, 98))	('patients', 'Species', '9606', (67, 75))	('longer OS', 'Disease', (54, 63))	('LOH at 1p', 'Var', (9, 18))	('pGBM', 'Chemical', '-', (133, 137))	('patients', 'Species', '9606', (119, 127))	('oligodendroglioma', 'Disease', (81, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
74498	26981133	Analysis of MGMT promotor showed that 42% of specimens were methylated (41% in tMSLCs (+), 47% in tMSLCs (-)) and that median OS tended to be longer in patients with methylation while lacking statistical significance (18.6 versus 15.0 months, P = 0.650).	('tMSLCs', 'Disease', (79, 85))	('MGMT', 'Gene', (12, 16))	('MGMT', 'Gene', '4255', (12, 16))	('longer', 'PosReg', (142, 148))	('methylation', 'Var', (166, 177))	('patients', 'Species', '9606', (152, 160))	('methylated', 'Var', (60, 70))
74507	26981133	It remains unclear, however, how the presence of tMSLCs aggravates the natural history of a brain tumor or contributes to tumor progression.	('brain tumor', 'Disease', (92, 103))	('aggravates', 'PosReg', (56, 66))	('tumor', 'Disease', (98, 103))	('brain tumor', 'Disease', 'MESH:D001932', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('brain tumor', 'Phenotype', 'HP:0030692', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('presence', 'Var', (37, 45))	('tMSLCs', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('contributes', 'Reg', (107, 118))	('natural history', 'CPA', (71, 86))	('tumor', 'Disease', (122, 127))
74544	26247958	Following mannitol-based disruption of BBB, multiple agents have also been administered intra-arterially, such as carmustine, cyclophosphamide, procarbazine, methotrexate, and doxorubicin.	('BBB', 'Gene', (39, 42))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (126, 142))	('procarbazine', 'Chemical', 'MESH:D011344', (144, 156))	('carmustine', 'Chemical', 'MESH:D002330', (114, 124))	('disruption', 'Var', (25, 35))	('mannitol', 'Chemical', 'MESH:D008353', (10, 18))	('doxorubicin', 'Chemical', 'MESH:D004317', (176, 187))	('methotrexate', 'Chemical', 'MESH:D008727', (158, 170))
74546	26247958	Despite this long history, hyperosmotic blood-brain barrier disruption is not part of standard practice in part because it requires repeated hospitalizations, often necessitates general anesthesia, and it increases the risk of seizures and strokes.	('strokes', 'Phenotype', 'HP:0001297', (240, 247))	('stroke', 'Phenotype', 'HP:0001297', (240, 246))	('seizures', 'Disease', 'MESH:D012640', (227, 235))	('strokes', 'Disease', 'MESH:D020521', (240, 247))	('increases', 'PosReg', (205, 214))	('strokes', 'Disease', (240, 247))	('seizures', 'Phenotype', 'HP:0001250', (227, 235))	('seizures', 'Disease', (227, 235))	('hyperosmotic', 'Var', (27, 39))
74571	26247958	In yet another preclinical study, FUS increased the concentration of temozolomide in the brain and this correlated with decreased tumor progression and increased animal survival.	('decreased tumor', 'Disease', (120, 135))	('FUS', 'Chemical', '-', (34, 37))	('increased', 'PosReg', (152, 161))	('temozolomide', 'Chemical', 'MESH:D000077204', (69, 81))	('animal survival', 'CPA', (162, 177))	('decreased tumor', 'Disease', 'MESH:D009369', (120, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('rat', 'Species', '10116', (59, 62))	('FUS', 'Var', (34, 37))	('concentration of temozolomide', 'MPA', (52, 81))	('increased', 'PosReg', (38, 47))
74589	26247958	Thermotherapy can induce cell membrane destruction and ultimately results in coagulative necrosis.	('necrosis', 'Disease', (89, 97))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('cell membrane destruction', 'CPA', (25, 50))	('Thermotherapy', 'Var', (0, 13))	('induce', 'Reg', (18, 24))	('results in', 'Reg', (66, 76))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (77, 97))
74640	25787115	The following primary antibodies were used: Oct-4, GFAP (1:200, Cell Signaling), ALDH1A1 (1:200), smooth muscle actin (1:50), GATA4 (1:200; Sigma-Aldrich), CD44 (1:400, Abcam) and beta-III tubulin (1:200, Millipore).	('GFAP', 'Gene', '2670', (51, 55))	('CD44', 'Gene', (156, 160))	('ALDH1A1', 'Gene', '216', (81, 88))	('beta-III tubulin', 'Protein', (180, 196))	('Oct-4', 'Gene', (44, 49))	('GFAP', 'Gene', (51, 55))	('GATA4', 'Gene', '2626', (126, 131))	('Oct-4', 'Gene', '5460', (44, 49))	('GATA4', 'Gene', (126, 131))	('ALDH1A1', 'Gene', (81, 88))	('CD44', 'Gene', '960', (156, 160))	('1:200', 'Var', (90, 95))	('1:400', 'Var', (162, 167))
74670	25787115	Upon phosphorylation, signal is transmitted to downstream signalling pathways such as MAPK and Akt, which subsequently stimulate tumour growth and invasion.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour growth', 'Disease', 'MESH:D006130', (129, 142))	('MAPK', 'Pathway', (86, 90))	('phosphorylation', 'Var', (5, 20))	('stimulate', 'PosReg', (119, 128))	('invasion', 'CPA', (147, 155))	('Akt', 'Pathway', (95, 98))	('tumour growth', 'Disease', (129, 142))
74672	25787115	Upon screening of major RTKs, ephrin type-B receptor 4 (EphB4) RTK, which has a regulatory role in neural and vascular development, was found to be significantly activated in iGSCs (Fig.5C).	('iGSCs', 'Var', (175, 180))	('EphB4', 'Gene', (56, 61))	('ephrin type-B receptor 4', 'Gene', '2050', (30, 54))	('ephrin type-B receptor 4', 'Gene', (30, 54))	('EphB4', 'Gene', '2050', (56, 61))	('activated', 'PosReg', (162, 171))
74704	25787115	In fact, aberrant activity of the EphB4 receptor has recently been shown to stimulate tumour growth and vascularization in different kinds of tumours, including glioma.	('aberrant activity', 'Var', (9, 26))	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('vascularization', 'CPA', (104, 119))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('tumour growth', 'Disease', (86, 99))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('EphB4', 'Gene', (34, 39))	('EphB4', 'Gene', '2050', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('tumour growth', 'Disease', 'MESH:D006130', (86, 99))	('glioma', 'Disease', (161, 167))	('stimulate', 'PosReg', (76, 85))
74709	25787115	NOTCH activation stimulates tumour growth, increases stem cell-like colonies and confers resistance to therapy.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour growth', 'Disease', (28, 41))	('stem cell-like colonies', 'CPA', (53, 76))	('NOTCH activation', 'Var', (0, 16))	('stimulates', 'PosReg', (17, 27))	('increases', 'PosReg', (43, 52))	('tumour growth', 'Disease', 'MESH:D006130', (28, 41))
74714	25787115	Aberrant beta-catenin activity is a poor prognostic factor for GBM.	('GBM', 'Disease', (63, 66))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', (9, 21))	('beta-catenin', 'Gene', '1499', (9, 21))	('activity', 'MPA', (22, 30))
74718	25787115	In addition, gene silencing of Axin2 results in diminished beta-catenin activity and reversal of the epithelial-mesenchymal transition (EMT) process.	('reversal', 'Reg', (85, 93))	('Axin2', 'Gene', (31, 36))	('Axin2', 'Gene', '8313', (31, 36))	('beta-catenin', 'Gene', '1499', (59, 71))	('gene silencing', 'Var', (13, 27))	('diminished', 'NegReg', (48, 58))	('epithelial-mesenchymal transition', 'CPA', (101, 134))	('beta-catenin', 'Gene', (59, 71))
74729	25796440	This shift is normally a highly regulated process and its dysregulation has been shown to promote malignancy.	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('dysregulation', 'Var', (58, 71))	('promote', 'PosReg', (90, 97))	('malignancy', 'Disease', (98, 108))
74752	25796440	These changes in the ECM then further enhance tumor growth and invasion.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('enhance', 'PosReg', (38, 45))	('tumor', 'Disease', (46, 51))	('changes', 'Var', (6, 13))	('invasion', 'CPA', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
74777	25796440	The aberrant activation of the Wnt pathway promotes cancer progression in many cancers types.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('promotes', 'PosReg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('aberrant', 'Var', (4, 12))	('Wnt pathway', 'Pathway', (31, 42))	('activation', 'PosReg', (13, 23))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
74779	25796440	beta-catenin is overexpressed in gliomas and its knockdown in vitro reduced the invasiveness of GBM cells.	('invasiveness of GBM cells', 'CPA', (80, 105))	('knockdown', 'Var', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('beta-catenin', 'Gene', '1499', (0, 12))	('gliomas', 'Disease', 'MESH:D005910', (33, 40))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('gliomas', 'Disease', (33, 40))	('reduced', 'NegReg', (68, 75))	('beta-catenin', 'Gene', (0, 12))
74783	25796440	The knockdown of Wnt1 caused formation of smaller intra-cranial tumors in mice that were noninvasive while the knockdown of Wnt3a completely prevented tumor formation.	('mice', 'Species', '10090', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Wnt1', 'Gene', (17, 21))	('tumor', 'Disease', (151, 156))	('smaller', 'NegReg', (42, 49))	('intra-cranial tumors', 'Disease', (50, 70))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('intra-cranial tumors', 'Disease', 'MESH:D003390', (50, 70))	('knockdown', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
74784	25796440	Knockdown of the transcription factor Lef1 has also been shown to inhibit invasion of GBM in vitro.	('Lef1', 'Gene', '51176', (38, 42))	('Knockdown', 'Var', (0, 9))	('Lef1', 'Gene', (38, 42))	('invasion of GBM', 'CPA', (74, 89))	('inhibit', 'NegReg', (66, 73))
74788	25796440	Wnt5a has been shown to be highly overexpressed glioma cells and its knockdown in vitro suppressed the expression of matrix metalloproteinase-2 and invasion in GBM cells.	('invasion in GBM cells', 'CPA', (148, 169))	('glioma', 'Disease', 'MESH:D005910', (48, 54))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('expression', 'MPA', (103, 113))	('Wnt5a', 'Gene', (0, 5))	('Wnt5a', 'Gene', '7474', (0, 5))	('matrix metalloproteinase-2', 'Gene', (117, 143))	('suppressed', 'NegReg', (88, 98))	('matrix metalloproteinase-2', 'Gene', '4313', (117, 143))	('knockdown', 'Var', (69, 78))	('glioma', 'Disease', (48, 54))
74790	25796440	Wnt2 is also overexpressed in gliomas and its knockdown with siRNA in vitro reduced the invasiveness of GBM cells (Figure 1).	('Wnt2', 'Gene', '7472', (0, 4))	('invasiveness of GBM cells', 'CPA', (88, 113))	('knockdown', 'Var', (46, 55))	('gliomas', 'Disease', 'MESH:D005910', (30, 37))	('gliomas', 'Phenotype', 'HP:0009733', (30, 37))	('gliomas', 'Disease', (30, 37))	('reduced', 'NegReg', (76, 83))	('Wnt2', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
74793	25796440	Therefore inhibitors of Wnt signaling can have multiple side effects such as muscle spasms and cramps, alopecia (type of hair loss), fatigue, weight loss, and bone loss or breakage.	('alopecia', 'Phenotype', 'HP:0001596', (103, 111))	('muscle spasms', 'Phenotype', 'HP:0003394', (77, 90))	('type of hair loss', 'Disease', 'MESH:D000505', (113, 130))	('bone loss', 'Disease', (159, 168))	('cramps', 'Disease', (95, 101))	('inhibitors', 'Var', (10, 20))	('fatigue', 'Disease', (133, 140))	('hair loss', 'Phenotype', 'HP:0001596', (121, 130))	('fatigue', 'Phenotype', 'HP:0012378', (133, 140))	('cramps', 'Disease', 'MESH:D009120', (95, 101))	('Wnt signaling', 'Pathway', (24, 37))	('bone loss', 'Phenotype', 'HP:0002797', (159, 168))	('muscle spasms', 'Disease', (77, 90))	('muscle spasms', 'Disease', 'MESH:D013035', (77, 90))	('weight loss', 'Disease', 'MESH:D015431', (142, 153))	('alopecia', 'Disease', (103, 111))	('fatigue', 'Disease', 'MESH:D005221', (133, 140))	('weight loss', 'Phenotype', 'HP:0001824', (142, 153))	('type of hair loss', 'Disease', (113, 130))	('weight loss', 'Disease', (142, 153))	('bone loss', 'Disease', 'MESH:D016301', (159, 168))
74795	25796440	For instance, SEN461 (Siena), a small-molecule inhibitor of the Wnt pathway, has been shown to inhibit canonical Wnt signaling by stabilizing Axin and increasing beta-catenin degradation in vitro and in vivo.	('Axin', 'Gene', '8312', (142, 146))	('beta-catenin', 'Gene', (162, 174))	('inhibit', 'NegReg', (95, 102))	('canonical Wnt signaling', 'Pathway', (103, 126))	('SEN461', 'Chemical', '-', (14, 20))	('Axin', 'Gene', (142, 146))	('beta-catenin', 'Gene', '1499', (162, 174))	('SEN461', 'Var', (14, 20))	('increasing', 'PosReg', (151, 161))	('stabilizing', 'Reg', (130, 141))
74801	25796440	Therefore, PI3K activates Akt signaling while PTEN suppresses it.	('Akt', 'Gene', '207', (26, 29))	('PTEN', 'Gene', (46, 50))	('PTEN', 'Gene', '5728', (46, 50))	('PI3K', 'Var', (11, 15))	('Akt', 'Gene', (26, 29))	('activates', 'PosReg', (16, 25))
74803	25796440	In many cancers, the PI3K/Akt signaling pathway is overactivated, often through the deletion or mutation of PTEN, or the hyperactivation of PI3K.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('hyperactivation', 'PosReg', (121, 136))	('cancers', 'Disease', (8, 15))	('deletion', 'Var', (84, 92))	('PTEN', 'Gene', (108, 112))	('Akt', 'Gene', '207', (26, 29))	('PTEN', 'Gene', '5728', (108, 112))	('mutation', 'Var', (96, 104))	('Akt', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PI3K', 'Pathway', (140, 144))	('overactivated', 'PosReg', (51, 64))
74809	25796440	Sulindac (Merck), also known as Clinoril, is a non-steroidal anti-inflammatory drug (NSAID) and its metabolites have been shown to inhibit GBM invasion in vitro by dephosphorylation of Akt at Ser473, which caused a decrease in MMP-2 gene expression and activity.	('decrease', 'NegReg', (215, 223))	('Clinoril', 'Chemical', 'MESH:D013467', (32, 40))	('inhibit', 'NegReg', (131, 138))	('dephosphorylation', 'MPA', (164, 181))	('Sulindac', 'Chemical', 'MESH:D013467', (0, 8))	('MMP-2', 'Gene', (227, 232))	('GBM invasion', 'CPA', (139, 151))	('activity', 'MPA', (253, 261))	('Ser473', 'Var', (192, 198))	('Akt', 'Gene', '207', (185, 188))	('Merck', 'Chemical', '-', (10, 15))	('MMP-2', 'Gene', '4313', (227, 232))	('expression', 'MPA', (238, 248))	('Ser473', 'Chemical', '-', (192, 198))	('Akt', 'Gene', (185, 188))
74810	25796440	When sulindac was combined with LY294002, a PI3K inhibitor, they synergistically inhibited GBM invasion.	('sulindac', 'Chemical', 'MESH:D013467', (5, 13))	('inhibited', 'NegReg', (81, 90))	('GBM invasion', 'CPA', (91, 103))	('LY294002', 'Var', (32, 40))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
74818	25796440	BKM120 (Novartis), also known as Buparlisib, is a pan-class I PI3K inhibitor in glioma cells that can cross the blood-brain barrier.	('glioma', 'Disease', (80, 86))	('Buparlisib', 'Chemical', 'MESH:C571178', (33, 43))	('BKM120', 'Var', (0, 6))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))
74820	25796440	Treatment of various GBM cell lines showed a dose-dependent inhibition of growth while treatment of mice with intracranial U87MG xenografts increased the median survival without any obvious adverse effects, such as weight loss or decreased activeness.	('weight loss', 'Disease', (215, 226))	('decreased', 'NegReg', (230, 239))	('weight loss', 'Phenotype', 'HP:0001824', (215, 226))	('activeness', 'CPA', (240, 250))	('growth', 'MPA', (74, 80))	('mice', 'Species', '10090', (100, 104))	('inhibition', 'NegReg', (60, 70))	('median survival', 'CPA', (154, 169))	('U87MG', 'Var', (123, 128))	('weight loss', 'Disease', 'MESH:D015431', (215, 226))	('decreased activeness', 'Phenotype', 'HP:0000752', (230, 250))	('increased', 'PosReg', (140, 149))
74824	25796440	In addition, there are studies verifying the efficacy of BKM120 in combination with other inhibitors, including a phase Ib/II study of INC280, a c-Met inhibitor, and BKM120 in recurrent GBM (NCT01870726) and another phase Ib/II study of BKM120 and one of the alkylating agents, carboplatin or lomustine, also in recurrent GBM (NCT0193461).	('BKM120', 'Chemical', 'MESH:C571178', (57, 63))	('NCT0193461', 'Var', (327, 337))	('lomustine', 'Chemical', 'MESH:D008130', (293, 302))	('c-Met', 'Gene', (145, 150))	('c-Met', 'Gene', '4233', (145, 150))	('BKM120', 'Chemical', 'MESH:C571178', (237, 243))	('carboplatin', 'Chemical', 'MESH:D016190', (278, 289))	('BKM120', 'Chemical', 'MESH:C571178', (166, 172))	('NCT01870726', 'Var', (191, 202))
74826	25796440	XL147 (Sanofi), also referred to as SAR245408, is one of these dual PI3K/mTOR inhibitors and has been shown to have cytotoxic effects on GBM cells and anti-cancer effects in nude mice with intracranial xenografts.	('XL147', 'Var', (0, 5))	('GBM cells', 'CPA', (137, 146))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('nude mice', 'Species', '10090', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cytotoxic effects', 'CPA', (116, 133))
74827	25796440	Furthermore, XL147 and TMZ had additive effects in vivo with no obvious adverse effects on the mice, suggesting the potential of combining these two drugs in treating GBM.	('GBM', 'Disease', (167, 170))	('mice', 'Species', '10090', (95, 99))	('combining', 'Interaction', (129, 138))	('XL147', 'Var', (13, 18))	('TMZ', 'Chemical', 'MESH:D000077204', (23, 26))
74841	25796440	The tGLI1 variant is expressed in most GBM specimens and patient-derived xenografts, but undetectable in normal brain cells or tissues.	('variant', 'Var', (10, 17))	('GLI1', 'Gene', (5, 9))	('GLI1', 'Gene', '2735', (5, 9))	('patient', 'Species', '9606', (57, 64))
74852	25796440	LDE225 (Novartis), also known as sonidegib or erismodegib, is another Smo inhibitor that can cross the blood-brain barrier and is being studied in GBM.	('Smo', 'Gene', '6608', (70, 73))	('Smo', 'Gene', (70, 73))	('LDE225', 'Var', (0, 6))
74887	25796440	Inhibition of miR-125b with shRNA has been shown to sensitize GSCs to TMZ by down-regulating MMP-2 and MMP-9 through PIAS3, an inhibitor of STAT3 signaling, in vitro and in vivo.	('TMZ', 'Chemical', 'MESH:D000077204', (70, 73))	('MMP-9', 'Gene', '4318', (103, 108))	('PIAS3', 'Gene', (117, 122))	('MMP-2', 'Gene', (93, 98))	('MMP-9', 'Gene', (103, 108))	('down-regulating', 'NegReg', (77, 92))	('STAT3', 'Gene', '6774', (140, 145))	('Inhibition', 'Var', (0, 10))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('PIAS3', 'Gene', '10401', (117, 122))	('STAT3', 'Gene', (140, 145))	('MMP-2', 'Gene', '4313', (93, 98))
74893	25796440	The administration of TMZ in addition to radiotherapy has been reported in a phase 3 trial to improve the median survival from 12 months to <15 months.	('median survival', 'MPA', (106, 121))	('TMZ', 'Chemical', 'MESH:D000077204', (22, 25))	('improve', 'PosReg', (94, 101))	('TMZ', 'Var', (22, 25))
74967	23494481	Plasmid (pBMN-Z-I-Neo) containing D34A caspase-resistant bcl-2 (a generous gift from Dr. Nolan, Stanford University) was introduced in a retrovirus vector as described.	('D34A', 'Var', (34, 38))	('caspase-resistant', 'Gene', (39, 56))	('D34A', 'Mutation', 'p.D34A', (34, 38))
74990	23494481	We observed a no increase and a significant decrease in caspase-3 activity, respectively, with BSO 5 mM and EA 75 muM treatment.	('EA', 'Chemical', 'MESH:D004976', (108, 110))	('decrease', 'NegReg', (44, 52))	('caspase-3', 'Gene', '836', (56, 65))	('activity', 'MPA', (66, 74))	('BSO', 'Chemical', '-', (95, 98))	('BSO 5 mM', 'Var', (95, 103))	('muM', 'Gene', '56925', (114, 117))	('muM', 'Gene', (114, 117))	('caspase-3', 'Gene', (56, 65))
75011	23494481	GSH depletion-induced effect on bcl-2 and cytochrome c indicated mediation of apoptotic process in death of SK-N-SH cells.	('cytochrome c', 'Gene', (42, 54))	('cytochrome c', 'Gene', '54205', (42, 54))	('bcl-2', 'MPA', (32, 37))	('SK-N-SH', 'CellLine', 'CVCL:0531', (108, 115))	('effect', 'Reg', (22, 28))	('depletion-induced', 'Var', (4, 21))	('GSH', 'Chemical', '-', (0, 3))
75021	23494481	Thus, U-87 cells in co-culture can protect SK-N-SH cells against GSH depletion induced by EA treatment and the mechanism of this neuroprotection, at least in part, could involve neutralization of ROS.	('SK-N-SH', 'CellLine', 'CVCL:0531', (43, 50))	('GSH', 'Chemical', '-', (65, 68))	('ROS', 'Chemical', 'MESH:D017382', (196, 199))	('ROS', 'Protein', (196, 199))	('neutralization', 'Var', (178, 192))	('GSH depletion', 'MPA', (65, 78))	('EA', 'Chemical', 'MESH:D004976', (90, 92))
75063	23494481	Our study indicates that mtGSH depletion leads to mitochondrial dysfunction and mt-mediated apoptosis.	('mtGSH', 'Chemical', '-', (25, 30))	('mt-mediated apoptosis', 'CPA', (80, 101))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (50, 75))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (50, 75))	('mitochondrial dysfunction', 'Disease', (50, 75))	('depletion', 'Var', (31, 40))
75070	33828082	The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM).	('glioblastoma', 'Phenotype', 'HP:0012174', (176, 188))	('GBM', 'Phenotype', 'HP:0012174', (190, 193))	('PTEN', 'Gene', (87, 91))	('mutation', 'Var', (92, 100))	('glioblastoma', 'Disease', (176, 188))	('glioblastoma', 'Disease', 'MESH:D005909', (176, 188))
75071	33828082	The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset.	('Cancer', 'Disease', (120, 126))	('alteration', 'Var', (30, 40))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('GBM', 'Phenotype', 'HP:0012174', (87, 90))	('PTEN', 'Gene', (25, 29))
75072	33828082	We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN.	('patient', 'Species', '9606', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutant', 'Var', (69, 75))	('proteins', 'Protein', (76, 84))	('overexpress', 'PosReg', (51, 62))	('U87MG', 'CellLine', 'CVCL:0022', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
75073	33828082	We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes ('edge mutations') localized to the cell periphery, while the R173C mutant localized to the nucleus.	('C124S', 'Mutation', 'p.C124S', (82, 87))	('R173C', 'Var', (281, 286))	('R173C', 'Mutation', 'rs121913293', (281, 286))	('R130Q', 'Mutation', 'rs121909229', (89, 94))	('H93Y', 'Mutation', 'rs1438980002', (76, 80))	('H93Y', 'Var', (76, 80))	('R173C', 'Mutation', 'rs121913293', (100, 105))	('R173C', 'Var', (100, 105))	('R130Q', 'Var', (89, 94))	('C124S', 'Var', (82, 87))
75074	33828082	Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors.	('substitutions', 'Var', (38, 51))	('Akt', 'Gene', '207', (84, 87))	('Akt', 'Gene', (84, 87))
75075	33828082	Further, some missense mutations ('edge mutations') in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.	('enhanced', 'PosReg', (85, 93))	('invasiveness', 'CPA', (94, 106))	('dysfunctional cytoskeletal assembly', 'Disease', 'MESH:C564991', (123, 158))	('missense mutations', 'Var', (14, 32))	('dysfunctional cytoskeletal assembly', 'Disease', (123, 158))	('phosphatase', 'Gene', (59, 70))
75076	33828082	Deletion in chromosome 10 is a hallmark of glioblastoma (GBM) regarding copy-number variations.	('GBM', 'Phenotype', 'HP:0012174', (57, 60))	('hallmark of glioblastoma', 'Disease', 'MESH:D005909', (31, 55))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('hallmark of glioblastoma', 'Disease', (31, 55))	('copy-number variations', 'Var', (72, 94))	('Deletion', 'Var', (0, 8))
75077	33828082	Studies using The Cancer Genome Atlas (TGCA) have shown frequent PTEN mutations as well as deletions in GBM cohorts.	('PTEN', 'Gene', (65, 69))	('mutations', 'Var', (70, 79))	('deletions', 'Var', (91, 100))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('GBM', 'Phenotype', 'HP:0012174', (104, 107))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))	('Cancer', 'Disease', (18, 24))
75085	33828082	In this study, we describe the mutational landscape of PTEN in GBM patients and experimentally validate the functional properties of several hotspot substitutions that are found in the phosphatase domain of PTEN.	('patients', 'Species', '9606', (67, 75))	('substitutions', 'Var', (149, 162))	('PTEN', 'Gene', (207, 211))	('GBM', 'Phenotype', 'HP:0012174', (63, 66))	('PTEN', 'Gene', (55, 59))
75086	33828082	We also illustrated the clinical significance of PTEN mutations by analyzing the radiographic failure patterns observed in GBM patients.	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (127, 135))	('GBM', 'Disease', (123, 126))	('PTEN', 'Gene', (49, 53))
75088	33828082	As expected, most GBM tumors were IDH1-wild-type (WT) (93.1%, 282/303), and PTEN mutation was exclusively found in these IDH1-WT tumors (P-value < 0.001, Fisher's exact test) (Supplementary Fig.	('IDH1', 'Gene', '3417', (34, 38))	('IDH1', 'Gene', (121, 125))	('IDH1-WT tumors', 'Disease', (121, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('IDH1', 'Gene', '3417', (121, 125))	('PTEN', 'Gene', (76, 80))	('GBM tumors', 'Disease', (18, 28))	('GBM tumors', 'Disease', 'MESH:D005910', (18, 28))	('mutation', 'Var', (81, 89))	('IDH1-WT tumors', 'Disease', 'MESH:C536751', (121, 135))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('found', 'Reg', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('GBM', 'Phenotype', 'HP:0012174', (18, 21))	('IDH1', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
75089	33828082	PTEN mutations were identified in almost a third of the cases (29.0%, 88/303), and PTEN deletion was confirmed in 39.6% of tumors (103/260).	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('deletion', 'Var', (88, 96))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
75090	33828082	Among patients with available mutation profiles and copy-number variation data, only 13.5% (35/260) exhibited concurrent PTEN deletion and mutation.	('PTEN', 'Gene', (121, 125))	('mutation', 'Var', (139, 147))	('exhibited', 'Reg', (100, 109))	('deletion', 'Var', (126, 134))	('patients', 'Species', '9606', (6, 14))
75092	33828082	Regarding the dominant-negative effect of PTEN mutation, patients were categorized as follows; mutation only, deletion only, or with both mutation and deletion alleles.	('PTEN', 'Gene', (42, 46))	('mutation', 'Var', (47, 55))	('deletion', 'Var', (110, 118))	('patients', 'Species', '9606', (57, 65))
75093	33828082	1C, there was no statistically significant difference in prognosis as a function of the alteration status of PTEN, however, patients with PTEN mutation only showed the shortest median overall survival (OS) compared to those with deletion only or both alterations (median OS, 286, 384, 408 and 437 days for patients with mutation only, deletion only, both alteration and wild type (WT), respectively).	('PTEN', 'Gene', (138, 142))	('overall survival', 'MPA', (184, 200))	('mutation', 'Var', (143, 151))	('shortest', 'NegReg', (168, 176))	('patients', 'Species', '9606', (124, 132))	('patients', 'Species', '9606', (306, 314))
75094	33828082	From analyzing the literature review and our study cohort, several PTEN hotspot mutations were identified: D24N, H93Y, C124S, R130Q, G132D, R173C, and K289E.	('C124S', 'Var', (119, 124))	('G132D', 'Var', (133, 138))	('R173C', 'Var', (140, 145))	('C124S', 'Mutation', 'p.C124S', (119, 124))	('D24N', 'Var', (107, 111))	('K289E', 'SUBSTITUTION', 'None', (151, 156))	('R130Q', 'Mutation', 'rs121909229', (126, 131))	('R173C', 'Mutation', 'rs121913293', (140, 145))	('H93Y', 'Var', (113, 117))	('K289E', 'Var', (151, 156))	('D24N', 'Mutation', 'rs786201995', (107, 111))	('G132D', 'Mutation', 'rs121909241', (133, 138))	('H93Y', 'Mutation', 'rs1438980002', (113, 117))	('R130Q', 'Var', (126, 131))
75095	33828082	Of these, five missense mutations (D24N, H93Y, R130Q, G132D, and R173C) are known to be maintained throughout the temporal evolution of GBMs while the other two (C124S and K289E) are well-known mutations in previous PTEN studies.	('H93Y', 'Mutation', 'rs1438980002', (41, 45))	('K289E', 'SUBSTITUTION', 'None', (172, 177))	('H93Y', 'Var', (41, 45))	('D24N', 'Var', (35, 39))	('G132D', 'Var', (54, 59))	('R130Q', 'Mutation', 'rs121909229', (47, 52))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('R173C', 'Var', (65, 70))	('K289E', 'Var', (172, 177))	('R130Q', 'Var', (47, 52))	('C124S', 'Var', (162, 167))	('R173C', 'Mutation', 'rs121913293', (65, 70))	('D24N', 'Mutation', 'rs786201995', (35, 39))	('C124S', 'Mutation', 'p.C124S', (162, 167))	('G132D', 'Mutation', 'rs121909241', (54, 59))
75096	33828082	The catalytically inactive C124S substitution is a representative loss-of-function substitution, whereas the K289E substitution, which is located within the C2 domain, retains WT phosphatase activity.	('K289E', 'Var', (109, 114))	('C124S', 'Var', (27, 32))	('phosphatase activity', 'MPA', (179, 199))	('C124S', 'Mutation', 'p.C124S', (27, 32))	('K289E', 'SUBSTITUTION', 'None', (109, 114))
75097	33828082	U87MG cell line has in-frame deletion within exon 3 of PTEN, and usually used as a negative control for PTEN functional studies.	('deletion', 'Var', (29, 37))	('U87MG', 'CellLine', 'CVCL:0022', (0, 5))	('PTEN', 'Gene', (55, 59))
75098	33828082	Intact PTEN phosphatase activity, measured by the converted ratio of PI--P2, was confirmed in the WT, D24N, and K289E overexpressing U87MG cell lines, whereas cells overexpressing other PTEN mutants exhibit no phosphatase activity (Fig.	('K289E', 'Var', (112, 117))	('activity', 'MPA', (24, 32))	('D24N', 'Mutation', 'rs786201995', (102, 106))	('U87MG', 'CellLine', 'CVCL:0022', (133, 138))	('PTEN', 'Gene', (186, 190))	('PTEN', 'Gene', (7, 11))	('D24N', 'Var', (102, 106))	('K289E', 'SUBSTITUTION', 'None', (112, 117))	('phosphatase', 'Enzyme', (12, 23))	('PI--P2', 'Chemical', 'MESH:D019269', (69, 75))
75101	33828082	To comprehend the functional implication of PTEN mutations in the present study, we examined the subcellular localization of PTEN mutants using U87MG cell lines, infected by lentivirus carrying PTEN mutant DNA (H93Y, D24N, R130Q, G132D, C124S, or R173C).	('D24N', 'Var', (217, 221))	('R130Q', 'Var', (223, 228))	('G132D', 'Var', (230, 235))	('C124S', 'Var', (237, 242))	('D24N', 'Mutation', 'rs786201995', (217, 221))	('R173C', 'Var', (247, 252))	('C124S', 'Mutation', 'p.C124S', (237, 242))	('infected', 'Disease', 'MESH:D007239', (162, 170))	('U87MG', 'CellLine', 'CVCL:0022', (144, 149))	('H93Y', 'Mutation', 'rs1438980002', (211, 215))	('R173C', 'Mutation', 'rs121913293', (247, 252))	('R130Q', 'Mutation', 'rs121909229', (223, 228))	('infected', 'Disease', (162, 170))	('G132D', 'Mutation', 'rs121909241', (230, 235))
75102	33828082	Most PTEN mutants were located within the cytoplasm, while R173C was exclusively found in the nucleus (Fig.	('R173C', 'Mutation', 'rs121913293', (59, 64))	('PTEN', 'Gene', (5, 9))	('R173C', 'Var', (59, 64))	('mutants', 'Var', (10, 17))
75103	33828082	Interestingly, the H93Y, C124S, and R130Q substitutions were particularly found at the cell periphery (Fig.	('R130Q', 'Mutation', 'rs121909229', (36, 41))	('C124S', 'Var', (25, 30))	('R130Q', 'Var', (36, 41))	('H93Y', 'Mutation', 'rs1438980002', (19, 23))	('C124S', 'Mutation', 'p.C124S', (25, 30))	('H93Y', 'Var', (19, 23))
75105	33828082	2D, F-actin and Cdc42 were co-localized with overexpressing PTEN mutants in U87MG cells, which implied that these PTEN mutants accumulated at the front of cells, regarding their polarity.	('mutants', 'Var', (65, 72))	('Cdc42', 'Gene', '998', (16, 21))	('PTEN', 'Gene', (114, 118))	('PTEN', 'Gene', (60, 64))	('Cdc42', 'Gene', (16, 21))	('mutants', 'Var', (119, 126))	('accumulated', 'PosReg', (127, 138))	('U87MG', 'CellLine', 'CVCL:0022', (76, 81))
75107	33828082	We have termed the cytoplasmic mutations as "edge mutations" (H93Y, C124S, and R130Q) and R173C as "nuclear mutation".	('R173C', 'Mutation', 'rs121913293', (90, 95))	('C124S', 'Var', (68, 73))	('H93Y', 'Mutation', 'rs1438980002', (62, 66))	('H93Y', 'Var', (62, 66))	('C124S', 'Mutation', 'p.C124S', (68, 73))	('R130Q', 'Var', (79, 84))	('R130Q', 'Mutation', 'rs121909229', (79, 84))	('R173C', 'Var', (90, 95))
75108	33828082	PTEN mutants from G129E (CLUMP cluster 4) exhibited cytoplasmic localization while those of Y177C (CLUMP cluster 1) showed nuclear compartmentalization, which supporting the functional relevance of CLUMP-defined clusters (Supplementary Fig.	('Y177C', 'Mutation', 'p.Y177C', (92, 97))	('Y177C', 'Var', (92, 97))	('cytoplasmic localization', 'MPA', (52, 76))	('G129E', 'Var', (18, 23))	('G129E', 'Mutation', 'rs121909218', (18, 23))	('nuclear compartmentalization', 'MPA', (123, 151))	('PTEN', 'Gene', (0, 4))
75109	33828082	The crystal structure of the PTEN protein showed that all residues in edge mutations located within the same pocket of the phosphatase domain in the crystal structure, where PI--P3 binds (Fig.	('PI--P3', 'Chemical', '-', (174, 180))	('binds', 'Interaction', (181, 186))	('located', 'Reg', (85, 92))	('mutations', 'Var', (75, 84))
75110	33828082	PTEN edge mutants (H93Y, C124S, and R130Q) were found in the cytoplasmic compartment, especially at the fronts of cells.	('R130Q', 'Mutation', 'rs121909229', (36, 41))	('C124S', 'Var', (25, 30))	('R130Q', 'Var', (36, 41))	('H93Y', 'Mutation', 'rs1438980002', (19, 23))	('C124S', 'Mutation', 'p.C124S', (25, 30))	('PTEN', 'Gene', (0, 4))	('H93Y', 'Var', (19, 23))
75112	33828082	Moreover, in vivo experiments revealed that mice with edge mutations showed poor survival outcome compared to PTEN-null mice, and this finding prompted us to examine the phenotypic characteristics of these mutations (Fig.	('survival outcome', 'CPA', (81, 97))	('poor', 'NegReg', (76, 80))	('mice', 'Species', '10090', (120, 124))	('mutations', 'Var', (59, 68))	('mice', 'Species', '10090', (44, 48))
75113	33828082	Interestingly, xenograft models with nuclear mutation (R173C) exhibited better prognosis than PTEN-null models (p-value=0.033, log-rank test), which indirectly supported the more pronounced hazardous effect of edge mutation on the prognosis (Supplementary Fig.	('R173C', 'Var', (55, 60))	('prognosis', 'CPA', (79, 88))	('R173C', 'Mutation', 'rs121913293', (55, 60))	('better', 'PosReg', (72, 78))
75114	33828082	To examine the phenotypical characteristics of edge mutations, we established the U87MG cells with exogenous PTEN mutants.	('mutants', 'Var', (114, 121))	('U87MG', 'CellLine', 'CVCL:0022', (82, 87))	('PTEN', 'Gene', (109, 113))
75115	33828082	According to in vitro trans-well invasion assay, all tumor cells with edge mutants exhibited significantly increased invasion capacity compared to tumors with nuclear mutants, except H93Y (Fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('increased', 'PosReg', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('invasion capacity', 'CPA', (117, 134))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('mutants', 'Var', (75, 82))	('H93Y', 'Mutation', 'rs1438980002', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (53, 58))
75117	33828082	Tumors with H93Y and G132D mutations showed increased invasive capacity compared to tumors with PTEN-null or nuclear mutation, however, failed to exhibit statistically significant difference.	('H93Y', 'Mutation', 'rs1438980002', (12, 16))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('G132D', 'Mutation', 'rs121909241', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('invasive capacity', 'CPA', (54, 71))	('Tumors', 'Disease', (0, 6))	('G132D', 'Var', (21, 26))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('increased', 'PosReg', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('H93Y', 'Var', (12, 16))
75119	33828082	PDCs with endogenous edge mutations (P087(H93Y) and P045(R130Q)) also showed similar spatial patterns of PTEN accumulation (Fig.	('R130Q', 'Mutation', 'rs121909229', (57, 62))	('H93Y', 'Mutation', 'rs1438980002', (42, 46))	('PTEN', 'Gene', (105, 109))	('P045(R130Q', 'Var', (52, 62))	('accumulation', 'PosReg', (110, 122))	('P087(H93Y', 'Var', (37, 46))
75122	33828082	Several anti-PI3K/Akt signaling drugs have been developed for clinical use; BKM120, a pan-class I PI3K inhibitor, is one of the most advanced agents readily crossing the blood-brain barrier.	('BKM120', 'Chemical', 'MESH:C571178', (76, 82))	('Akt', 'Gene', '207', (18, 21))	('Akt', 'Gene', (18, 21))	('BKM120', 'Var', (76, 82))
75123	33828082	PTEN-null PDCs (P090) with exogenous mutants were treated with BKM120 to inhibit the PI3K/Akt signaling pathway.	('Akt', 'Gene', (90, 93))	('BKM120', 'Chemical', 'MESH:C571178', (63, 69))	('mutants', 'Var', (37, 44))	('Akt', 'Gene', '207', (90, 93))	('inhibit', 'NegReg', (73, 80))
75124	33828082	Surprisingly, invasive phenotypes were not significantly diminished by BKM120, compared to PTEN-null PDCs (Fig.	('BKM120', 'Var', (71, 77))	('BKM120', 'Chemical', 'MESH:C571178', (71, 77))	('diminished', 'NegReg', (57, 67))
75125	33828082	Edge mutants were still present at leading edges while retaining their invasive branches in U87MG cells with edge mutants (Fig.	('mutants', 'Var', (114, 121))	('U87MG', 'CellLine', 'CVCL:0022', (92, 97))	('invasive branches', 'MPA', (71, 88))
75126	33828082	Persistent co-localization of F-actin and edge mutants in P089 with edge mutants following BKM120 treatment further supports the therapeutic resistance against BKM120 in these cells (Fig.	('BKM120', 'Chemical', 'MESH:C571178', (160, 166))	('BKM120', 'Chemical', 'MESH:C571178', (91, 97))	('F-actin', 'Protein', (30, 37))	('mutants', 'Var', (73, 80))	('co-localization', 'Interaction', (11, 26))
75127	33828082	These data suggested that the invasive phenotype of edge mutations is not dependent on the PI3K/Akt signaling pathway.	('mutations', 'Var', (57, 66))	('Akt', 'Gene', '207', (96, 99))	('Akt', 'Gene', (96, 99))
75128	33828082	Several genomic signatures associated with cytoskeletal microtubule assembly were identified by gene set enrichment analysis in GBM patients with PTEN edge mutations (Supplementary Fig.	('PTEN edge', 'Gene', (146, 155))	('GBM', 'Disease', (128, 131))	('mutations', 'Var', (156, 165))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('patients', 'Species', '9606', (132, 140))
75129	33828082	This finding was further corroborated at the protein level, with several cytoskeletal proteins highly expressed in U87MG cells overexpressing PTEN edge mutants (Supplementary Table S1).	('PTEN', 'Gene', (142, 146))	('U87MG', 'CellLine', 'CVCL:0022', (115, 120))	('highly expressed', 'PosReg', (95, 111))	('mutants', 'Var', (152, 159))
75131	33828082	PDCs expressing edge mutants exhibited significantly fewer invasive cellular projections following colchicine treatment (Fig.	('invasive cellular projections', 'CPA', (59, 88))	('colchicine', 'Chemical', 'MESH:D003078', (99, 109))	('fewer', 'NegReg', (53, 58))	('mutants', 'Var', (21, 28))
75134	33828082	We observed that tubulin aggresomes were more frequent in U87MG cells with edge mutants.	('frequent', 'PosReg', (46, 54))	('U87MG', 'CellLine', 'CVCL:0022', (58, 63))	('tubulin aggresomes', 'Protein', (17, 35))	('U87MG', 'Var', (58, 63))
75135	33828082	PDCs with endogenous edge mutations also showed the same changes following BKM120 and microtubule inhibitor treatment (Fig.	('mutations', 'Var', (26, 35))	('BKM120', 'Chemical', 'MESH:C571178', (75, 81))	('BKM120', 'Var', (75, 81))
75137	33828082	To validate these findings in vivo, we established orthotopic xenograft models with a tumor bearing the PTEN edge mutation R130Q (P090-R130Q).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('R130Q', 'Mutation', 'rs121909229', (135, 140))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('R130Q', 'Mutation', 'rs121909229', (123, 128))	('R130Q', 'Var', (123, 128))
75141	33828082	Interestingly, patients with PTEN edge mutations had locally invasive radiographic phenotypes upon recurrence (Fig.	('PTEN', 'Gene', (29, 33))	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (39, 48))
75142	33828082	However, the number of patients was limited by the small size of the total cohort, we adapted CLUMP-defined mutation clusters to measure the incidence of distinct failure patterns as a function of PTEN mutations.	('patients', 'Species', '9606', (23, 31))	('PTEN', 'Gene', (197, 201))	('mutations', 'Var', (202, 211))
75145	33828082	GBM patients with PTEN mutations, regardless of the type or residue, had increased incidence of the combined type of recurrence pattern (30.1% with PTEN mutations vs. 18.3% in PTEN-WT, P-value = 0.071, Fisher's exact test) (Supplementary Fig.	('PTEN', 'Gene', (148, 152))	('PTEN', 'Gene', (18, 22))	('mutations', 'Var', (153, 162))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (4, 12))
75146	33828082	Analysis of the mutational landscape of GBM patients revealed that PTEN mutations could be categorized into two major subsets, missense mutations in the phosphatase domain and truncations of the C2 domain.	('mutations', 'Var', (72, 81))	('GBM', 'Phenotype', 'HP:0012174', (40, 43))	('patients', 'Species', '9606', (44, 52))	('truncations', 'Var', (176, 187))	('missense mutations in', 'Var', (127, 148))	('PTEN', 'Gene', (67, 71))	('phosphatase', 'Protein', (153, 164))
75147	33828082	In other words, a missense mutation is likely more disastrous than PTEN deletion or PTEN-destabilizing mutations in the context of malignancy.	('malignancy', 'Disease', (131, 141))	('missense mutation', 'Var', (18, 35))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))
75151	33828082	Studies using Dictyostelium discoideum demonstrated reciprocal spatial distribution of PI3K and PTEN at the leading edge and the rear of chemotaxing cells, respectively.	('PI3K', 'Var', (87, 91))	('Dictyostelium discoideum', 'Species', '44689', (14, 38))	('PTEN', 'Gene', (96, 100))
75160	33828082	Enhanced tumor invasion attributed to PTEN edge mutations during chemotaxis suggests the possible role of PTEN mutations in the context of TME.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('PTEN', 'Gene', (106, 110))	('PTEN edge', 'Gene', (38, 47))	('mutations', 'Var', (48, 57))	('Enhanced', 'PosReg', (0, 8))
75162	33828082	We found that edge mutants exhibited invasive phenotypes associated with dysfunctional cytoskeletal assembly, suggesting a microtubule inhibitor as a therapeutic option for these mutant-harboring GBMs.	('dysfunctional cytoskeletal assembly', 'Disease', (73, 108))	('dysfunctional cytoskeletal assembly', 'Disease', 'MESH:C564991', (73, 108))	('exhibited', 'Reg', (27, 36))	('GBM', 'Phenotype', 'HP:0012174', (196, 199))	('mutants', 'Var', (19, 26))
75163	33828082	A CLUMP-defined subgroup containing the edge mutations showed a locally invasive recurrence pattern, while patients with any PTEN mutation were mostly exhibited the combined failure pattern, which was totally different from local invasion.	('patients', 'Species', '9606', (107, 115))	('mutations', 'Var', (45, 54))	('locally invasive recurrence', 'CPA', (64, 91))
75167	33828082	Some missense mutations in the phosphatase domain, named edge mutations, caused enhanced invasiveness, which was associated with a dysfunctional cytoskeletal assembly.	('dysfunctional cytoskeletal assembly', 'Disease', 'MESH:C564991', (131, 166))	('enhanced', 'PosReg', (80, 88))	('missense mutations in', 'Var', (5, 26))	('invasiveness', 'CPA', (89, 101))	('dysfunctional cytoskeletal assembly', 'Disease', (131, 166))
75168	33828082	Clinically, mutation-specific therapeutic options should be considered in treating GBM patients with PTEN mutations.	('GBM', 'Phenotype', 'HP:0012174', (83, 86))	('PTEN', 'Gene', (101, 105))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (106, 115))
75176	33828082	Genes which were differentially expressed in GBM tumors with PTEN edge mutations were identified ('DEGseq') and used to identify the GO gene sets significantly enriched in these samples("clusterProfile").	('GBM tumors', 'Disease', 'MESH:D005910', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('GBM tumors', 'Disease', (45, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('PTEN edge', 'Gene', (61, 70))	('mutations', 'Var', (71, 80))	('GBM', 'Phenotype', 'HP:0012174', (45, 48))
75177	33828082	We propagated GBM PDXs to evaluate the effect of different PTEN mutants by implanting U87MG cell lines with distinct PTEN mutations (PTEN-null, C124S, H93Y, R130Q, and R173C) into the flanks of 6-8 weeks female BALB/c-nude mice, which were purchased from Orient Bio Inc (Seongnam, Korea).	('H93Y', 'Mutation', 'rs1438980002', (151, 155))	('H93Y', 'Var', (151, 155))	('PTEN', 'Gene', (117, 121))	('C124S', 'Var', (144, 149))	('nude mice', 'Species', '10090', (218, 227))	('R130Q', 'Mutation', 'rs121909229', (157, 162))	('R173C', 'Var', (168, 173))	('C124S', 'Mutation', 'p.C124S', (144, 149))	('GBM', 'Phenotype', 'HP:0012174', (14, 17))	('R173C', 'Mutation', 'rs121913293', (168, 173))	('R130Q', 'Var', (157, 162))	('U87MG', 'CellLine', 'CVCL:0022', (86, 91))
75180	33828082	Patient-derived GBM tumor cells with R130Q PTEN mutation (P090-R130Q) were dissociated and suspended with Hank's Balanced Salt solution (HBSS; 14170-122, Gibco).	("Hank's Balanced Salt solution", 'Chemical', '-', (106, 135))	('R130Q', 'Mutation', 'rs121909229', (37, 42))	('R130Q', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('GBM', 'Phenotype', 'HP:0012174', (16, 19))	('R130Q', 'Mutation', 'rs121909229', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('HBSS', 'Chemical', '-', (137, 141))	('P090-R130Q', 'Var', (58, 68))	('Patient', 'Species', '9606', (0, 7))	('tumor', 'Disease', (20, 25))
75202	33828082	Search parameters were two missed trypsin cleavage sites, cysteine carbamidomethylation (+57.0215 Da) as fixed modifications, and methionine oxidation (+15.9949 Da) as a variable modification.	('cysteine', 'Chemical', 'MESH:D003545', (58, 66))	('cysteine carbamidomethylation', 'MPA', (58, 87))	('+15.9949 Da', 'Var', (152, 163))	('methionine', 'Chemical', 'MESH:D008715', (130, 140))	('+57.0215 Da', 'Var', (89, 100))
75204	33828082	; patient-derived genome data analysis: S.W.C., H.K., J.K.S., H.J.C., and H.S.	('J.K.S.', 'Disease', (54, 60))	('H.J.C.', 'Var', (62, 68))	('patient', 'Species', '9606', (2, 9))
75218	31766676	As recently reported in the III International Conference on Virgin Olive Oil and Health Consensus Report, EVOO intake is also associated with reduced risk of most ageing-related diseases including cardiovascular and neurodegenerative diseases (CVD and NDD), and some types of cancer.	('neurodegenerative diseases', 'Disease', (216, 242))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (216, 242))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('reduced', 'NegReg', (142, 149))	('NDD', 'Disease', (252, 255))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (216, 242))	('Olive', 'Species', '4146', (67, 72))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (216, 241))	('NDD', 'Disease', 'None', (252, 255))	('ageing-related diseases', 'Disease', (163, 186))	('EVOO', 'Var', (106, 110))
75247	31766676	In particular, a o-diOH substitution confers a high antioxidant property, whereas single hydroxyl substitutions, e.g., tyrosol, provide none.	('o-diOH', 'Var', (17, 23))	('o-diOH', 'Chemical', 'MESH:C031356', (17, 23))	('hydroxyl', 'Chemical', 'MESH:D017665', (89, 97))	('tyrosol', 'Chemical', 'MESH:C011867', (119, 126))	('antioxidant property', 'MPA', (52, 72))
75299	31766676	As a master regulator of protein, lipid and carbohydrate metabolism, altered autophagy may concomitantly promote metabolic disorders and diseases associated with ageing, unhealthy diets, and inflammation.	('promote', 'PosReg', (105, 112))	('inflammation', 'Disease', 'MESH:D007249', (191, 203))	('metabolic disorders', 'Disease', 'MESH:D008659', (113, 132))	('altered', 'Var', (69, 76))	('inflammation', 'Disease', (191, 203))	('metabolic disorders', 'Disease', (113, 132))	('carbohydrate', 'Chemical', 'MESH:D002241', (44, 56))	('autophagy', 'CPA', (77, 86))
75300	31766676	Indeed, knockout of the Atg7 gene in mice, an essential gene for autophagy, shows in vivo typical Parkinson' disease (PD) features like Lewy bodies (LBs) formation, including endogenous synuclein and neuronal loss, as well as hepatomegaly with mutant hepatocytes showing accumulation of ubiquitin-positive aggregates.	('neuronal loss', 'Disease', (200, 213))	('hepatomegaly', 'Phenotype', 'HP:0002240', (226, 238))	('endogenous synuclein', 'MPA', (175, 195))	('Lewy bodies', 'Phenotype', 'HP:0100315', (136, 147))	('LBs', 'Phenotype', 'HP:0100315', (149, 152))	('ubiquitin-positive aggregates', 'MPA', (287, 316))	('Lewy bodies', 'Disease', (136, 147))	('mutant', 'Var', (244, 250))	("Parkinson' disease", 'Disease', (98, 116))	('Atg7', 'Gene', '74244', (24, 28))	('neuronal loss', 'Phenotype', 'HP:0002529', (200, 213))	("Parkinson' disease", 'Disease', 'MESH:D010300', (98, 116))	('neuronal loss', 'Disease', 'MESH:D009410', (200, 213))	('hepatomegaly', 'Disease', 'MESH:D006529', (226, 238))	('hepatomegaly', 'Disease', (226, 238))	('Atg7', 'Gene', (24, 28))	('PD', 'Disease', 'MESH:D010300', (118, 120))	('mice', 'Species', '10090', (37, 41))
75317	31766676	They suggested that autophagy might be activated by inhibition of the mTOR pathway, reflected by the phosphorylation decrease of its target p70S6 protein kinase, shown in cell culture.	('autophagy', 'CPA', (20, 29))	('p70S6', 'Var', (140, 145))	('mTOR', 'Gene', (70, 74))	('activated', 'PosReg', (39, 48))	('mTOR', 'Gene', '2475', (70, 74))	('decrease', 'NegReg', (117, 125))	('inhibition', 'NegReg', (52, 62))	('phosphorylation', 'MPA', (101, 116))
75337	31766676	found that inhibition of autophagy in a Triple-Negative Breast Cancer cell line promoted migration and invasion, as demonstrated by exposition with Hepatocyte Growth Factor (HGT), or 3-methyladenine, an inhibitor of autophagy.	('Breast Cancer', 'Disease', 'MESH:D001943', (56, 69))	('promoted', 'PosReg', (80, 88))	('autophagy', 'CPA', (25, 34))	('3-methyladenine', 'Chemical', 'MESH:C025946', (183, 198))	('Breast Cancer', 'Phenotype', 'HP:0003002', (56, 69))	('rat', 'Species', '10116', (92, 95))	('Hepatocyte Growth Factor', 'Gene', '3082', (148, 172))	('rat', 'Species', '10116', (123, 126))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('inhibition', 'Var', (11, 21))	('Breast Cancer', 'Disease', (56, 69))	('Hepatocyte Growth Factor', 'Gene', (148, 172))	('migration', 'CPA', (89, 98))	('invasion', 'CPA', (103, 111))
75356	31766676	found that the larvae of a transgenic strain CL2006 of Caenorhabditis elegans fed with OleA, showed in the cytoplasm of muscle cells of the body wall, a reduction of Abeta plaque deposits, a lower content of toxic Abeta oligomers, a marked decrease of paralysis, and an increase of life expectancy compared with untreated animals.	('decrease of paralysis', 'Disease', 'MESH:D010243', (240, 261))	('Caenorhabditis elegans', 'Species', '6239', (55, 77))	('reduction', 'NegReg', (153, 162))	('paralysis', 'Phenotype', 'HP:0003470', (252, 261))	('increase', 'PosReg', (270, 278))	('life expectancy', 'CPA', (282, 297))	('decrease of paralysis', 'Disease', (240, 261))	('Abeta plaque deposits', 'Disease', (166, 187))	('Abeta plaque deposits', 'Disease', 'MESH:C566671', (166, 187))	('lower', 'NegReg', (191, 196))	('content of toxic Abeta oligomers', 'MPA', (197, 229))	('transgenic', 'Var', (27, 37))	('Ole', 'Chemical', 'MESH:C002769', (87, 90))
75365	31766676	Using another amyloidogenic protein, a variant of human beta2-microglobulin (beta2m) a 99 residue-long human protein belonging to the major histocompatibility complex class I (MHC I) associated with a familial form of systemic amyloidosis, they showed that it exhibited an enhanced amyloidogenic tendency to aggregate in vitro with respect to the wild-type protein.	('aggregate', 'MPA', (308, 317))	('human', 'Species', '9606', (103, 108))	('beta2m', 'Gene', '567', (77, 83))	('systemic amyloidosis', 'Disease', (218, 238))	('amyloidosis', 'Phenotype', 'HP:0011034', (227, 238))	('beta2m', 'Gene', (77, 83))	('beta2-microglobulin', 'Gene', '567', (56, 75))	('variant', 'Var', (39, 46))	('beta2-microglobulin', 'Gene', (56, 75))	('systemic amyloidosis', 'Disease', 'MESH:D009101', (218, 238))	('amyloidogenic tendency', 'MPA', (282, 304))	('associated with', 'Reg', (183, 198))	('human', 'Species', '9606', (50, 55))	('enhanced', 'PosReg', (273, 281))
75384	31766676	Additional evidence suggests that one of the best inhibitors of human colon carcinoma cells is the HT oleate form, suggesting that long chain fatty acids, such oleate, may facilitate Ole activity.	('Ole', 'Chemical', 'MESH:C002769', (183, 186))	('human', 'Species', '9606', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('colon carcinoma', 'Disease', 'MESH:D015179', (70, 85))	('facilitate', 'PosReg', (172, 182))	('colon carcinoma', 'Disease', (70, 85))	('fatty acids', 'Chemical', 'MESH:D005227', (142, 153))	('oleate', 'Chemical', 'MESH:D019301', (160, 166))	('oleate', 'Chemical', 'MESH:D019301', (102, 108))	('long chain', 'Var', (131, 141))	('Ole activity', 'MPA', (183, 195))	('HT', 'Chemical', 'MESH:C005975', (99, 101))
75387	31766676	Of a particular importance was the finding that Ole analog 24 expresses a promotion of natural immune responses, from Natural Killer cells and Limphokine-activated Killer cells.	('Ole analog', 'Var', (48, 58))	('promotion', 'PosReg', (74, 83))	('natural immune responses', 'CPA', (87, 111))	('Ole', 'Chemical', 'MESH:C002769', (48, 51))
75402	31766676	The use of HDAC inhibitors in cancer treatment represents a new approach to therapy, like reactivation of tumor suppressor genes.	('men', 'Species', '9606', (42, 45))	('reactivation', 'Var', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
75436	31766676	In addition to chemotherapy, Ole has been proved to enhance the radiation sensitivity of nasopharyngeal carcinoma cells repressing mRNA-519d.	('mRNA-519d', 'Var', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (89, 113))	('radiation sensitivity', 'CPA', (64, 85))	('Ole', 'Chemical', 'MESH:C002769', (29, 32))	('carcinoma', 'Disease', (104, 113))	('enhance', 'PosReg', (52, 59))	('carcinoma', 'Disease', 'MESH:D002277', (104, 113))
75472	31779130	Whereas CD28 activity polarizes T cells towards effector cells relying on glycolytic energy metabolism and evincing profound effector functions at the expense of a limited persistence, 4-1BB imposes a shift towards fatty acid oxidation and memory destiny, resulting in enhanced longevity of 4-1BB co-stimulated CAR-T cells.	('4-1BB', 'Var', (185, 190))	('shift', 'Reg', (201, 206))	('CD28', 'Gene', '940', (8, 12))	('longevity', 'CPA', (278, 287))	('fatty acid', 'Chemical', 'MESH:D005227', (215, 225))	('fatty acid oxidation', 'MPA', (215, 235))	('enhanced', 'PosReg', (269, 277))	('CD28', 'Gene', (8, 12))
75497	31779130	The short intracellular domain, which does not possess intrinsic catalytic capacities itself, features two threonine phosphorylation sites, Thr2256 for protein kinase C alpha (PKCalpha) and Thr2314 for extracellular signal related kinase.	('Thr2256', 'Var', (140, 147))	('threonine', 'Chemical', 'MESH:D013912', (107, 116))	('protein kinase C alpha', 'Gene', '5578', (152, 174))	('PKCalpha', 'Gene', '5578', (176, 184))	('PKCalpha', 'Gene', (176, 184))	('protein kinase C alpha', 'Gene', (152, 174))	('Thr2314', 'Chemical', '-', (190, 197))	('Thr2256', 'Chemical', '-', (140, 147))	('Thr2314', 'Var', (190, 197))
75499	31779130	Direct association of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) with CSPG4 via a D-domain has also been confirmed.	('ERK1/2', 'Gene', '5595;5594', (78, 84))	('association', 'Interaction', (7, 18))	('CSPG4', 'Gene', (91, 96))	('D-domain', 'Var', (103, 111))	('ERK1/2', 'Gene', (78, 84))
75514	31779130	Moreover, several clinical trials evaluating the safety and efficacy of CAR-T cells directed against c-MET (NCT03060356), CD20 (NCT03893019), and CD70 (NCT02830724) are recruiting patients.	('CD70', 'Gene', '970', (146, 150))	('NCT02830724', 'Var', (152, 163))	('c-MET', 'Gene', (101, 106))	('NCT03060356', 'Var', (108, 119))	('NCT03893019', 'Var', (128, 139))	('c-MET', 'Gene', '4233', (101, 106))	('patients', 'Species', '9606', (180, 188))	('CD70', 'Gene', (146, 150))
75526	31779130	The presence of CD70 in melanoma cells exhibits a dichotomy between uniform expression on primary lesions and a considerably lower expression in metastases, which predisposes the selection of antigen-negative clones compromising tumor eradication.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('metastases', 'Disease', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('CD70', 'Gene', (16, 20))	('compromising', 'NegReg', (216, 228))	('metastases', 'Disease', 'MESH:D009362', (145, 155))	('expression', 'MPA', (131, 141))	('tumor', 'Disease', (229, 234))	('expression', 'MPA', (76, 86))	('CD70', 'Gene', '970', (16, 20))	('lower', 'NegReg', (125, 130))	('presence', 'Var', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))
75528	31779130	Indeed, a small number of studies reported dramatic melanoma regression, ensuing anti-CD20 targeting.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma regression', 'Disease', (52, 71))	('anti-CD20 targeting', 'Var', (81, 100))	('melanoma regression', 'Disease', 'MESH:D008545', (52, 71))
75535	31779130	Binding of CSPG4 to collagen VI has also been implicated in relaying survival signals to cancer cells by virtue of PI3K activity.	('relaying survival signals', 'MPA', (60, 85))	('implicated', 'Reg', (46, 56))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('PI3K', 'Var', (115, 119))	('cancer', 'Disease', (89, 95))	('Binding', 'Interaction', (0, 7))	('CSPG4', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
75543	31779130	Correspondingly, sh-RNA-mediated abrogation of CSPG4 expression in a subcutaneous model of A375M melanoma impaired melanoma proliferation and increased the percentage of apoptotic and necrotic tumor cells.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('abrogation', 'Var', (33, 43))	('necrotic tumor', 'Disease', (184, 198))	('increased', 'PosReg', (142, 151))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('necrotic tumor', 'Disease', 'MESH:D009369', (184, 198))	('CSPG4', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('melanoma impaired melanoma proliferation', 'Disease', (97, 137))	('melanoma impaired melanoma proliferation', 'Disease', 'MESH:D008545', (97, 137))
75546	31779130	presented in-vitro results on the simultaneous blockade of CSPG4 and V600E-mutated BRAF using mAb 225.28 together with a selective BRAF inhibitor.	('BRAF', 'Gene', (131, 135))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('BRAF', 'Gene', '673', (83, 87))	('V600E-mutated', 'Var', (69, 82))	('CSPG4', 'Gene', (59, 64))	('blockade', 'NegReg', (47, 55))	('BRAF', 'Gene', (83, 87))	('BRAF', 'Gene', '673', (131, 135))
75560	31779130	In the clinical setting, it would be reasonable to start with serial mRNA-CSPG4-CAR-T cell infusions, and in the case of absent toxicity proceed to stably transfected CAR-T cells.	('mRNA-CSPG4-CAR-T', 'Var', (69, 85))	('toxicity', 'Disease', (128, 136))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))
75564	31779130	The incorporation of inhibitory signals in a co-expressed CAR can divert T cells off from non-malignant tissues by inhibitory signaling through the iCAR upon binding to antigens over-expressed on certain healthy cells.	('incorporation', 'Var', (4, 17))	('inhibitory signaling', 'MPA', (115, 135))	('iCAR', 'Protein', (148, 152))	('divert', 'Reg', (66, 72))	('rat', 'Species', '10116', (11, 14))	('binding', 'Interaction', (158, 165))
75588	31779130	Especially, CAR-T cells targeting CD123, which is expressed on leukemia-initiating-cells, could induce complete remissions in an ongoing trial (NCT02159495) led by the City of Hope National Medical Center.	('induce', 'Reg', (96, 102))	('CD123', 'Var', (34, 39))	('leukemia', 'Disease', (63, 71))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('leukemia', 'Disease', 'MESH:D007938', (63, 71))
75589	31779130	Another promising target antigen is FMS-like tyrosine kinase 3 (FLT3), which could be successfully exploited using FLT3-targeting CAR-T cells demonstrating potent reactivity against AML blasts expressing wild-type or FLT3 with internal tandem duplication (FLT3-ITD).	('rat', 'Species', '10116', (149, 152))	('FLT3', 'Gene', (217, 221))	('internal tandem duplication', 'Var', (227, 254))	('FLT3', 'Gene', '2322', (256, 260))	('FLT3', 'Gene', '2322', (64, 68))	('FLT3', 'Gene', (115, 119))	('reactivity', 'MPA', (163, 173))	('FMS-like tyrosine kinase 3', 'Gene', '2322', (36, 62))	('FLT3', 'Gene', '2322', (115, 119))	('AML', 'Disease', 'MESH:D015470', (182, 185))	('FLT3', 'Gene', (256, 260))	('FLT3', 'Gene', (64, 68))	('FLT3', 'Gene', '2322', (217, 221))	('AML', 'Disease', (182, 185))	('FMS-like tyrosine kinase 3', 'Gene', (36, 62))
75593	31779130	Investigators from Pennsylvania observed that CAR-T cells directed against CD123 eliminated primary AML in immunodeficient mice, but at the expense of normal HSCs, which were also completely erased by CD123-CAR-T cells resulting in permanent pancytopenia.	('CD123-CAR-T', 'Var', (201, 212))	('CD123', 'Var', (75, 80))	('eliminated', 'NegReg', (81, 91))	('pancytopenia', 'Phenotype', 'HP:0001876', (242, 254))	('AML', 'Disease', 'MESH:D015470', (100, 103))	('pancytopenia', 'Disease', (242, 254))	('immunodeficient', 'Disease', 'MESH:D007153', (107, 122))	('immunodeficient', 'Disease', (107, 122))	('pancytopenia', 'Disease', 'MESH:D010198', (242, 254))	('AML', 'Disease', (100, 103))	('mice', 'Species', '10090', (123, 127))
75598	31779130	Nevertheless, genetic manipulation of stem cells raises concerns about a potential malignant transformation of HSCs by the inadvertent knockout of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('knockout', 'Var', (135, 143))	('HSCs', 'Disease', (111, 115))	('genetic', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
75601	31779130	The mechanisms responsible for CSPG4-presence in MLL have not been elucidated so far, but some hypotheses indicate that CSPG4 might be up-regulated ensuing promotor demethylation caused by the translocation-induced disruption of the MLL1 methyltransferase gene.	('disruption', 'Var', (215, 225))	('MLL1', 'Gene', '4297', (233, 237))	('up-regulated', 'PosReg', (135, 147))	('promotor', 'MPA', (156, 164))	('CSPG4', 'Gene', (120, 125))	('MLL1', 'Gene', (233, 237))
75609	31779130	Although CSPG4 presence has been confirmed in lymphoid and myeloid leukemias, CSPG4 seems to be primarily expressed in 11q23 rearranged MLL.	('myeloid leukemias', 'Phenotype', 'HP:0012324', (59, 76))	('CSPG4', 'Gene', (9, 14))	('11q23 rearranged', 'Var', (119, 135))	('leukemias', 'Phenotype', 'HP:0001909', (67, 76))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (59, 75))	('myeloid leukemias', 'Disease', 'MESH:D007951', (59, 76))	('CSPG4', 'Gene', (78, 83))	('myeloid leukemias', 'Disease', (59, 76))	('leukemia', 'Phenotype', 'HP:0001909', (67, 75))
75615	31779130	In contrast to melanoma, where CSPG4 acts as an oncogenic driver by providing growth-promoting signals and blocking apoptosis (see melanoma section), CSPG4 up-regulation in MLL leukemia cells is perceived to be a side-product resulting from the deregulated epigenetic regulation inherent to this leukemia subtype.	('MLL leukemia', 'Disease', 'MESH:D007938', (173, 185))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('leukemia', 'Phenotype', 'HP:0001909', (177, 185))	('up-regulation', 'PosReg', (156, 169))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('MLL leukemia', 'Disease', (173, 185))	('leukemia', 'Phenotype', 'HP:0001909', (296, 304))	('leukemia', 'Disease', 'MESH:D007938', (296, 304))	('leukemia', 'Disease', (296, 304))	('CSPG4', 'Gene', (150, 155))	('epigenetic', 'Var', (257, 267))	('leukemia', 'Disease', (177, 185))	('leukemia', 'Disease', 'MESH:D007938', (177, 185))
75616	31779130	Consequently, CSPG4 shut down is not associated with overt repercussions on leukemia progression, predisposing the emergence of CSPG4-negative escape variants.	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('leukemia', 'Disease', (76, 84))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('shut', 'Var', (20, 24))	('CSPG4', 'Gene', (14, 19))
75622	31779130	A considerable number of primary GBM harbor genetic alterations in the epidermal growth factor receptor gene resulted in the de-novo generation of a unique truncated EGFR variant, termed EGFR variant III (EGFRvIII).	('epidermal growth factor receptor', 'Gene', '1956', (71, 103))	('rat', 'Species', '10116', (56, 59))	('EGFR', 'Gene', '1956', (187, 191))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (166, 170))	('EGFR', 'Gene', (205, 209))	('genetic alterations', 'Var', (44, 63))	('rat', 'Species', '10116', (137, 140))	('EGFR', 'Gene', (187, 191))	('epidermal growth factor receptor', 'Gene', (71, 103))
75632	31779130	Finally, several other antigens on glioblastoma are targeted in other trials, e.g., ephrin type-A receptor 2 (EphA2) (NCT02575261), GD2 (NCT03252171), and mucin 1 (MUC1) (NCT02839954, NCT02617134).	('NCT02617134', 'Var', (184, 195))	('NCT02839954', 'Var', (171, 182))	('NCT03252171', 'Var', (137, 148))	('EphA2', 'Gene', (110, 115))	('mucin 1', 'Gene', '4582', (155, 162))	('ephrin type-A receptor 2', 'Gene', '1969', (84, 108))	('glioblastoma', 'Disease', (35, 47))	('ephrin type-A receptor 2', 'Gene', (84, 108))	('EphA2', 'Gene', '1969', (110, 115))	('NCT02575261', 'Var', (118, 129))	('glioblastoma', 'Disease', 'MESH:D005909', (35, 47))	('MUC1', 'Gene', (164, 168))	('MUC1', 'Gene', '4582', (164, 168))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('mucin 1', 'Gene', (155, 162))
75643	31779130	The inhibition of CSPG4 signaling diminished AKT and ERK activity, reduced tumor-associated inflammation, decreased the transcription of pro-mitogenic early growth response protein 1 (EGR1), and facilitated the execution of pro-apoptotic programs.	('decreased', 'NegReg', (106, 115))	('execution', 'MPA', (211, 220))	('transcription', 'MPA', (120, 133))	('diminished', 'NegReg', (34, 44))	('inflammation', 'Disease', 'MESH:D007249', (92, 104))	('inhibition', 'Var', (4, 14))	('ERK', 'Gene', (53, 56))	('facilitated', 'PosReg', (195, 206))	('activity', 'MPA', (57, 65))	('CSPG4', 'Protein', (18, 23))	('tumor', 'Disease', (75, 80))	('AKT', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('inflammation', 'Disease', (92, 104))	('pro-apoptotic programs', 'CPA', (224, 246))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('AKT', 'Gene', '207', (45, 48))	('EGR1', 'Gene', (184, 188))	('ERK', 'Gene', '5594', (53, 56))	('reduced', 'NegReg', (67, 74))	('EGR1', 'Gene', '1958', (184, 188))
75661	31779130	Finally, targeting CSPG4-positive GMB-associated vasculature could result in acute cranial hemorrhage, with potentially lethal consequences.	('result in', 'Reg', (67, 76))	('CSPG4-positive', 'Gene', (19, 33))	('acute cranial hemorrhage', 'Disease', 'MESH:D000081032', (77, 101))	('acute cranial hemorrhage', 'Disease', (77, 101))	('GMB', 'Chemical', 'MESH:C032138', (34, 37))	('cranial hemorrhage', 'Phenotype', 'HP:0002170', (83, 101))	('targeting', 'Var', (9, 18))
75673	31779130	So far two active clinical trials evaluating the targetability of MUC1 derivatives have been registered and are about to commence recruitment (NCT04020575, NCT04025216).	('MUC1', 'Gene', (66, 70))	('MUC1', 'Gene', '4582', (66, 70))	('NCT04020575', 'Var', (143, 154))	('NCT04025216', 'Var', (156, 167))
75679	31779130	CAR-T cells expressing this NKG2D-CAR recognized TNBC cells in vitro and significantly delayed tumor growth in NSG mice subcutaneously inoculated with TNBC cells.	('delayed', 'NegReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mice', 'Species', '10090', (115, 119))	('NKG2D-CAR', 'Var', (28, 37))	('tumor', 'Disease', (95, 100))
75681	31779130	Furthermore, the arsenal of target structures for the CAR-T cell therapy of TNBC encompasses the integrin alphavbeta3, the receptor tyrosine kinase AXL, the integrin-like cell surface protein TEM8, the receptor tyrosine kinase c-MET (NCT01837602), and ROR1.	('integrin alphavbeta3', 'Gene', (97, 117))	('TEM8', 'Gene', '84168', (192, 196))	('ROR1', 'Gene', (252, 256))	('AXL', 'Gene', (148, 151))	('NCT01837602', 'Var', (234, 245))	('c-MET', 'Gene', '4233', (227, 232))	('integrin alphavbeta3', 'Gene', '3685', (97, 117))	('TNBC', 'Gene', (76, 80))	('TEM8', 'Gene', (192, 196))	('c-MET', 'Gene', (227, 232))	('AXL', 'Gene', '558', (148, 151))	('ROR1', 'Gene', '4919', (252, 256))
75698	31779130	Further experiments evaluating the effects of CSPG4 ablation on tumor growth in a murine breast cancer model revealed a reduced early progression phase.	('ablation', 'Var', (52, 60))	('tumor', 'Disease', (64, 69))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('early progression phase', 'CPA', (128, 151))	('CSPG4', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('murine', 'Species', '10090', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('reduced', 'NegReg', (120, 127))
75707	31779130	A key feature of TNBC biology is a high degree of genetic instability, which is in part expedited by hereditary or acquired mutations in genes, e.g., breast cancer type 1 susceptibility protein (BRCA1), encoding proteins responsible for orchestrating DNA damage repair and cell cycle control.	('BRCA1', 'Gene', '672', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (124, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer type 1 susceptibility protein', 'Gene', (150, 193))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (150, 193))	('BRCA1', 'Gene', (195, 200))	('rat', 'Species', '10116', (244, 247))
75711	31779130	With the central nervous system being a primary site of metastasis in breast cancer, CSPG4-CAR-T cells are expected to enter the brain, infiltrate metastatic lesions and mediate effector functions, such as cytokine secretion and target cell lysis.	('metastatic lesions', 'CPA', (147, 165))	('target cell lysis', 'CPA', (229, 246))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('infiltrate', 'Reg', (136, 146))	('cytokine secretion', 'MPA', (206, 224))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mediate', 'Reg', (170, 177))	('rat', 'Species', '10116', (142, 145))	('CSPG4-CAR-T', 'Var', (85, 96))
75713	31779130	In patients with a high metastatic burden in the central nervous system, the use of CSPG4-CAR-T cells might entail the risk of causing acute cerebral hemorrhage by eliminating tumor-associated vasculature.	('cerebral hemorrhage', 'Disease', 'MESH:D002543', (141, 160))	('cerebral hemorrhage', 'Disease', (141, 160))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (3, 11))	('CSPG4-CAR-T cells', 'Var', (84, 101))	('cerebral hemorrhage', 'Phenotype', 'HP:0001342', (141, 160))	('eliminating', 'NegReg', (164, 175))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
75729	31779130	CAR Chimeric antigen receptor  ATT Adoptive T-cell therapy  ALL Acute lymphoblastic leukemia  DLBCL Diffuse large B-cell lymphoma  CSPG4 Chondroitin sulfate proteoglycan 4  scFv Single-chain Fragment variable  FDA Food and drug administration  EMA European medicines agency  TME Tumor microenvironment  MCSP Melanoma-associated chondroitin sulfate proteoglycan  HMW-MAA High molecular weight melanoma-associated antigen  NG2 Neural/glial antigen 2  GAG Glycosaminoglycan  CS Chondroitin sulfate  RTK Receptor tyrosine kinases  PKCalpha Protein kinase C alpha  MAPK Mitogen-activated-protein-kinase  FAK Focal adhesion kinase  TIL Tumor-infiltrating lymphocyte  r/r refractory and relapsing  FLT3 FMS-like tyrosine kinase 3  FLT3-ITD FLT3 with internal tandem duplication  HSC Hematopoietic stem cell  MLL Mixed lineage leukemia  GBM Glioblastoma  BiTE Bi-specific T-cell engager  GSC Glioblastoma stem cell  EGR1 Early growth response protein 1  TNBC Triple-negative breast cancer  ER  estrogen receptors   EGFR epidermal growth factor receptor  VEGFRvIII Vascular endothelial growth factor receptor variant III  PARP Poly(ADP-ribose) polymerase	('Glioblastoma', 'Disease', 'MESH:D005909', (833, 845))	('Protein kinase C alpha', 'Gene', '5578', (536, 558))	('Chondroitin sulfate proteoglycan 4', 'Gene', '1464', (137, 171))	('EGFR', 'Gene', '1956', (1007, 1011))	('breast cancer', 'Phenotype', 'HP:0003002', (967, 980))	('Tumor', 'Phenotype', 'HP:0002664', (279, 284))	('Glioblastoma', 'Phenotype', 'HP:0012174', (833, 845))	('Protein kinase C alpha', 'Gene', (536, 558))	('Focal adhesion kinase', 'Gene', '5747', (603, 624))	('Chondroitin sulfate proteoglycan 4', 'Gene', (137, 171))	('HMW-MAA', 'Gene', (362, 369))	('CS', 'Chemical', 'MESH:D002809', (304, 306))	('rat', 'Species', '10116', (642, 645))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('FMS-like tyrosine kinase 3', 'Gene', (696, 722))	('breast cancer', 'Disease', 'MESH:D001943', (967, 980))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (70, 92))	('FAK', 'Gene', (599, 602))	('breast cancer', 'Disease', (967, 980))	('rat', 'Species', '10116', (236, 239))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('leukemia  GBM Glioblastoma  BiTE', 'Disease', 'MESH:D005909', (819, 851))	('Focal adhesion kinase', 'Gene', (603, 624))	('MCSP', 'Gene', '1464', (303, 307))	('leukemia  GBM Glioblastoma  BiTE', 'Disease', (819, 851))	('scFv', 'Gene', '652070', (173, 177))	('FLT3', 'Gene', (733, 737))	('Glioblastoma', 'Disease', (833, 845))	('scFv', 'Gene', (173, 177))	('PKCalpha', 'Gene', '5578', (527, 535))	('GAG', 'Chemical', 'MESH:D006025', (449, 452))	('internal', 'Var', (743, 751))	('EGFR', 'Gene', (1047, 1051))	('Acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (64, 92))	('PARP', 'Gene', '142', (1113, 1117))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('High molecular weight melanoma-associated antigen', 'Gene', (370, 419))	('Glioblastoma', 'Disease', 'MESH:D005909', (884, 896))	('FAK', 'Gene', '5747', (599, 602))	('Melanoma-associated chondroitin sulfate proteoglycan', 'Gene', '1464', (308, 360))	('epidermal growth factor receptor', 'Gene', (1012, 1044))	('MCSP', 'Gene', (303, 307))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('FLT3', 'Gene', '2322', (733, 737))	('EGFR', 'Gene', (1007, 1011))	('epidermal growth factor receptor', 'Gene', '1956', (1012, 1044))	('Glioblastoma', 'Phenotype', 'HP:0012174', (884, 896))	('Acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (64, 92))	('PARP', 'Gene', (1113, 1117))	('PKCalpha', 'Gene', (527, 535))	('Tumor', 'Phenotype', 'HP:0002664', (630, 635))	('Acute lymphoblastic leukemia', 'Disease', (64, 92))	('EGR1', 'Gene', (908, 912))	('Melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('FLT3', 'Gene', (724, 728))	('cancer', 'Phenotype', 'HP:0002664', (974, 980))	('EGR1', 'Gene', '1958', (908, 912))	('High molecular weight melanoma-associated antigen', 'Gene', '1464', (370, 419))	('CS', 'Chemical', 'MESH:D002809', (131, 133))	('melanoma', 'Phenotype', 'HP:0002861', (392, 400))	('Neural/glial antigen 2', 'Gene', (425, 447))	('B-cell lymphoma', 'Disease', (114, 129))	('FLT3', 'Gene', (691, 695))	('FMS-like tyrosine kinase 3', 'Gene', '2322', (696, 722))	('CS', 'Chemical', 'MESH:D002809', (472, 474))	('FLT3', 'Gene', '2322', (724, 728))	('HMW-MAA', 'Gene', '1464', (362, 369))	('Neural/glial antigen 2', 'Gene', '81651', (425, 447))	('leukemia', 'Phenotype', 'HP:0001909', (819, 827))	('Glioblastoma', 'Disease', (884, 896))	('EGFR', 'Gene', '1956', (1047, 1051))	('FLT3', 'Gene', '2322', (691, 695))
75732	28881623	This receptor has been successfully targeted for diagnostic and therapeutic purposes using modified IL-13 ligand and more recently using a specific peptide, Pep-1L.	('modified', 'Var', (91, 99))	('Pep-1', 'Gene', '66054', (157, 162))	('IL-13', 'Gene', (100, 105))	('peptide', 'Chemical', 'MESH:D010455', (148, 155))	('Pep-1', 'Gene', (157, 162))
75735	28881623	[64Cu]Pep-1L binding was blocked by unlabeled ligand, demonstrating specificity.	('Pep-1', 'Gene', (6, 11))	('binding', 'Interaction', (13, 20))	('Pep-1', 'Gene', '66054', (6, 11))	('Cu', 'Chemical', 'MESH:D003300', (3, 5))	('[64Cu', 'Var', (0, 5))
75740	28881623	Peptides that target cancer cell surface receptors are a promising platform to deliver diagnostics and therapeutics specifically to transformed but not normal tissue.	('Peptides', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
75752	28881623	Peptide-based approaches offer an advantage due to their small size and fast clearance, which has been shown to potentially increase the tumor-to-background ratio.	('increase', 'PosReg', (124, 132))	('tumor', 'Disease', (137, 142))	('Peptide-based', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
75803	28881623	Importantly, doxycycline-induced B16F10-Tet-IL13RA2 subcutaneous tumors demonstrated significantly more [64Cu]Pep-1L uptakeon PET/CT imaging compared to uninduced controls (Figure 6).	('doxycycline', 'Chemical', 'MESH:D004318', (13, 24))	('more', 'PosReg', (99, 103))	('PET', 'Gene', '22095', (126, 129))	('B16F10', 'CellLine', 'CVCL:0159', (33, 39))	('tumors', 'Disease', (65, 71))	('PET', 'Gene', (126, 129))	('Pep-1', 'Gene', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (52, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Pep-1', 'Gene', '66054', (110, 115))	('Tet', 'Chemical', 'MESH:C010349', (40, 43))	('Cu', 'Chemical', 'MESH:D003300', (107, 109))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('B16F10-Tet-IL13RA2', 'Var', (33, 51))